RESEARCH GRANTS FOR CLINICAL STUDIES OF KIDNEY DISEASES RELEASE DATE: April 15, 2003 (see correction NOT-DK-03-005) (see reissuance PAR-04-065) PA NUMBER: PAR-03-105 EXPIRATION DATE: After March 18, 2004, unless reissued. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov) APPLICATION RECEIPT DATES: July 18, 2003; March 18, 2004 CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.849 THIS PAR CONTAINS THE FOLLOWING INFORMATION o Purpose of the PAR o Research Objectives o Mechanism(s) of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PAR The Division of Kidney, Urologic, and Hematologic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has a longstanding and substantial interest in research concerning the prevention and treatment of kidney disorders. This program announcement (PAR) specifically encourages the submission of applications for pilot and feasibility studies, clinical trials, and epidemiological studies related to kidney disease research that are particularly innovative and/or potentially of high impact. It is anticipated that applications for pilot and feasibility studies may lead to full-scale clinical trials in the prevention, diagnosis or treatment of kidney disease. These grants may be used for trials that evaluate pharmacological, dietary, surgical, or behavioral interventions for the prevention or treatment of kidney disease. In view of the extent and severity of various co-morbidities (i.e., cardiovascular disease, infections, and depression) observed in patients with kidney disease, these grants may also assess interventions that prevent or treat co-morbid conditions in the setting of renal disease. Pilot epidemiological studies are also encouraged, especially related to kidney disease, or co-morbid condition, prevention. It is anticipated that these grants will in some cases serve as a basis of planning future multi-center research project grant applications (R01) or for cooperative agreement (U01) awards. Both new and experienced investigators in relevant fields and disciplines are encouraged to apply for these grants. RESEARCH OBJECTIVES Background Recent estimates of chronic kidney disease (CKD) in the US population, obtained through analysis of the Third National Health and Nutrition Examination Survey (NHANES III), indicate that it is a common medical problem with an estimated prevalence of 11% in the adult US population. Most cases of CKD observed in the US occur in the setting of diabetes, hypertension, glomerulonephritis and polycystic kidney disease. With an increasing incidence of CKD, the incidence of end-stage renal disease (ESRD) has also been steadily increasing in the adult US population. US Renal Data System (USRDS) data indicate that from 1992 – 2000 the number of patients with ESRD has increased from 220 to 334 per million population. These increases in CKD and ESRD rates reflect a marked increase in patient morbidity and mortality related to underlying kidney disease, as well as a significant increase in utilization of health care resources to provide appropriate care for affected patients. The increasing rate of ESRD has also markedly increased waiting time for cadaveric transplantation such that the rate of kidney transplants per patient year on dialysis has steadily declined over the last decade. Similarly, USRDS data indicate that the rates of the primary causes of CKD in pediatric patients have increased over the last two decades. This increase has been most evident in the near doubling of the incidence of glomerulonephritis in African American children and children of other non- Caucasian races. Rates of cystic, hereditary, and congenital diseases in all racial groups have also almost doubled during this time period. Acute renal failure in hospitalized patients is also a significant problem in the US, ranging from 1-15% of hospitalized patients. Medical management of acute renal failure has traditionally consisted of supportive care, with renal replacement therapy implemented for the most severe cases. Despite such interventions in acute renal failure, however, mortality rates in affected patients remain very high (>50% in some series). In view of these observations suggesting a marked and progressive increase in CKD and ESRD in the US population, NIDDK has sponsored a number of large, multi-center studies of specific kidney disorders. These studies include prospective investigations in chronic kidney disease, dialysis access, polycystic kidney disease, focal and segmental glomerulosclerosis, and acute renal failure. In planning and performing these studies, however, it has been apparent that the process for identifying appropriate interventions for multi-center trials in kidney disease could be improved. This is particularly evident in the current small number of clinical studies related to kidney disease that could ultimately be expanded to large-scale clinical trials. The goal of this PAR is to provide flexibility for initiating preliminary, short-term studies, thus allowing new ideas to be investigated in a more expeditious manner without stringent requirements for preliminary data. Additionally this PAR could facilitate Phase II clinical trials for projects in which satisfactory preliminary data has been collected. Such support is needed to encourage experienced investigators as well as new investigators to pursue new approaches, underdeveloped topics, or more risky avenues of research. If successful, these awards should lead to significant scientific advances in the treatment of kidney diseases. As kidney disease occurs in variety of clinical settings, and is associated with a number of co-morbid conditions, it is anticipated that applications submitted in response to this PAR could address a number of different aspects concerning the prevention, diagnosis, or treatment of kidney disease. Relevant topics of study evaluating kidney disease in adults or children could include (but are not limited to): o Prevention, diagnosis, or therapy of chronic kidney disease, (and disease progression) including studies of diabetic nephropathy, hypertensive nephrosclerosis, polycystic kidney disease, or chronic allograft nephropathy; o Studies assessing dialysis therapy, dialysis access, anemia of renal disease, and nutritional or cardiovascular aspects