and Human Services (HHS)
EXPIRED
PROTEOMICS AND METABOLOMICS IN TYPE 1 DIABETES AND ITS COMPLICATIONS RELEASE DATE: October 24, 2003 RFA Number: RFA-DK-03-024 (see correction NOT-DK-04-001) Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATIONS: National Institutes of Health (NIH) (http://www.nih.gov/) COMPONENTS OF PARTICIPATING ORGANIZATIONS: 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/) National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov/) National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.847, 93.867, 98.837, 93.855, 93.853, 93.865 LETTER OF INTENT RECEIPT DATE: February 18, 2004 APPLICATION RECEIPT DATE: March 18, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Eye Institute (NEI), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Neurological Disorders and Stroke (NINDS), and National Institute of Child Health and Human Development (NICHD) encourage the scientific community to use proteomics technologies to study type 1 diabetes (T1D) and its complications. Proteomic technologies have been successfully used for the identification of cancer biomarkers, for the identification of novel drug targets and for studying several biological processes relevant to human health. High throughput metabolic profiling has been recently implemented for metabolomic studies. However, as of today these technologies have been applied to study T1D and its complication only in a limited way. Moreover, currently available proteomic and metabolomic technologies represent a great opportunity for advancing the field of T1D and its complications. This RFA intends to promote the use of these technologies to study T1D and its complications emphasizing the importance of collaborative efforts between investigators with expertise in proteomics or metabolomics and investigators with expertise in T1D. RESEARCH OBJECTIVES T1D is an autoimmune disease characterized by the destruction of the insulin- secreting beta cells of the pancreas. Diabetes is difficult to control with the current therapies available and as a result patients with T1D may suffer devastating long term consequences including accelerated cardiovascular and peripheral vascular diseases, nephropathy, retinopathy, neuropathy, oral diseases and premature death. T1D affects an estimated one million Americans and the treatment of diabetes and its devastating complications results in significant health care expenditures. T1D has been extensively described as a chronic disease and the identification of several susceptibility loci indicate a genetic component. However, in several epidemiologic studies T1DM shows a pattern similar to an epidemic disease and migrant studies clearly indicate an environmental component. These studies suggest that if we could identify the environmental factors responsible for triggering the disease and develop appropriate controls, the large majority of T1DM cases could be prevented. The development of autoimmune diabetes in non-obese diabetic mice also indicate the importance of the environmental component and to further emphasize the importance of the environmental factors it should be mentioned that 80% of the cases of T1D occur in individuals with no apparent family history. In view of these studies it is apparent that characterization of the proteome and metabolome at different states of the disease could lead to invaluable information for understanding the etiology and development of T1D and its complications. Proteomic approaches have been successfully used for studying complex biological problems and for the identification of disease markers. Recent developments in proteomics indicate that the technologies available are already sufficiently advanced to approach many questions relevant to T1D and its complications. Some of these technologies include: two-dimensional gel electrophoresis for profiling complex mixtures coupled to mass spectrometry or other methods for protein identification; isotopically labeled reagents for the comparison of two different biological states (e.g. disease versus control) using mass spectrometry; protein or antibody arrays; yeast two- hybrid systems, phage display or immunoprecipitation coupled to mass spectrometry for studying protein-protein interactions; characterization of macromolecular complexes using antibodies, DNA, RNA, or other molecules as bait followed by identification by mass spectrometry. Metabolites are the end products of many enzymatic reactions and changes in the metabolic profile of biofluids like urine and blood could be index of a particular metabolic state or disease. Even though there is no technology available for quantifying and identifying all metabolites present in a particular biofluid recent developments in mass spectrometry and nuclear magnetic resonance spectroscopy make it feasible to do high throughput profiling and quantify large subsets of metabolites. The application of metabolomic and proteomic technologies to the study of T1D and its complications could further our understanding of the etiology and development of this disease. Islet transplantation has been successfully used for freeing individuals with T1D from the need of insulin therapy. 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 requires two donor pancreata per recipient; therefore, current levels of organ donation provide sufficient organs for only a small fraction of the people who could potentially benefit from this therapy. Thus, there is an imminent need of improving the transplantation efficiency and proteomics could be used for better characterizing islets preparations. The complications of T1D account for much of the burden of the disease. Emerging information on the molecular mechanisms involved in the pathogenesis of complications has identified multiple potential targets for therapeutic intervention. The discovery of better targets and the early diagnosis of specific complications could allow early treatment preventing its development. Proteomics and metabolomics could be used for the analysis of biofluids of patients or animal models for identifying biomarkers of complications, including cardiovascular diseases, retinopathy, neuropathy and nephropathy. This RFA is intended to support innovative research that applies proteomic and metabolomic technologies to study T1D and its complications. A multi- disciplinary team composed of a basic or clinical scientist with expertise in T1D and a scientist with expertise in proteomics or metabolomics is envisioned as the ideal team for approaching most of the projects with relevance to this RFA. To foster the formation of these multidisciplinary teams a conference on Proteomics and Diabetes was held (http://www.niddk.nih.gov/fund/other/proteomics/index.htm). Furthermore, the following web sites contain information about several investigators, resources and consortia already working in the field of T1D that might be interested in collaborative projects (http://www.niddk.nih.gov/fund/diabetesspecialfunds/proteomics/; http://www.niddk.nih.gov/researchprograms/resources.htm; http://www.niddk.nih.gov/patient/patient.htm). Examples of projects that this RFA intends to solicit include but are not limited to: o Identification of surrogate markers for the progression of T1D and the development of complications in humans and animal models that develop autoimmune diabetes and/or the complications of diabetes o Application of proteomic technologies to study the inflammatory processes leading to the development of T1D and its complications o Application of proteomics and metabolomics to assess the risk of developing T1D or monitor response to therapy to prevent or reverse the autoimmune process o Application of proteomic technologies for identifying novel drug targets for the treatment and prevention of T1D and its complications, and for monitoring the efficacy of present treatments o The use of proteomic approaches for identifying markers for monitoring pancreatic beta cell differentiation, development, function, and/or mass o The characterization of the pancreatic islet proteome for identifying markers that might be used for improving the success rate in transplantation o The development of antibodies or protein/antibody arrays that could be used for studying T1D or screening islets to be transplanted and/or monitor their function after transplantation that can be used for screening islets to be transplanted and/or monitor their function after transplantation MECHANISMS OF SUPPORT This RFA will use 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 an 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. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will have to be submitted using a standard RO1 or R21 mechanism, will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2004. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non- modular research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. 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. 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. FUNDS AVAILABLE The participating ICs intend to commit approximately $3 million in FY 2004 to fund 6 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. 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. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) 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 meritorious applications. 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 institutions/organizations 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. SPECIAL REQUIREMENTS 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. 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: Salvatore Sechi, Ph.D. Division of Diabetes, Endocrinology, and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd. Rm. 611 Bethesda, MD 20892-5460 Telephone: (301) 594-8814 FAX: (301) 480-2688 E-mail: [email protected] John Paul Ridge, Ph.D. Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases 6700-B Rockledge Drive, Rm. 5259 Bethesda, MD 20892-7640 Telephone: (301) 496-7104 FAX: (301) 402-2571 E-mail: [email protected] 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 E-mail: [email protected] Pothur Srinivas, Ph.D., MPH Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Rockledge II, Rm. 10188 6701 Rockledge Drive Bethesda, MD 20892-7956 Phone: (301) 435-0550 FAX: (301) 480-2858 E-mail: [email protected] Paul L. Nichols, Ph.D. Systems and Cognitive Neuroscience National Institute of Neurological Disorders and Stroke Neuroscience Center, Rm. 2108 6001 Executive Blvd. Bethesda, MD 20892 Phone: (301) 496-9964 FAX: (301) 401-2060 E-mail: [email protected] Gilman D. Grave, M.D. Center for Research for Mothers and Children National Institute of Child Health and Human Development 6100 Executive Boulevard; Suite 4B-11 National Institutes of Health Bethesda, MD 20892-7510 Telephone: (301) 496-5593 Fax: (301) 480-9791 E-mail address: [email protected] o Direct your questions about peer review issues to: Francisco O. Calvo, Ph.D. Division of Extramural Activities, National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 752 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8897 FAX: (301) 480-3505 E-mail: [email protected] o Direct your questions about financial or grants management matters to: Ms. Denise Payne Grants Management Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Rm.733 Bethesda, MD 20892-5460 Telephone: (301) 594-8845 FAX: (301) 480-3504 E-mail: [email protected] Chris Davis Grants Management National Eye Institute 6120 Executive Blvd, Suite 350 Bethesda, MD 20892-7164 Telephone: (301) 451-2020 FAX: (301) 496-9997 E-mail: [email protected] Norma DeGuzman Grants Operation Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Rm. 7167 Bethesda, MD 20892-7926 Telephone: (301) 496-6740 Fax: (301) 480-1948 E-mail: [email protected] Karen Shields Grants Management Branch National Institute of Neurological Disorders and Stroke Neuroscience Center, Rm. 3290 6001 Executive Blvd. Bethesda, MD 20892 Phone: (301) 496-9231 FAX: (301) 402-0129 E-mail: [email protected] Gilman D. Grave, M.D. Center for Research for Mothers and Children National Institute of Child Health and Human Development 6100 Executive Boulevard; Suite 4B-11 National Institutes of Health Bethesda, MD 20892-7510 Telephone: (301) 496-5593 Fax: (301) 480-9791 E-mail address: [email protected] 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 National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 752 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8885 FAX: (301) 480-3505 SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: [email protected]. SUPPLEMENTARY 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, 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, 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, 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 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. 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/labels.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 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to: Chief, Review Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 752 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) APPLICATION PROCESSING: Applications must be received on or before 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. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Incomplete and/or nonresponsive applications will not be reviewed. Do not accept unsolicited R21/R33 applications. 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 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 written critique o Receive a second level review by an appropriate National Advisory Council or Board. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application's overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment 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. 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? Is the research partnership likely to contribute to new and important discoveries about type 1 diabetes? 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? 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? INVESTIGATOR: Are the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 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, the following items will be considered in the determination of scientific merit and the priority score: 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. PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: February 1, 2004 Application Receipt Date: March 1, 2004 Peer Review Date: June/July 2004 Council Review: September 2004 Earliest Anticipated Start Date: September 30, 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose- finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety 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 "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://stemcells.nih.gov/index.asp 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://stemcells.nih.gov/registry/). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, 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. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
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