BENCH TO BEDSIDE RESEARCH ON TYPE 1 DIABETES AND ITS COMPLICATIONS RELEASE DATE: August 30, 2002 (see reissuance RFA-DK-03-019) RFA: RFA-DK-03-001 National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov) National Institute of Allergy and Infectious Diseases (NIAID) (http://www.niaid.nih.gov) National Eye Institute (NEI) (http://www.nei.nih.gov/) National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) LETTER OF INTENT RECEIPT DATE: January 29, 2003 APPLICATION RECEIPT DATE: February 26, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations: PURPOSE OF THIS RFA This is a reissuance of RFA DK-02-022. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), National Eye Institute (NEI), and the National Heart, Lung, and Blood Institute (NHLBI) invite applications involving partnerships between clinical and basic biomedical researchers with the goal of translating advances in our understanding of the molecular basis of type 1 diabetes and its complications into new therapies for the prevention, treatment and cure of this disease. In these "bench to bedside" research partnerships, a team of clinical and basic scientists will conduct collaborative research that, if successful, will bring basic research advances from the laboratory to a point where a potential new therapy can be tested in patients or in preclinical studies in animal models. RESEARCH OBJECTIVES Background Type 1 diabetes is an autoimmune disease characterized by the destruction of the insulin-secreting beta cells of the pancreas by cytotoxic T cells. Diabetes is difficult to control with the current therapies available and as a result patients with type 1 diabetes may suffer devastating consequences including accelerated cardiovascular and peripheral vascular diseases, nephropathy, retinopathy, neuropathy, oral diseases and premature death. The incidence of type 1 diabetes appears to be increasing worldwide. Although the disease may occur at any age, the onset of type 1 diabetes peaks prior to twenty years of age. In some populations, about one percent of all newborns will develop type 1 diabetes during their lifetime. Recent advances in fundamental science and in our understanding of the pathophysiology underlying type 1 diabetes and its complications offer tremendous promise for the development of new therapies. Recently, a number of agents have shown promise for prevention or delay of type 1 diabetes in animals and limited human studies. However, for such agents to reach their full therapeutic potential, a number of obstacles must be overcome. These include access to existing animal models, as well as the development of improved models, in which to test new therapies and measures to predict or assess response to therapy in early trials of potential therapies. Also needed are improved methods to monitor disease progression, such as methods to assess beta cell mass and inflammation. Most recently the success of islet transplantation in freeing individuals with type 1 diabetes from the need for insulin therapy has yielded great excitement. However, this treatment is associated with significant side effects, and the long-term risks of the immunosuppressive agents used are not known. Moreover, the protocol required two donor pancreata per recipient; therefore, current levels of organ donation provide insufficient organs for only a small fraction of the people who could potentially benefit from this therapy. The recent success in islet transplantation provides additional impetus for research to develop methods to attain an unlimited supply of islets for transplantation; to improve methods for harvesting pancreata and isolating islets; to improve techniques for the administration of transplanted islets; and to develop approaches to minimize the toxicity of immunotherapy required for transplantation. The complications of type 1 diabetes account for much of the burden of disease. Emerging information on the molecular mechanisms involved in pathogenesis of complications has identified multiple potential targets for therapeutic intervention. In particular, inflammation is increasingly recognized as a contributing pathway to macrovascular disease. The development of surrogate markers for the development of complications and of animal models that develop the complications of diabetes is critical for testing new therapies for complications of type 1 diabetes. Hypoglycemia is a devastating complication of type 1 diabetes that often limits the ability to rigorously control blood glucose. Research is needed to foster translation of new understandings about the mechanisms of hypoglycemia unawareness and defective counter-regulation into new approaches to reduce the occurrence of hypoglycemia and pharmacologic approaches to restore counter- regulation. Improved devices for measuring and monitoring glycemia and/or development of closed loop systems linking glucose sensors and insulin delivery devices are also needed. Multi-disciplinary teams of basic and clinical scientists will be required to overcome these obstacles and hasten our ability to bring new approaches to therapy forward to be tested in clinical trials. Thus, the level of support that can be requested for pilot and feasibility studies is greater than is usually permitted under this mechanism. Objectives and Scope The overall objective of this RFA is to stimulate translational diabetes research by encouraging the formation of collaborative research teams composed of basic and clinical scientists focused on specific projects that have the potential to develop new