of ESRD; o Prevention, diagnosis, or therapy of glomerular disease, either idiopathic or secondary glomerular involvement in a systemic process; o Prevention, diagnosis, or therapy of acute renal failure, including that observed following renal transplantation; o Prevention, diagnosis, or therapy of co-morbid conditions associated with reduced kidney function; o Epidemiologic studies focusing on patients with reduced kidney function. MECHANISM(S) OF SUPPORT Support for this program will be through the NIH Exploratory/Development Research Grant (R21), the Exploratory/Development Research Grant Phase 2 (R33), and the Phased Innovation Award (R21/R33 combined). The R33 is a newly established NIH grant mechanism to provide a second phase for the support of innovative exploratory and development research initiated under the R21 mechanism. Under the Phased Innovation Award (R21/R33), transition of the R21 to the R33 phase will be expedited and is dependent on completion of negotiated milestones. This PAR 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. 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. 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. 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 PAR, 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 PAR, 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 PAR. The total project period for an application in response to this PAR may not exceed the following durations: 2 years for the R21 phase; 5 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. These awards are not renewable. For R21 and combined R21/R33 applications, the R21 phase may not exceed $275,000 direct costs for two years. 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. R33 applications up to $500,000 may be submitted with thorough budgetary justification. 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 PAR because it uses a new grant mechanism (R33). Refer to the WHERE TO SEND INQUIRIES section of this PAR for institute staff contacts. 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. 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 o Faith-based or community-based 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 The NIH is interested in ensuring that the research resources developed through this PAR become readily available to the research community for further research, development, and application. It is the expectation that this sharing will lead to beneficial knowledge for patients with kidney disease. Data sharing will also allow more effective use of NIH resources by avoiding unnecessary duplication of data collection, and thereby facilitate the support of a larger number of research projects. For the combined R21/R33 applications and the R33 applications submitted in response to the PAR, a paragraph describing a data sharing plan should be included at the end of the Research Plan section. This paragraph should describe the procedures that will be implemented for data sharing, and provide a timeline for making the data available to the general research community. As the rights and privacy of subjects who participate in NIH- sponsored research must be protected at all times, data sharing plans for human studies should discuss how the rights and confidentiality of participants will be protected. Data intended for broader use should be free of identifiers that would permit linkages to the research participants and stripped of variables that could lead to deductive identification of individual participants. Costs associated with data sharing can be included in the budget section of the application. The scientific review group will evaluate the adequacy of the proposed plan for sharing and data access. Comments on the plan and any concerns will be presented in an administrative note in the Summary Statement. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PAR 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: Catherine M. Meyers, M.D. Inflammatory Kidney Diseases Program Director Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Room 641 Bethesda, MD 20892-5458 Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: cm420i@nih.gov o Direct your questions about peer review issues to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Blvd., Room 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817 Telephone: (301) 594-8897 FAX: (310) 480-3505 Email: fc15y@nih.gov o Direct your questions about financial or grants management matters to: Ms. Aretina Perry-Jones Grants Management Specialist Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Room 745 MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8862 FAX: (301) 480-3504 Email: ap19s@nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: 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. The clarity and completeness of the R21/R33 application with regard to specific goals and feasibility milestones for each phase are therefore critical. 1. Face Page of the application: Item 2. Check the box marked "YES" and type the number and title of this PAR. 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 $275,000 over 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 $275,000 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, its innovative nature, its relationship to presently available knowledge or capabilities, and its expected impact on the diagnosis, treatment or prevention of kidney disease 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 research 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 kidney disease research. Clearly identify how the project, if successful, would result in new capabilities for the treatment, diagnosis, or prevention of kidney disease or 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. If limited relevant preliminary data are available that would aid the review, they should be described in this section. The R33 phase of the application 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. 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. A paragraph describing a data sharing plan should be included at the end of the Research Plan section of the R33 phase of the application, as described in SPECIAL REQUIREMENTS. SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R21 APPLICATION WHEN SUBMITTED WITHOUT THE R33 PHASE. MODULAR GRANT APPLICATION: R21 applications submitted without the R33 Phase should be submitted in a modular grant format, unless exceeding the $275,000 two-year 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 PAR. 