NEW STRATEGIES FOR THE TREATMENT OF TYPE 1 DIABETES Release Date: September 30, 1999 RFA: DK-00-001 National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Allergy and Infectious Diseases National Institute of Child Health and Human Development Letter of Intent Receipt Date: March 14, 2000 Application Receipt Date: April 14, 2000. THIS 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, the National Institute of Allergy and Infectious Diseases, and the National Institute of Child Health and Human Development invite investigator-initiated research grant applications for clinical studies of new approaches to therapy for type 1 diabetes. The focus of this initiative includes studies of cell-based therapies, glucose sensing devices, pumps, biomechanical-artificial pancreas, gene therapy, immunomodulation to arrest or reverse type 1 diabetes mellitus, and methods to detect and prevent hypoglycemia. These applications should propose clinical studies on individuals with type 1 diabetes. For studies of immunomodulation to reverse diabetes, individuals recently diagnosed with type 1 diabetes might be the appropriate patient population. Support for preclinical or clinical studies necessary to obtain approval for an investigational new drug or for an investigational device could be requested if the application also includes a clinical component. Collaborative efforts linking expertise in molecular biology, cell biology, bioengineering, gene therapy, and immunology to expertise in type 1 diabetes are strongly encouraged. While it is anticipated that improved glycemic control will prevent or delay complications, studies of therapies designed to address other aspects of prevention or therapy of complications are not responsive to this RFA. 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 Request for Applications (RFA), NEW STRATEGIES FOR THE TREATMENT OF TYPE 1 DIABETES, is related to one or more of the priority areas. 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, the Interactive Research Project Grant (IRPG) award mechanisms and the exploratory/developmental grant (R21) award mechanism. R21 awards are to demonstrate feasibility and obtain preliminary data testing innovative ideas that represent clear departure from ongoing research interests. Guidelines for preparing IRPG applications are available from the program official or from the internet at: https://grants.nih.gov/grants/guide/pa-files/PA-96- 001.html Awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement. The R21 exploratory/developmental studies are intended to: (1) provide initial support for new investigators; (2) allow exploration of innovative new leads or new directions for established investigators in diabetes; and (3) stimulate investigators from other areas to lend their expertise to research in this area. Pilot and feasibility grants are not intended to support or supplement ongoing funded research of an established investigator. This program enables investigators to explore the feasibility of a novel concept related to development of new therapies for type 1 diabetes and generate sufficient data to pursue it through other funding mechanisms. These grants will not be renewable; continuation of projects developed under this program will be through the regular research project mechanism (R01). R21 grants will be limited to $100,000 direct costs per year and are limited to two years duration. 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 total requested project period for applications submitted in response to this RFA may not exceed three (3) years. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at https://grants.nih.gov/grants/funding/modular/modular.htm FUNDS AVAILABLE For FY 2000, $3 million will be committed to fund applications submitted in response to this RFA. It is anticipated that 8 to 12 awards will be made. However, this funding level is dependent upon the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NIDDK, the award of grants pursuant to this RFA is also contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Type 1 diabetes results from immune destruction of the beta cells of the pancreas leading to loss of insulin secretion and resultant hyperglycemia. Therapy with insulin prevents ketoacidosis but not the devastating long-term outcomes of diabetes. The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive treatment regimens to achieve tight control of blood glucose can significantly reduce the onset and progression of diabetic complications in individuals with type 1 diabetes. Intensive treatment of type 1 diabetes, although effective in improving long-term outcome, is difficult to implement for many patients and does not achieve euglycemia. The level of glycemic control achieved using currently available intensive treatment methods is at best 4-5 standard deviations above the mean value for the nondiabetic population, as measured by glycated hemoglobin (HbA1c). Intensive therapy is also limited by the accompanying increased frequency of severe hypoglycemia and weight gain, resulting in an increasing prevalence of overweight patients with type 1 diabetes. This RFA solicits applications for clinical studies of promising new therapeutic approaches for the treatment of individuals with type 1 diabetes. The objectives are to develop better methods of optimizing glucose control in patients with type 1 diabetes, to test promising strategies for immunomodulation to reverse type 1 diabetes, and to develop approaches to prevent hypoglycemia and prevent or reverse hypoglycemia unawareness. The needs and opportunities to develop better methods to achieve tight control of blood glucose were clearly stated in the recently published Report of the Congressionally-Established Diabetes Research Working Group entitled "Conquering Diabetes: A Strategic Plan for the 21st Century." This report outlines a number of recommendations to improve therapy for type 1 diabetes. It calls for increased research in a number of areas. These include: evaluation of antigen-specific, cytokine or antibody-based immunotherapy; application of cell based therapies; prevention of transplant rejection or destruction by autoimmune mechanisms; evaluation of alternate strategies for insulin administration including mechanical approaches and alternate routes for insulin administration; and improved methods to prevent and detect hypoglycemia. Scope and Objectives The optimal treatment for individuals with type 1 diabetes would be to reverse the disease. Towards this end, new clinical interventions in the autoimmune disease process that lead to type 1 diabetes are being developed. Currently being considered for application to diabetes are strategies already being utilized to block the progression of other autoimmune diseases. T cell activation can be inhibited with an antibody that binds to a cell membrane component (CD40L or CTLA4) of an activating T cell and prevents further T cells from being activated (co- stimulatory blockade). A second strategy would be to induce tolerance to known islet cell antigens such as glutamic acid decarboxylase (GAD) or IA-2. Another strategy involves suppression or modulation of lymphocyte function using appropriate cytokines such as IL-4 or IL-10. Individuals recently diagnosed with type 1 diabetes might be a population in which these strategies could be successful in arresting or reversing the disease process. Evaluation of the success of clinical protocols for immunomodulation/tolerance induction in individuals with newly diagnosed type 1 diabetes may be confounded by the occurrence of a spontaneous and transient resolution of diabetes (the "honeymoon" period). Such proposals must address how efficacy will be