therapies for type 1 diabetes or its complications. Applications must involve a team of clinical and basic scientists from a single or multiple institutions. It is expected that the combined expertise of the investigators will foster the development of a basic research finding to the point where the underlying hypothesis can be tested in a clinical trial or an animal model to assess its value in the treatment and/or prevention of type 1 diabetes or its complications. Applications should focus on developing and testing methods for the prevention, cure or improved treatment of type 1 diabetes or its complications. Applications can also propose to develop new animal models or surrogate endpoints that will facilitate the testing of new therapeutic agents. When compelling preliminary data suggests potential therapeutic value of a new pharmacologic agent, support may be requested for preclinical animal studies needed to move forward into clinical trials, including studies to determine optimal dosing and toxicity. Research may include studies of etiology and pathogenesis of type 1 diabetes or its complications only in the context of a hypothesis that has clear potential to lead to a new target or strategy for prevention or therapy or to a new surrogate marker or animal model that will be useful for clinical trials. Relevant topics listed below are examples and should not be construed as required or limiting: o Development and/or testing of strategies to retard or reverse the immune and/or inflammatory processes leading to the development of type 1 diabetes and its macro and microvascular complications o Development and/or testing of measures to identify and quantify the risk of developing type 1 diabetes or to assess response to therapy to prevent or reverse the autoimmune process and beta cell loss (i.e. pathogenic T-cell assays, imaging of beta cell mass or inflammation, etc.) o Development of improved approaches to pancreas harvesting and/or islet isolation, evaluation, or administration o Development and/or testing of strategies to develop new or improved sources of beta cells/islets or to enhance the regeneration or viability of beta cells/islets o Development and/or testing of improved methods of immunoalteration of beta cells/islets or of the immune response in an attempt to prevent autoimmune and host-versus-graft destruction of beta cells/islets o Development and/or testing of devices to measure glucose in blood, saliva or other body fluids and/or deliver insulin which offer advantages over current devices o Development of non-human primate or other animal models of type 1 diabetes or its complications which closely parallel the human disease; investigators should make clear that tissues and developed animal models will be made available to the research community and provide a plan for the dissemination of these models o Identification and/or evaluation of surrogate endpoints which can be used in clinical trials to prevent, delay or reverse type 1 diabetes and its complications o Development or testing of innovative pharmacological agents and interventions to prevent or halt the progression of type 1 diabetes or its complications MECHANISMS OF SUPPORT Support for this program will be through the NIH Exploratory/Development Research Grant (R21), the Exploratory/Development Research Grant Phase 2 (R33), and the Phased Innovation Award (R21/R33 combined). The R33 is a newly established NIH grant mechanism to provide a second phase for the support of innovative exploratory and development research initiated under the R21 mechanism. Under the Phased Innovation Award (R21/R33), transition of the R21 to the R33 phase will be expedited and is dependent on completion of negotiated milestones. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (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 format. Otherwise, follow the instructions for non- modular research grant applications. Specific features of the Phased Innovation Award Mechanism (R21/33 Combined) include: o Single submission and evaluation of both a feasibility/pilot phase (R21) and an expanded development phase (R33) as one application. o Expedited transition of the R21 feasibility phase to an R33 development phase. o Flexible budgets. o Flexible staging of feasibility and development phases. The use of the multiple mechanisms will allow projects to be submitted at various stages of development. The R21 will provide support for projects in early stages of development where there is little or no preliminary data available and it is difficult to predict success sufficiently to develop an extended R33 phase. The R33 will provide support for projects in which feasibility has been demonstrated and thus are ready for extended development. The combined R21/R33 will provide support for projects that require feasibility demonstration, and the aims and milestones of the R21 are sufficiently predictable to consider the extended R33 phase. Responsibility for the planning, direction and execution of the proposed research project will be solely that of the applicant. Except as otherwise stated in this RFA, awards will be administered under the NIH grants policy as stated in the NIH Grants Policy Statement, March 2001, available from the internet only at http://grants.nih.gov/grants/policy/nihgps_2001/. Under this RFA, applicants may submit either an R21 application, a combined R21/R33 application (Phased Innovation Award application) or the R33 application alone, if feasibility can be documented, as described in the SUBMITTING AN APPLICATION