BENCH TO BEDSIDE RESEARCH ON TYPE 1 DIABETES AND ITS COMPLICATIONS Release Date: October 11, 2001 RFA: RFA-DK-02-022 National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov) National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov/) National Eye Institute (http://www.nei.nih.gov/) National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov/) Letter of Intent Receipt Date: February 14, 2002 Application Receipt Date: March 14, 2002 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Disease (NIAID), National Eye Institute (NEI), and 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. 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, Bench to Bedside Research on Type 1 Diabetes and Its Complications, 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/. 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. The clinical and basic biomedical researchers forming the partnership do not have to be from the same applicant institution. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM 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. Transition of the R21 to the R33 phase will be expedited and is dependent on completion of negotiated milestones. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the NIH. Complete and detailed instructions and information on Modular Grant applications have been incorporated into the PHS 398 (rev. 5/2001). Additional information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm 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 APPLICATION PROCEDURES 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. Although the R33 application has no official budgetary limit, applicants requesting in excess of $500,000 direct costs in any single year of the grant period require prior approval before submission. 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 INQUIRIES sections 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 09/30/02. FUNDS AVAILABLE The sponsoring ICs intend to commit approximately $3 million total costs in FY 2002 to fund 8 to 12 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. 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. However, to reach this potential a number of obstacles must be overcome. These include inadequate animal models in which to test new therapies and lack of measures to predict or assess response to therapy in early trials of potential therapies. Most recently the success of islet transplantation in freeing individuals with type 1 diabetes from the need for insulin therapy has yielded great excitement and a new impetus for research to develop methods to attain an unlimited source of islets for transplantation and to minimize the toxicity of immunotherapy required for transplantation. 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. 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 1diabetes or its complications. Research may include studies of etiology and pathogenesis only in the context of a hypothesis that has clear potential to lead to a new target or strategy for prevention or therapy. Applicants proposing research on certain topics which are relevant to this solicitation (e.g. surrogate markers for use in clinical trials for therapy of microvascular disease, pilot projects for prevention of nephropathy, new strategies to prevent hypoglycemia, new methods to image beta cells or the microcirculation, or gene therapy approaches is islet transplantation) may also wish to consider other solicitations that have been or may soon be issued, further information can be found at http://www.niddk.nih.gov/fund/crfo/may2002council/recently-cleared.htm 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 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 quantitate risk of developing type 1 diabetes or to assess response to therapy to prevent or reverse the autoimmune process and beta cell loss 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 long-term complications 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 sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are 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 research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. 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. 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. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. 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 RFA 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. LETTER OF INTENT Prospective applicants are asked to submit, by February 14, 2002, 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 plan the review. The letter of intent is to 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 APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html must be used in applying for these grants. This version of the PHS 398 is available in an interactive, searchable format. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. 1. SPECIFIC INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION AWARD APPLICATION: Applications are to be submitted on the grant application form PHS 398 (rev. 05/01) and will be accepted at the application deadline indicated on the first page of this solicitation. This version of the PHS 398 is available in an interactive, searchable PDF format at: http://grants.nih.gov/grants/forms.htm. Applications should be prepared according to the instructions provided unless specified otherwise within this SECTION. 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 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. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions provided in Section C of the application 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: 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 nor 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. 2. SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R21 APPLICATION WHEN SUBMITTED WITHOUT THE R33 PHASE. Applications for R21 grants are to be submitted on the grant application form PHS 398 (rev. 05/01) and prepared according to instructions provided for R21 applications in the previous section except that milestones and discussion of the implication of the milestones to an R33 phase are not required. The grant application form PHS 398 is available in an interactive, searchable PDF format at: http://grants.nih.gov/grants/forms.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. Maximum budget is $250,000 direct costs per year for two years. 3. SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R33 APPLICATION WHEN SUBMITTED WITHOUT THE R21 PHASE. Applications for R33 grants are to be submitted on the grant application form PHS 398 (rev. 05/01) and prepared according to the instructions provided unless specified otherwise within items 1-4 below. The grant application form PHS 398 is available in an interactive, searchable PDF format at: http://grants.nih.gov/grants/forms.htm. 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: 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 above. 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 exploratory/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. FOR ALL APPLICATIONS Appendix: All instructions in the Form 398 application kit apply. 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. 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 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) 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 the Scientific Review Administrator notifies the applicants. 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 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 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 appropriate NIH Institute 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. (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? 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? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Milestones: How appropriate, realistic and quantifiable are the proposed research milestones against which to evaluate the demonstration and feasibility for transition to the R33 development phase? What is the timeframe for achieving the milestones and is it appropriate? (4) Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (5) Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? 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 ? (6) 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 Criteria: For the 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. 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 that 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. 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: February 14, 2002 Application Receipt Date: March 14, 2002 Peer Review Date: June/July, 2002 Council Review: September, 2002 Earliest Anticipated Start Date: September 30, 2002 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: 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. 603 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) 496-0484 FAX: (301) 402-0528 Email: pd8n@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 Direct inquiries regarding fiscal matters to: Donald Ellis Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 709B MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8849 FAX: (301) 594-9523 E-mail: de30z@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 Margie Baritz Grants Management Specialist National Eye Institute 6120 Executive Blvd Suite 350, MSC 7164 Bethesda, MD 20892-7164 Telephone: (301) 496-5884 FAX: (301) 496-99977 E-mail: mb41k@nih.gov Ms. Jane Davis Grants Operations Branch National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 7156 Bethesda, MD 20892-7926 Telephone: (301)435-0166 FAX: (301)480-3310 E-mail: jd53j@nih.gov 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). 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.


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