PROSPECTIVE STUDY OF CHRONIC KIDNEY DISEASE IN CHILDREN RELEASE DATE: November 26, 2002 RFA: DK-03-012 (Reissued as RFA-DK-07-501) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.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/) LETTER OF INTENT RECEIPT DATE: January 21, 2003 APPLICATION RECEIPT DATE: February 21, 2003 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 Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations: PURPOSE OF THIS RFA The Division of Kidney, Urologic, and Hematologic Diseases (DKUHD) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), in collaboration with the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Child Health and Human Development (NICHD), invites cooperative agreement applications for two Clinical Coordinating Centers and a Data Coordinating Center to conduct a prospective epidemiological study of children with chronic kidney disease. The primary goals of this study are to determine the risk factors for decline in renal function; the incidence of, and risk factors for, impaired neurocognitive development and function; the prevalence of risk factors for cardiovascular disease; and the long-term effects of growth failure and its treatment. RESEARCH OBJECTIVES Background The incidence of end-stage renal disease (ESRD) in patients age 0 – 19 years in the United States is 15 per million population, according to the 2002 USRDS Annual Data Report. The primary etiologies vary with age, but structural anomalies predominate. Data in the most recent report from the Chronic Renal Insufficiency arm of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) indicate about two thirds of the patients on the registry had some type of structural anomaly. Numerous metabolic derangements occur in chronic kidney disease (CKD)and significantly impact on the overall well-being of affected children. Of the negative effects of pediatric renal disease, growth impairment is the best documented and studied, but there is very little systematic information about the magnitude of other developmental problems. In fact, there have been no large-scale prospective studies of pediatric chronic kidney disease. Short stature is one of the more commonly recognized effects of CKD, first recognized over a century ago. The height deficits are greatest for younger patients and it has been previously documented that the risk for growth failure is highest in patients developing CKD at birth or early in infancy. The degree of renal failure, and particularly a GFR < 25 ml/min/1.73m2, has been touted as critical to poor growth. Recent data also link poor growth to increased morbidity and mortality. When CKD develops during the neonatal period or in early infancy, there are significant problems with neurocognitive development. Some studies suggest an incidence of severe neurodevelopmental delay as high as 60% - 85% in this subpopulation. Growth in head circumference is uniformly subnormal. Gross motor delay, along with global developmental retardation and a lack of maturation on electroencephalography are common. Myoclonic seizures and cerebellar dysfunction have also been described in infants. However, there is virtually no information on the impact of a decrease in renal function that develops later in childhood. Overall, the impact of renal disease and uremia on neurocognitive development has been the subject of little systematic evaluation. Both the nature and magnitude of impaired neurocognitive development in pediatric patients with renal failure is unknown. Renal failure, however commonly affects both the central and peripheral nervous systems. Chronic uremic encephalopathy is associated with problems in learning and memory. These symptoms are believed to result from altered metabolic states in the CNS with ionic changes and possibly impaired synaptic function. Renal failure may also be accompanied by neuropathy and involvement of large diameter axons. There is substantial uncertainty whether earlier institution of renal replacement therapy offers advantages for the child's development. The incidence of hypertension in children with CKD is reported at 38- 78%. As a general rule, hypertension is infrequent in congenital renal disease, but is almost universal in primary glomerular disease and renal injury caused by systemic disease. In addition, uremic cardiomyopathy can be seen in pediatric patients with advanced CKD or ESRD, and may be associated with congestive heart failure. A recent report indicates that hyperhomocysteinemia is found in children with CRF, but it is unclear whether treatment of hyperhomocysteinemia in children decreases the risk for future atherosclerosis. Hyperhomocysteinemia has been identified as a risk factor for development of atherosclerosis in adults with CRF. Cardiovascular disease is a major problem in the adult nephrology patient population, but the incidence and types of cardiovascular disease present in children is unknown. For patients who have kidney failure starting in childhood, the incidence of risk factors for cardiovascular disease needs to be clearly