NEW THERAPIES FOR DIABETIC FOOT DISEASE Release Date: November 23, 1999 RFA: DK-00-009 National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Nursing Research Letter of Intent Receipt Date: March 24, 2000 Application Receipt Date: April 25, 2000 THIS REQUEST FOR APPLICATIONS (RFA) USES THE MODULAR GRANT AND JUST-IN-TIME CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of Nursing Research (NINR) invite investigator-initiated research grant applications to 1) study the etiology and pathogenesis of diabetic foot ulcers, and 2) develop effective prevention and treatment modalities. Diabetes is the leading cause of non-traumatic lower extremity amputations in the United States, and foot ulcers are a major predictor of future amputation in patients with diabetes. Even without amputation, diabetic foot ulcers contribute a major economic burden to society and impair quality of life for the individual. Despite advances in wound care, the incidence of diabetic foot ulcers, and of amputations, remains high. New diagnostic, prognostic and therapeutic strategies need to be developed to reduce the burden of diabetic foot disease. New insights into the etiology and pathogenesis of ulceration in the diabetic foot will help develop more effective measures for prevention as well as treatment. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, New Therapies for Diabetic Foot Disease, is related to the priority area of diabetes and chronic diseases. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000 ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and nonprofit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) award mechanism. Except as otherwise stated in this announcement, awards will be administered under Public Health Service (PHS) grants policy as stated in the PHS Grants Policy Statement. Applicants from institutions which have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator- initiated applications and be reviewed according to the customary peer review procedures. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The anticipated award date is September 30, 2000. FUNDS AVAILABLE NIDDK intends to commit approximately $1.5 million in FY 2000 to fund 5-8 new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to 5 years. NINR will commit $300,000 in FY2000 to fund one application relevant to the NINR mission. Because the nature and scope of the research proposed may vary, the size of each award will also vary. It is anticipated that most applications will request less than $300,000 in direct costs during the first year. However, budgets may be larger if there is compelling justification. Applicants anticipating requesting more than $500,000 in direct costs in any year should consult with the NIDDK program official listed under INQUIRIES at an early opportunity. Although the financial plans of NIDDK and NINR provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit RESEARCH OBJECTIVES Background An estimated 16 million Americans are known to have diabetes, and millions more are considered to be at risk for developing the disease. Diabetic foot lesions are responsible for more hospitalizations than any other complication of diabetes. Among patients with diabetes, 15% will develop a foot ulcer, and 12-24% of individuals with a foot ulcer will require amputation. Indeed, diabetes is the leading cause of non-traumatic lower extremity amputations in the United States. Diabetic foot ulcers adversely affect the quality of life for the individual, in addition, the cost of caring for diabetic foot ulcers imposes a significant burden on society. Much is known about the risk factors for developing foot ulcers in the diabetic patient. Ulcers are most often caused by repetitive mechanical stress that is not recognized by the patient because of peripheral neuropathy and the loss of sensation. A motor component to the peripheral neuropathy may lead to muscle atrophy, flexion deformity and/or abnormal gait, which, in turn, creates increased pressure points. Autonomic neuropathy causes dyshidrosis and dry skin, which is more prone to cracking. Finally, autonomic neuropathy may also be associated with arteriovenous shunting and altered skin perfusion. Diabetologists generally agree that careful foot exams are a cornerstone to preventing foot ulceration. Yet studies indicate that only 40 60 percent of patients with diagnosed diabetes have had a foot exam within the past year. In addition, no guidelines exist for what constitutes a proper foot exam or what the optimal interval of such examinations should be. Although general medical progress has been made in improving wound care, the incidence of lower extremity amputations continues to rise. Strategies for wound care that will lead to healing of ulcers and reduced amputation rates are critically needed. Current treatment modalities include off-loading, debridement, dressings, antibiotics and vascular reconstruction. Unfortunately, however, there are no widely accepted, scientifically established guidelines for assessing and treating diabetic foot ulcers. Much recent progress has been made in learning about the biology of wound healing. The acute response to injury involves the activation of the hemostatic cascade, which includes the release of growth factors and cytokines. The second phase of wound healing involves the recruitment of neutrophils and establishes an inflammatory response. Macrophages recruited as part of the inflammatory response release additional growth factors and cytokines, which attract fibroblasts and endothelial cells to the site of injury. This third phase is marked by the proliferation of these cells and the deposition of extracellular matrix. The final, or remodeling, phase of wound healing is characterized by keratincyte migration into the healing wound site. The diabetic foot ulcer is a chronic wound and does not exhibit the orderly cascade of events which characterizes normal wound healing. Instead, diabetic ulcers appear to be stuck in the proliferative phase and are characterized by ongoing inflammation. The reasons for failure to heal are incompletely understood but are believed to include abnormalities in inflammatory cells in diabetics, peripheral neuropathy and repeated injury, and vascular disease. A more precise understanding of the biology of wound healing, and its abnormalities in diabetes, should lead to new therapeutic modalities. Scope and Objectives The goal of this RFA is to stimulate the application of new molecular technologies to understanding the etiology and pathogenesis of diabetic foot ulcers, and to foster interdisciplinary approaches to the treatment and prevention of diabetic foot disease. NINR is interested in clinical research to determine factors or interventions associated with improvement in foot care and skin ulcer prevention