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, its innovative nature, its relationship to presently available knowledge or capabilities, and its expected impact on the diagnosis, treatment or prevention of kidney disease or its complications. 3. Research Plan: Sections a – d of the Research Plan of the R21 application may not exceed 15 pages, including tables and figures. 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 research 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 kidney disease research. Clearly identify how the project, if successful, would result in new capabilities for the treatment and prevention of kidney disease or its complications. Item c, Preliminary Studies/Progress Report: R21 applications should provide current thinking or evidence in the field to support the project. If limited relevant preliminary data are available that would aid the review, however, they should be described in this section. Item d, Research Design and Methods: Instructions for PHS 398 should be followed. R21 appendix materials should be limited, as is consistent with the exploratory nature of the R21 mechanism, and should not be used to circumvent the page limit for the Research Plan. Copies of appendix material will only be provided to the primary reviewers of the application and will not be reproduced for wider distribution. The following materials may be included in the appendix: o Up to five publications, including manuscripts (submitted or accepted for publication), abstracts, patents, or other printed materials directly relevant to the project. These may be stapled as sets. o Surveys, questionnaires, data collection instruments, and clinical protocols. These may be stapled as sets. o Original glossy photographs or color images of gels, micrographs, etc., provided that a photocopy (may be reduced in size), is also included within the 15-page limit of items a – d of the Research Plan. 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 PAR. 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, its innovative nature, its relationship to presently available knowledge or capabilities, and its expected impact on the diagnosis, treatment or prevention of kidney disease 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: Sections a – d of the Research Plan of the R33 application may not exceed 25 pages, including tables and figures. 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 research 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 kidney disease research. Clearly identify how the project, if successful, would result in new capabilities for the diagnosis, treatment or prevention of kidney disease or 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 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. A paragraph describing a data sharing plan should be included at the end of the Research Plan section of the R33 application, as described in SPECIAL REQUIREMENTS. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. 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. 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 (5) of the appendix material must be sent to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 752 Bethesda, MD 20892-5452 Telephone: (301) 594-8885 FAX: (301) 480-3505 Email: fc15y@nih.gov APPLICATION PROCESSING: Applications must be mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PAR 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 a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Incomplete or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to this PAR will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDDK in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Diabetes and Digestive and Kidney Diseases 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: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning the application's overall score, weighting them as appropriate for each application. 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? 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: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 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? SPECIAL REVIEW CONSIDERATIONS FOR R21 APPLICATIONS: Because the research plan is limited to 15 pages, an exploratory/development grant application need not have background material or preliminary information as one might normally expect in an R01 application. Accordingly, reviewers should focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers should place less emphasis on methodological details and certain indicators traditionally used in evaluating the scientific merit of the R01 applications including supportive preliminary data. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator- generated data. Preliminary data are not required for R21 applications. 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: 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 will be assessed. 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 DATA SHARING: The adequacy of the proposed plan to share data for the combined R21/R33 and the R33 applications submitted in response to this PAR. This evaluation will be presented in an administrative note in the Summary Statement, and will not factor into the numerical score. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. This evaluation will be presented in an administrative note in the Summary Statement, and will not factor into the numerical score. AWARD CRITERIA Applications submitted in response to a PAR will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program 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) MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT- OD-02-001.html; a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PAR 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 PAR is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance 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. 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.


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