delineated. Research Scope and Goals The primary goals of this program are to recruit a cohort of 600 children with mild to moderately impaired kidney function and to follow these children in a prospective fashion for five years in order to define factors that impact on their well-being. Examples that illustrate possible areas of research are presented below. They are intended only to provide a broad direction for research and should be considered illustrative and not restrictive. Some potential goals are: o Determination of the risk factors for accelerated decline in renal function. o Determination of the incidence of, and risk factors for, impaired neurocognitive development and function. o Determination of the nature (sensory, motor, visual and temporal processing; learning and memory; attention; social cognition and affect) and magnitude of neurocognitive impairment in pediatric CRF o To establish brain structure/function correlates of neurocognitive impairment in pediatric CRF (imaging, behavioral and psychophysiological methodologies) o Examination of genetic contributions to disease. o Determination of the implications of growth failure and its treatment on morbidity and mortality. o Determination of the prevalence of risk factors for cardiovascular disease. The information obtained from this prospective cohort study of chronic kidney disease will establish natural history and outcome measures for intervention/prevention trials. Applicants should develop testable hypotheses on critical issues that can be resolved in the context of this study. The total sample size for the cohort study is projected to be approximately 600. It is anticipated that this number of participants will permit subcohort studies of neurocognitive impairment and cardiovascular disease. STUDY ORGANIZATION This prospective epidemiological study will be a cooperative arrangement of two Clinical Coordinating Centers, one Data Coordinating Center, and the Division of Kidney, Urologic and Hematologic Diseases. Clinical Coordinating Centers are responsible for protocol development, conducting the study, and disseminating research findings. The Clinical Coordinating Centers are required to participate in a cooperative and interactive manner with each other and with the Data Coordinating Center. The Data Coordinating Center will support protocol development and provide sample size calculations, statistical advice, data analysis, data management and quality control, and coordinate the activities of the Steering Committee, and overall study coordination and quality assurance. A Steering Committee composed of the principal investigators of the Clinical Coordinating Centers and the Data Coordinating Center and the NIDDK Project Scientist will be the main governing body of the study. A representative from both NINDS and NICHD will also participate at all steering committee meetings for input regarding research interests and topics specific to these participating Institutes. Each Clinical Coordinating Center, the Data Coordinating Center, and the NIDDK will have one vote of the Steering Committee. The Steering Committee will have primary responsibility for the general organization of the study, finalizing common protocols, facilitating the conduct and monitoring of the studies, and reporting study results. Subcommittees of the Steering Committee will be established as necessary; for example, it is envisioned that committees will be established for study design, forms development, ancillary and sub- studies, recruitment, publications and presentations, and others as necessary. An independent External Advisory Committee (EAC) will be established by the NIDDK, NINDS and NICHD from among experts in areas such as pediatric nephrology, pediatric neurology, pediatric neuropsychology, pediatric cardiology, pediatric endocrinology, nephrology, pathology, biostatistics, epidemiology and ethics, who are not otherwise involved in the study, as well as lay persons. The EAC will review the protocol prior to implementation and monitor protocol performance and participant safety at least annually. Study Phases The timetable for this cohort study may be subdivided into four phases over a five-year period. Phase I (Months 1-6): Development of the Study Protocol. Work to be performed during this phase includes the development of the study protocol by the Steering Committee, including forms for data collection. If necessary, Central Laboratories, including a Central GFR Laboratory, will be established. If the Central NIDDK Biosample Repository is available, it will be used as the study repository for genetic and other material. If the Central NIDDK Biosample Repository is not available or is not chosen as the sample repository at the time the study is in the protocol development phase, an alternative repository for central storage and distribution of samples will need to be established. The DCC will begin computer programming to establish the database for the study. Prior to implementation of the cohort study, the protocol will be reviewed and must be approved by the External Advisory