section of this RFA. The total project period for an application in response to this RFA may not exceed the following durations: 2 years for the R21 phase; 3 years for the R33 phase; 5 years for a combined R21/R33 proposal. In the combined application, the R21 phase may not extend beyond 2 years. For R21 and combined R21/R33 applications, the R21 phase may not exceed $250,000 direct costs per year. R21 budgets can exceed this cap to accommodate F&A costs to subcontracts to the project, in which case a non-modular budget format must be used. The R33 application has a budgetary limit of $500,000 direct costs for each year. It is strongly recommended that applicants contact institute staff at an early stage of application development to convey critical information, such as potentially large budget requests or to discuss programmatic responsiveness of the proposed project. Early contact with institute staff is particularly critical relative to this RFA because it uses a new grant mechanism (R33) as well as an expedited review procedure. Refer to the WHERE TO SEND INQUIRIES section of this RFA for institute staff contacts. The combined R21/R33 application offers two advantages over the regular application process: 1. Single submission and evaluation of both the R21 and the R33 phases as one application. 2. Minimal or no funding gap between the R21 and R33. The award of the R33 funds will be based on program priorities, the availability of funds and the successful completion of negotiated scientific milestones as determined by program staff in the context of peer review recommendations. To be eligible for the Phased Innovation Award, the R21 phase must include well- defined quantifiable milestones that will be used to judge the progress and success of the proposed research, as well as a credible plan for the R33 phase. The Phased Innovation Award must have a section labeled Milestones at the end of the Research Plan of the R21 application. This section must include well- defined quantifiable milestones for the completion of the R21 portion of the application, a discussion of the suitability of the proposed milestones for assessing the success in the R21 phase, and a discussion of the implications of successful completion of the milestones for the proposed R33 study. 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 only solicitation. At this time there are no definite plans to reissue this solicitation. Upon termination of these awards, investigators seeking continued funding may compete with all investigator- initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2003. FUNDS AVAILABLE The sponsoring ICs intend to commit approximately $2 million total costs in FY 2003 to fund 4 to 8 new grants in response to this RFA. An applicant may request a project period of 2 (R21 phase alone), 3 (R33 phase alone) or 5 (R21/R33 combined) years. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the sponsoring ICs 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. 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 or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. 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 RFA and welcome the opportunity to answer questions from potential applicants. 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: James F. Hyde, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 609 MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 594-7692 FAX: (301) 435-6047 E-mail: jh486z@nih.gov Elaine Collier, M.D. Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases 6700-B Rockledge Drive, Room 5135, MSC 7640 Bethesda, MD 20892-7640 Telephone: (301) 496-7104 FAX: (301) 402-2571 E-mail: ec5x@nih.gov Peter A. Dudley, Ph.D. Division of Extramural Research National Eye Institute Executive Plaza South, Suite 350 Bethesda, MD 20892-7164 Telephone: (301) 451-2020 FAX: (301) 402-0528 Email: pad@nei.nih.gov Momtaz Wassef, Ph.D. Leader, Atherosclerosis Research Group Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10186 Bethesda, MD 20892-7956 Telephone: (301) 435-0550 FAX: (301) 480-2848 E-mail: mw47d@nih.gov o Direct your questions about peer review issues to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8897 FAX: (301) 480-3505 Email: CalvoF@extra.niddk.nih.gov o Direct your questions about financial or grants management matters to: Kathleen J. Shino, M.B.A. Supervisory Grants Management Specialist Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 708 MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8869 FAX: (301) 480-3504 E-mail: ShinoK@extra.niddk.nih.gov Pamela G. Fleming Grants Management Officer National Institute of Allergy and Infectious Diseases Division of Extramural Activities Room 2119 6700-B Rockledge Drive, MSC 7614 Bethesda, MD 20892-7614 (Regular Mail) Bethesda, MD 20817 (Express Mail) Phone: (301) 402-6580 FAX: (301) 493-0597 E-mail: pf49e@nih.gov Chris Davis Grants Management Specialist National Eye Institute 6120 Executive Blvd Suite 350, MSC 7164 Bethesda, MD 20892-7164 Telephone: (301) 451-2020 FAX: (301) 496-99977 E-mail: cad@nei.nih.gov David L. Reiter Grants Operations Branch National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7044 Bethesda, MD 20892-7926 Telephone: (301)435-0177 FAX: (301)480-3310 E-mail: dr36t@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA 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 IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (For express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8897 FAX: (301) 480-3505 SUBMITTING AN APPLICATION Applications (R21, R21/R33, and R33) must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: I. SPECIFIC INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION AWARD APPLICATION: The R21/R33 application must include the specific aims for each phase and clear measurable goals (milestones) that would demonstrate feasibility and justify transition to the R33 phase. Applications must include a specific section labeled Milestones following the Research Plan of the R21 phase. Milestones should be well described, quantifiable and scientifically justified and not simply a restatement of the specific aims. A discussion of the milestones relative to the progress of the R21 phase, as well as, the implications of successful completion of the milestones for the R33 phase should be included. This section should be indicated in the Table of Contents. Applications lacking this information as determined by the NIH program staff, will be returned to the applicant without review. For funded applications, completion of the R21 milestones will elicit an NIH expedited review that will determine whether or not the R33 should be awarded. The release of R33 funds will be based on successful completion of negotiated scientific milestones, program priorities, and on the availability of funds. The expedited review may result in additional negotiations of award. The R21/R33 combined applications must be submitted as a single application, with one face page. Although it is submitted as a single application, it should be clearly organized into two phases. To accomplish a clear distinction between the two phases, applicants are directed to complete Sections a-d of the Research Plan twice: one write-up of Sections a-d and milestones for the R21 phase and sections a-d again for the R33 phase. The Form 398 Table of Contents should be modified to show sections a-d for each phase as well as the milestones. There is a page limit of 25 pages for the composite a-d text of all applications (i.e., section a-d and milestones for the R21 phase plus sections a-d for the R33 phase must be contained within the 25 page limit for R21/R33 applications.) In preparing the R21/R33 application, investigators should consider the fact that applications will be assigned a single priority score. In addition, as discussed in the REVIEW CONSIDERATIONS section, the initial review panel has the option of recommending only the R21 phase for support. However, an application with an R33 Phase that is so deficient in merit that it is not recommended for support will reflect upon the judgment of the applicant. For these reasons, the clarity and completeness of the R21/R33 application with regard to specific goals and feasibility milestones for each phase are critical. The presentation of milestones that are not sufficiently scientifically rigorous to be valid for assessing progress in the R21 phase will reflect upon the scientific judgment of the applicant in this application. 1. Face Page of the application: Item 2. Check the box marked "YES" and type the number and title of this RFA. Also indicate that the application is submitted as an R21/R33. Item 7a, DIRECT COSTS REQUESTED FOR INITIAL PERIOD OF SUPPORT: For the R21 phase of the combined R21/R33 application, direct costs are limited to a maximum of $250,000 per year for a maximum of two years and the award may not be used to supplement an ongoing project. The requested budgets can exceed this cap to accommodate for F&A costs to subcontracts to the project. Insert the first year of R21 support in item 7a. Item 8a, DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT: For the R21 phase of the combined R21/R33 application, direct costs requested for the proposed period may not exceed $500,000 for two years of support. The statement in item 7a above pertaining to subcontract costs also applies here. Insert sum of all years of requested support in item 8a 2. Page 2 - Description: As part of the description, identify concisely the research team ("bench to bedside partnership"), the fundamental research to be performed or the technology/tool to be developed, its innovative nature, its relationship to presently available knowledge or capabilities, and its expected impact on the diagnosis, treatment or prevention of type 1 diabetes or its complications. 3. Budget: The application should provide a DETAILED BUDGET for Initial Budget Period (form page 4), for each of the initial years of the R21 and R33 phases as well as a budget for the entire proposed period of support (form page 5). Form pages should indicate which years are R21 and R33. All budgets should include a justification for each item requested. 4. Research Plan: Item a, Specific Aims: The applicants must present specific aims that the applicant considers to be scientifically appropriate for the relevant phases of the project. The instructions in the PHS 398 booklet for this section of research grant applications suggest that the applicant state the hypotheses to be tested. Furthermore for the R21 phase, preliminary data are not required, although they should be included when available. Item b, Background and Significance: Elaborate on the innovative nature of the proposed research. Clarify how the fundamental research or tools/technologies to be developed as proposed in this project will result in a significant improvement over existing approaches. Explain the potential of the proposed studies for having a broad impact on a compelling area of type 1 diabetes research. Clearly identify how the project, if successful, would result in new capabilities for