in diabetes. Such studies may involve the development and testing of effective patient and health care provider education or other intervention strategies to prevent or treat skin ulcers. Appropriate topics for investigations responsive to this RFA would include but are not limited to: o Studies of how diabetes affects the expression and/or action of cytokines, growth factors or small molecules involved the process of wound healing. o Studies of the effects of hyperglycemia on bacterial growth and on the function of white blood cells and macrophages, and of how such changes might predispose to infection or alter ulcer healing. o Studies of how endothelial gene expression and/or function are affected by diabetes, including endothelial/matrix interactions. o Studies of how diabetes-induced alterations in blood flow and/or endothelial function affect the wound healing process. o Trials to establish optimal, cost-effective methods for assessing blood flow and determining which patients would benefit from perfusion studies and/or revascularization. o Studies of how hyperglycemia affects keratinocyte biology. o Studies to characterize ulcers and develop strategies for stratification that would be useful in the evaluation of treatment and prevention regimens in clinical trials. Such studies should also seek to establish criteria that would be helpful in predicting which ulcers are likely to heal and which patients should undergo amputation. o Controlled, randomized trials to establish optimal therapeutic regimens to facilitate the healing of new ulcers. Such trials should evaluate the relative merits of currently used therapies, including (but not limited to) debridement, antibiotics, growth factors, off- loading, and revascularization. Such trials might include assessment not only of time to complete healing, but include analysis of cost-effectiveness, examining such issues as hospitalization and amputation rates, as well as productivity and quality of life issues for the patient. o Studies to establish scientific principles for the design and use of footwear and other strategies to prevent the development and/or recurrence of foot ulcers. Studies to evaluate who would benefit from such interventions. o Studies to develop and evaluate effective patient and/or health care provider education strategies, to facilitate compliance with prevention and treatment regimens. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide For Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS. It is the policy of NIH 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. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by March 24, 2000, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIDDK staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK Natcher Building, Room 6AS-37F 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-710-0267, email: GrantsInfo@nih.gov. The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers, and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations, o CHECKLIST: This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The program announcement title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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) At time of submission, two additional copies of the application must be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK Natcher Building, Room 6AS-37F 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Applications must be received by the application receipt date listed in the heading of the RFA. If an application is received after that date, it will be returned to the applicant without review. Supplemental documents containing significant revision or additions will not be accepted, unless applicants are notified by the Scientific Review Administrator. The Center for Scientific Review (CSR) will not accept any application in response to this RFA 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 substantial revisions of applications previously reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by NIDDK and NINR. Incomplete and/or non- responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIDDK in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and 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, assigned a priority score, and receive a second level review by the Advisory Councils of NIDDK and NINR. 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, reviewer will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that 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. (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 these studies on the concepts or methods that drive this field? (2) 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? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (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)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o Adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration to the proposed research. o The adequacy of the proposed protection of humans, animals, or the environment, to the extent that they may be adversely affected by the project proposed in the application. o Availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries which are not readily available in the United States or which provide augmentation of existing U.S. resources. Schedule Letter of Intent Receipt Date: March 24, 2000 Application Receipt Date: April 25, 2000 Peer Review Date: June-July 2000 Council Review: September 2000 Earliest Anticipated Start Date: September 30, 2000 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. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Barbara Linder, M.D., Ph.D. DDEMD NIDDK Building 45, Room 5AN18A Bethesda, MD 20892-6600 Telephone: (301) 594-0021 FAX: (301) 480-3503 E-mail: linderb@extra.niddk.nih.gov Nell Armstrong, Ph.D., R.N. NINR, NIH Building 45, Room 3AN12 Bethesda, MD 20892-6600 Telephone: (301) 594-5973 FAX: (301) 480-8260 E-mail: nell_armstrong@nih.gov Direct inquiries regarding fiscal matters to: Nancy Dixon Division of Extramural Activities NIDDK 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8854 FAX: (301) 480-4237 E-mail: dixonn@extra.niddk.nih.gov Jeff Carow Grants and Contracts Management Office NINR Building 45, Room 3AN12 Bethesda, MD 20892-6600 Telephone: (301) 594-6869 FAX: (301) 480-8260 E-mail: jeff_carow@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847 and No. 93.361. Awards are under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78- 410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or 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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


NIH Office of Extramural Research Logo
   Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS) 		  USA.gov - Government Made Easy
NIH... Turning Discovery Into Health®