Committee. Phase II (Months 7-30): Recruitment of Cohort Study Participants / Initiate Follow-up. Over this period of 24 months potentially eligible participants will be identified, and will undergo baseline assessment. Those found eligible will be invited to enter into the cohort study. A subcohort of participants will undergo specific neurocognitive, growth or cardiac assessments. Concurrent with recruitment, follow-up of all study participants will be conducted in a standardized fashion over regular intervals. Phase III (Months 31-54): Follow-up. The major activity during this period will be follow-up clinic visits. Renal function will be measured, and additional studies as defined by the final protocol, will be performed in all cohort study participants. A subcohort of participants will undergo specific neurocognitive assessments, cardiovascular studies, or growth assessments. The last follow-up visit of cohort study participants will be scheduled during the final four months of this phase. Phase IV (Months 55-60): Final Data Analysis and Close-out of the Study. During the final six months of the program, the activities include final data analysis and preparation of manuscripts on the findings from the cohort study. The Clinical Coordinating Centers, Data Coordinating Center and all central facilities (excluding the Central Repository) will be closed-out in the last two months of this phase of the study. It is anticipated that the NIDDK will maintain the Central Repository for genetic and other material beyond the five years of this program. MECHANISM OF SUPPORT This RFA will use NIH U01 award mechanism. The NIH (U01) is a cooperative agreement award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award". The anticipated award date is September 30, 2003. FUNDS AVAILABLE The NIDDK, NINDS and NICHD plan to commit approximately $2,000,000 in FY 2003 to fund two Clinical Coordinating Centers and one Data Coordinating Center. An applicant should request a project period of five years. It is anticipated that the award for the DCC will be approximately $600,000 direct costs (no more than $800,000 total costs) per year. The amount awarded to each CC will vary between $400,000 to $500,000 direct costs (no more than $600,000 total costs) per year. Although the financial plans of the NIDDK, NINDS and NICHD 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. At this time, it is not known if this RFA will be reissued. 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 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 ability to recruit and retain a sufficient number of participants into this study is the most important requirement for a successful Clinical Coordinating Center. It is expected that each Clinical Coordinating Center will recruit a total of 300 participants over a period of 24 months. The Clinical Coordinating Centers and the Data Coordinating Center must also participate in a collaborative and interactive manner to develop the study protocol and carry out the study. Cooperative Agreement Terms and Conditions of Award The following terms and conditions will be incorporated into the award statement and provided to each Principal Investigator as well as to the institutional officials at the time of the award. These terms are in addition to, not in lieu of, otherwise applicable Office of Management and Budget (OMB) administrative guidelines, HHS Grant Administration Regulations at 45 CFR Part 74 and 92, and other HHS and NIH Grants Administration policy statements. The administrative and funding instrument used for this program is the cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with awardees is anticipated during the performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with the cooperative agreement concept, the dominant role and prime responsibility for the planned activity reside with the awardees for the project as a whole, although specific tasks and activities in carrying out the activity will be shared among the awardees and NIDDK Project Scientist. Awardees' Rights and Responsibilities: Awardees will have substantial and lead responsibilities in all tasks and activities. These include protocol development, enrollment of study participants, data collection, quality control of the data, management of the study, final data analysis and interpretation, and preparation of publications. The awardees agree to work cooperatively with the other Clinical Coordinating Centers and the Data Coordinating Center and agree to follow the common protocol developed by the Steering Committee. The awardees agree also to transmit the trial data in a timely manner. Awardees will retain custody of and have primary rights to their data developed under these awards for the duration of the awards, subject to Government (e.g., NIDDK, NIH, or PHS) rights or access consistent with current HHS and NIH policies. Patient samples will be stored and retained in the Central Repository, and the samples will be available to study investigators and to other interested investigators. NIDDK Staff Responsibilities: The NIDDK will name a Project Scientist whose function will be to assist the Steering Committee in carrying out the trial. The Project Scientist will have substantial scientific- programmatic involvement in assisting protocol development, quality control, interim data analysis, final data analysis and interpretation, preparation of publications, and will provide assistance in coordination and performance monitoring. The NIDDK Project Scientist will also serve as Executive Secretary of the External Advisory Committee. The NIDDK program director assigned to administer the award will also serve as the Project Scientist, with substantial involvement above and beyond the normal program stewardship. The NIDDK reserves the right to terminate or curtail the study in the event of difficulties in recruitment, or other shortcomings in carrying out the study protocol, or human subject or ethical issues that may dictate a premature termination. Collaborative Responsibilities: The Steering Committee, composed of the Principal Investigators of the Clinical Centers, and the principal investigator of the Data Coordinating Center, the Chairperson of the Steering Committee, experts in the fields of pediatric neurology, endocrinology and cardiology and the NIDDK Project Scientist, will be the main governing board of the study. This committee will have the primary responsibility for developing the study protocol, facilitating the conduct of participant follow-up and testing, monitoring completeness of data collection adherence to the protocol, timely transmission of the data to the DCC, and reporting the study results. It will also be responsible for establishing study policies in such areas as access to patient data and specimens, ancillary studies, publications and presentations, and performance standards. Each member of the Steering Committee will have one vote (NIDDK will have one vote), and all major scientific decisions will be determined by a majority vote of the Steering Committee. A Chairperson will be chosen by the NIDDK from among the Steering Committee members (but not the NIH Project Scientist) or alternatively, from among experts in pediatric nephrology who are not participating directly in the trial. External Advisory Committee: An independent External Advisory Committee will be selected by the NIDDK, NINDS and NICHD. This group will include experts in pediatric nephrology, pediatric neurology, pediatric neuropsychology, pediatric cardiology, pediatric endocrinology, nephrology, biostatistics, epidemiology, and lay representatives, who are not otherwise involved in the trial. The External Advisory Committee will review the study protocol prior to implementation and evaluate interim and final results, monitor data quality, participant safety, and provide operational and policy advice to the Steering Committee and to the NIDDK. The NIDDK Project Scientist will serve as Executive Secretary of the Committee. The members of the Committee will review progress and report to the NIDDK at least once each year, or more often if necessary. Approval of the protocol by the Committee is necessary prior to implementation. Arbitration: Any disagreement that may arise on scientific/programmatic matters (within the scope of the award) between the recipient and the NIDDK may be brought to arbitration. An arbitration panel will be composed of three members, one selected by the Steering Committee (with the NIDDK member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NIDDK, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16, or the rights of the NIDDK under applicable statutes, regulations, and terms of award. 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: Marva M. Moxey-Mims, M.D., Division of Kidney, Urologic, and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard Room 639, MSC 5458 Bethesda, Maryland 20892-5458 (for express or courier service use 20817) Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: mm726k@nih.gov Emmeline Edwards, Ph.D. Systems and Cognitive Neuroscience National Institute of Neurological Disorders and Stroke 6001 Executive Blvd. Rm. 2109 Rockville, MD 20892-9527 Telephone: (301) 496-9964 FAX: (301) 402-2060 Email: ee48r@nih.gov Lynne Haverkos, M.D., M.P.H. Child Development and Behavior Branch National Institute of Child Health and Human Development 6100 Executive Boulevard Room 4B05, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6881 FAX: (301) 480-0230 Email: haverkol@mail.nih.gov o Direct your questions about peer review issues to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities National Institute of Diabetes, Digestive, and Kidney Diseases 6707 Democracy Boulevard Room 752, MSC 5452 Bethesda, Maryland 20892-5452 Bethesda, Maryland 20827 (for courier service) Telephone: (301) 594-8897 Fax: (301) 480-3505 Email: fc15y@nih.gov o Direct your questions about financial or grants management matters to: Teresa Farris Marquette Grants Management Specialist Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Room 728MSC 5452 6707 Democracy Boulevard Bethesda, Maryland 20892-5452 (for