the treatment and prevention of type 1 diabetes and its complications. Item c, Preliminary Studies/Progress Report: While preliminary data are not required for the submission of the R21 phase, this section should provide current thinking or evidence in the field to substantiate the feasibility of the R33 phase. While preliminary data are not required for submission of the R21 phase, easily understandable data that provide relevant information to aid the review should be included when available. The R33 phase need not repeat information already provided in the R21 phase. Item d, Research Design and Methods: Follow the instructions in the PHS 398 booklet. In addition, for the R21 phase of combined R21/R33 applications only, the following information must be included as a final section of Item d: Applications must include a specific section labeled Milestones following the Research Design and Methods of the R21 phase. Milestones should be well described, quantifiable, and scientifically justified and not be simply a restatement of the specific aims. The milestones should not be a reiteration of the Specific Aims of the research project, but should be tangible accomplishments. A discussion of the milestones relative to the success of the R21 phase, as well as the implications of successful completion of the milestones for the R33 phase and the page number of the milestones section should be listed. This section should be indicated in the Table of Contents. Applications lacking this information as determined by the Institute program staff, will be returned to the applicant without review. For funded applications, completion of the R21 milestones will elicit an Institute expedited review that will determine whether or not the R33 should be awarded. The release of R33 funds will be based on successful completion of milestones, program priorities and on the availability of funds. The expedited review may result in additional negotiations of award. II. SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R21 APPLICATION WHEN SUBMITTED WITHOUT THE R33 PHASE. MODULAR GRANT APPLICATION: R21 only applications should be submitted in a modular grant format, unless exceeding the $250,000 budgetary cap in order to accommodate F&A costs to subcontracts to the project. The total project period for an R21 application may not exceed two years. 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. 1. Face page of the application: Item 2. Check the box marked "YES" and type the number of this RFA. Also indicate that the application is for an R21. 2. Page 2, Description: As part of the description, identify concisely the research team ("bench to bedside partnership"), the fundamental research to be performed or the technology/tool to be developed, its innovative nature, its relationship to presently available knowledge or capabilities, and its expected impact on the diagnosis, treatment or prevention of type 1 diabetes or its complications. 3. Research Plan: Item a, Specific Aims: The applicants must present specific aims that the applicant considers to be scientifically appropriate for the relevant phases of the project. The instructions in the PHS 398 booklet for this section of research grant applications suggest that the applicant state the hypotheses to be tested. Furthermore for the R21 phase, preliminary data are not required, although they should be included when available. Item b, Background and Significance: Elaborate on the innovative nature of the proposed research. Clarify how the fundamental research or tools/technologies to be developed as proposed in this project will result in a significant improvement over existing approaches. Explain the potential of the proposed studies for having a broad impact on a compelling area of type 1 diabetes research. Clearly identify how the project, if successful, would result in new capabilities for the treatment and prevention of type 1 diabetes and its complications. Item c, Preliminary Studies/Progress Report: R21 applications should provide current thinking or evidence in the field to support the project. While preliminary data are not required, easily understandable data that provide relevant information to aid review could be included when available. Item d, Research Design and Methods: Instructions for PHS 398 should be followed. III. SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R33 APPLICATION WHEN SUBMITTED WITHOUT THE R21 PHASE. Applications for R33 grants are to be prepared according to the instructions provided in the PHS 398 booklet unless specified otherwise within items 1-4 below. 1. Face Page of the application: Item 2. Check the box marked "YES" and type the number and title of this RFA. Also, indicate that the application is for an R33. 2. Page 2 - Description: As part of the description, identify concisely the research team ("bench to bedside partnership"), the fundamental research to be performed or the technology/tool to be developed, its innovative nature, its relationship to presently available knowledge or capabilities, and its expected impact on the diagnosis, treatment or prevention of type 1 diabetes or its complications. 3. Budget: The application should provide a DETAILED BUDGET for the Initial Budget Period (form page 4) as well as a budget for the entire proposed period of support (form page 5). Budget should include a justification of all items requested. 