established. The present therapies for optimizing glucose control have inherent within them the risk of severe hypoglycemia which represents the single greatest barrier to tight control of blood glucose. The risk is magnified as a result of both impaired recognition of an impending episode and compromised counter- regulation to restore euglycemia. Thus, efforts to detect and prevent hypoglycemia would be enhanced by the development of new techniques for self-monitoring the circulating glucose concentration. Methods also need to be developed to facilitate recovery from hypoglycemia unawareness without the need for sub- optimal glucose control. Applications proposing development of methods to detect, prevent or limit hypoglycemia, to prevent hypoglycemia unawareness, and/or to facilitate recovery from hypoglycemia unawareness are encouraged. Cell-based therapies are a promising approach to restore insulin production in response to glucose in individuals with type 1 diabetes. Human islet transplantation trials are presently ongoing. However, it is clear that with present methods for harvesting and maintaining islets, there are insufficient human islets to treat all the individuals with type 1 diabetes. Therefore, several laboratories have been developing alternate sources of insulin producing cells. These approaches have included genetic manipulation of non-beta cells and transformed beta cells to achieve regulated insulin secretion in response to physiological levels of glucose or other physiological cues. Other researchers have been investigating methods of expanding human beta cells or their progenitors in culture. Studies of genetic manipulations and of immunomodulation to protect transplanted beta cells against rejection and autoimmunity are also underway. Human studies of these cell-based therapies are within the scope of this RFA. Improved mechanical approaches to insulin replacement and to assessment of blood glucose levels are a promising approach to optimizing glucose control. Within the past ten years, external insulin pumps have been shown to aid in the successful delivery of insulin for individuals with type 1 diabetes. There have also been several trials of implanted insulin pumps. These pumps have been shown to have significant advantages over multiple daily insulin injections. Development of non-invasive or minimally invasive glucose sensors is a very high priority area of research. While a number of approaches and devices appear promising, additional research to optimize sensor development and validate these devices in patients is necessary. Linkage of the insulin pumps to these sensors and development and testing of a ‘closed-loop’ system are within the scope of this RFA. R01 or R21 applications should focus on clinical studies to develop new approaches to the cure or improved treatment of type 1 diabetes. In addition, support for preclinical studies necessary to obtain approval for an investigational new drug or for an investigational device could be requested if the project also includes a clinical component. Studies directed at complications of type 1 diabetes other than hypoglycemia are not responsive to this RFA. Relevant topics listed below are examples and should not be construed as required or limiting. o Evaluate immunomodulation regimens to reverse or arrest immune destruction of beta cells in patients with new onset diabetes o Utilize cell based therapies to enhance or restore euglycemia o Evaluate methods to detect hypoglycemia o Evaluate methods to prevent or lessen the severity of hypoglycemia associated with intensive therapy o Develop methods to identify people at increased risk for hypoglycemia o Develop interventions to prevent or facilitate recovery from hypoglycemia unawareness o Test promising glucose sensors o Validate algorithms to relate blood glucose to glucose levels in the interstitial space o Evaluate linkage of a glucose sensor with an insulin pump to form a closed-loop system o Evaluate alternative methods of insulin administration, including mechanical devices offering substantial advantages over current pumps or alternate routes of insulin administration 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 new 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: https://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: https://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 14, 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 PHS398 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 https://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: https://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 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 your 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 on the RFA label and the YES box must be marked. The sample RFA label available at: https://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 April 14, 2000. 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 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 the 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 National Diabetes and Digestive and Kidney Diseases Advisory Council or other appropriate National Advisory Council. 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 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. o 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? o 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? o 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? o 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)? o 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. AWARD CRITERIA The anticipated date of award is September 30, 2000. Award criteria that will be used to make award decisions include: o Scientific merit as determined by peer review; o Level of interaction between researchers in appropriate disciplines; 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: Joan T. Harmon, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases NIDDK 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8813 FAX: 301-480-3503 E-mail: firstname.lastname@example.org Elaine Collier, M.D. Chief, Autoimmunity Section Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases 6700-B Rockledge Drive, Room 5135 Bethesda, MD 20892-7640 Tel (301) 496-7104 Fax (301) 402-2571 E-mail: email@example.com Gilman D. Grave, M.D. Center for Research for Mothers and Children National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B11 - MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5593 FAX: (301) 480-9791 Email: GRAVEG@HD01.NICHD.NIH.GOV Direct inquiries regarding fiscal and administrative matters to: Florence Danshes Division of Extramural Activities NIDDK 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8861 FAX: (301)480-3504 E-mail: firstname.lastname@example.org Maryellen Connell Grants Management Specialist NIAID, Division of Extramural Activities Room 2123 6700-B Rockledge Drive, MSC 7614 Bethesda, MD 20892-7614 (Regular Mail) Bethesda, MD 20817 (Express Mail) Phone: (301) 402-5576 FAX: (301) 480-3780 Email: email@example.com E. Douglas Shawver Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17 - MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1303 FAX: (301) 402-0915 Email: SHAWVERD@HD01.NIH.GOV AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847 (Diabetes, Endocrinology and Metabolism Research), No. 93.855 (Immunology, Allergy, and Transplantation Research) and No. 93.865 (Research for Mothers and Children). 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 NIH 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 NIH mission to protect and advance the physical and mental health of the American people.
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