express/courier service use 20817) Telephone: (301) 594-7682 FAX: (301) 480-3504 Email: tf102y@nih.gov Rita Sisco Grants Management Officer National Institute of Neurological Disorders and Stroke 6001 Executive Blvd. Rm. 3265 Rockville, MD 20892 Telephone: (301) 496-7488 FAX: (301) 402-0219 Email: rr46w@nih.gov Christopher Myers Grants Management Officer National Institute of Child Health and Human Development Building 6100E/Room 8A17 6100 Executive Blvd MSC 7510 Bethesda, MD 20892-7510 Email: cm143g@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes, Digestive, and Kidney Diseases 6707 Democracy Boulevard Room 752, MSC 5452 Bethesda, Maryland 20892-5452 Bethesda, Maryland 20827 (for courier service) Telephone: (301) 594-8897 Fax: (301) 480-3505 Email: fc15y@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: Clinical Coordinating Centers Applicants should describe their plans for participating in a multi- center epidemiological study to address the goals as stated in the RFA. Applicants should clearly state the level of GFR to be used as the definition of CKD for different age groups in the pediatric population. The design should include testable hypotheses for the study to address, entry and exclusion criteria, a proposed follow-up visit schedule, and tests to be performed. Sample size estimates and power calculations for each hypothesis should be included. Applicants should provide detailed information regarding the size of the potential pool of chronic kidney disease patients who will be willing to come to participate in screening visits to assess study eligibility, and a reasonable projection of the proportion of patients screened and found eligible that would be willing to participate in a long-term follow-up as outlined in this RFA. Realistic rates of study drop-outs and out-migration should be proposed. Efforts to maintain follow-up of study participants and to collect data from participants recruited from distant locations should be specified. The application should also include plans for data collection, and overall quality control of the study. A major effort will be placed on identifying risk factors for incident cases neurocognitive impairment and worsening with disease progression. To that end, a number of neurophysiological, neuropsychological and neuroanatomical assessment tools may be considered in the design of the cohort study protocol: electroencephalograms (EEG), magnetoencephalograms (MEG) sensory evoked potentials, and cognitive event related potentials (ERPs), functional magnetic resonance imaging (fMRI), neuropsychological assessment including measures of vigilance (attention), visual-spatial tasks, short- and intermediate-term memory, intelligence rating tests. Other measurements that assess more subtle impairment in higher brain function (executive functions) may also be proposed for implementation of the entire cohort or in defined subgroups. However, these recommendations must be supported by published literature and their utility and practicality in a multi- center study as described in this RFA must be considered. Data Coordinating Center Applicants for the DCC component are not required to be a Clinical Coordinating Center within the study, although applicants for the Clinical Coordinating Center sites may also submit a separate application to be the DCC. An administrative plan to coordinate the activities of the Central Laboratories (if required), including quality control and data transmission to the DCC should be included in the application. The experience of the DCC in developing and maintaining web-based data collection systems for multi-center studies should be documented. The proposal should include a Sharing Plan that outlines how specimens and data collected will be shared with the wider scientific community, through eventual transfer of these materials to the NIDDK Central Repository or through another mechanism determined by NIDDK. A description of anticipated problems in carrying out this study and their proposed solutions must be included in the application. Institutional Support: There should be evidence of strong institutional support for the study. An organizational structure for the study should be set forth in the application, delineating lines of authority and responsibility for dealing with anticipated problems in all general areas as well as stated willingness to follow the commonly agreed-upon protocol. Previous Experience: The applicant should include a succinct discussion of previous relevant research efforts in multi-center studies and epidemiological studies, and any relevant experience/success in working collaboratively with investigators outside their own research institution. Experience in the recruitment and retention of participants for long-term studies should be described. Previous participation in studies of racial and ethnic minority populations should be included. Suggested Personnel Requirements: The application must describe the expertise of key scientific, technical and administrative personnel and include a mechanism for replacing key professional