4. Research Plan: Item a, Specific Aims: The instructions in the PHS 398 booklet for this section of research grant applications suggest that the applicant state the hypotheses to be tested. Item b, Background and Significance: Elaborate on the innovative nature of the proposed research. Clarify how the fundamental research or tools/technologies to be developed as proposed in this project will result in a significant improvement over existing approaches. Explain the potential of the proposed studies for having a broad impact on a compelling area of type 1 diabetes research. Clearly identify how the project, if successful, would result in new capabilities for the treatment and prevention of type 1 diabetes and its complications. Item c, Preliminary Studies/Progress Report: This section must document that feasibility studies have been completed, and progress achieved, equivalent to that expected through the support of an R21 project. The application must clearly describe how the xploratory/developmental study is ready to scale up to an expanded development stage. In the event that an applicant feels that some aspect of the approach or tools or technology to be developed is too proprietary to disclose, applicants at a minimum should provide a demonstration (results) of the capabilities of the proposed approach, tool or technology. Item d, Research Design and Methods: Follow the instructions in the PHS 398 booklet. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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 RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. 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) At the time of submission, two additional copies of the application must be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. 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 already reviewed, but such applications must include an Introduction addressing the previous critique PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. 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 the NIDDK in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique 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 second level review by the appropriate Institute 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: o Significance o Approach o Innovation o Investigator o Environment 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. 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 your study address an important problem? If the aims of your application are achieved, how will scientific knowledge be advanced? What will be the effect of your studies on the concepts or methods that drive this field? What may be the anticipated societal benefit of the proposed activity? Is the research partnership likely to contribute to new and important discoveries about type 1 diabetes? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATORS: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of the other researchers? Is the research partnership critical to the achievement of the milestones and the success of the research project? Is the research team composed of both basic and clinical scientists who form a "bench to bedside partnership"? (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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: 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 included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. o OTHER REVIEW CRITERIA: For an R21/R33 application, the initial review group will evaluate the specific goals for each phase and the feasibility of the milestones that would justify expansion to the R33 phase. The initial review group will evaluate how appropriate, realistic and quantifiable your proposed research milestones are, and whether the milestones are adequate for the demonstration and feasibility for transition to the R33 development phase. They will also assess your timeframe for achieving the milestones and whether it is appropriate. A single priority score will be assigned to each scored application. As with any grant application, the initial review group has the option of recommending support for a shorter duration than that requested by the applicant, and basing the final merit rating on the recommended portion of the application. For the R21/R33 application, this may result in a recommendation that only the R21 phase be supported, based upon concerns related to the application's specific goals and the feasibility milestones justifying expansion to the R33 phase. Deletion of the R33 phase by the review panel or presentation of inadequate milestones in the application may affect the merit rating of the application. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: January 29, 2003 Application Receipt Date: February 26, 2003 Peer Review Date: June/July 2003 Council Review: September 2003 Earliest Anticipated Start Date: September 30, 2003 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 MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). 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 AMENDMENT "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. 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 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. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. 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. 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 RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.847 (NIDDK), 93.855, Immunology, Allergy and Transplantation Research (NIAID), 93.867 (NEI), and 93.837 (NHLBI)is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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.


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