or technical personnel should the need arise. For the Clinical Coordinating Centers, expertise in pediatric nephrology, pediatric neurology, clinical research study management, and clinical trials is required. Personnel may be full-time or part-time and may serve in more than one capacity. A suggested Clinical Coordinating Center study team might include, besides a Principal Investigator, a co-investigator (M.D. or Ph.D.), study coordinators, appointment-scheduler or administrative assistant and data entry clerk. For the Data Coordinating Center, personnel with training and experience in biostatistics, data management, computer programming and database development are required. Experience in the use of web- based data collection systems in a multi-center study setting is also necessary. Budget Preparation by Year Applicants must include an adequately justified year-by-year budget, reflecting the major changes in proposed activities as the study progress through its various phases. Note that budgets are not to be prepared in modules. The total budget should not exceed $600,000 per year for each Clinical Coordinating Center, or $800,000 per year for the Data Coordinating Center. NIDDK is also adopting a new approach regarding funding of Participating Clinical Centers during the patient recruitment phase. Funds provided to the Clinical Centers after the study is initiated will be allocated for infrastructure costs and for reimbursement for recruitment on a per participant recruited basis. Infrastructure costs normally may include support for items such as personnel, travel, and supplies. Phase I (First 6 months). The budget will be for development of the trial protocol by the Clinical Coordinating Centers in collaboration with the Data Coordinating Center. The Data Coordinating Center will establish the database necessary to accommodate the data transmitted by the Clinical Coordinating Centers. A web-based technology for data transmission will be established in Phase I that will be efficient, and will protect study participant privacy. The DCC will identify and establish subcontracts with Central Laboratories (if required by the study protocol) and other support centers as necessitated by the protocol. It is expected that the DCC will purchase all the necessary hardware and software for data transmission. The budget for this period should include only those personnel actively involved in protocol development. The travel budget for Phase I should be estimated based on travel for two key investigators to attend two-day, monthly meetings of the Steering Committee in the Washington, D. C. area. Phase II (Months 7 - 30). The budget for the Clinical Coordinating Centers should reflect the level of effort necessary to recruit the entire study cohort and perform baseline and follow-up studies. Costs should be included for specialized studies of renal function, neurocognitive function, growth and cardiovascular studies. The Data Coordinating Center will receive and store the data transmitted by the Clinical Coordinating Centers, assess its completeness, provide feedback to the Clinical Coordinating Centers regarding data quality, and prepare progress reports for the Steering Committee and the group of external advisors on the progress of the cohort study. The budget should include costs associated with a Central Biochemistry Laboratory and a Central GFR Laboratory. In addition, the budget should include costs associated with a central study repository for samples, whether or not the Central NIDDK Repository is selected to carry out that function. However, the Data Coordinating Center should budget staff to coordinate the activities of the Central Repository as it pertains to quality control. This phase of the program will require meeting approximately every four months in the Washington, D.C. area. The travel budget for Phase II should be estimated based on travel for the Principal Investigator and the Study Coordinator as well as any other key personnel for both the Clinical Centers and the Data Coordinating Center. Budgets for the Data Coordinating Center should include travel for any consultants. Travel for key staff at the Clinical Centers and the Data Coordinating Center should be budgeted each year for central training. Phase III (Months 31-54). The major activities in this phase are follow-up and assessment of cohort study participants. Renal function measurements and other specialized studies will continue during follow- up. A Central Biochemistry Laboratory and Central GFR Laboratory will continue to operate to handle follow-up data. The Central Repository will receive, process, and store specimens from cohort study participants. In-clinic visit follow-up of the cohort study participants will be terminated during the last several months of Phase III. Three meetings of the investigators should be budgeted for each year of this phase of the study. Central training will occur annually and key staff should be budgeted to travel to the Washington, D. C. area. For a Clinical Coordinating Center, the budget should request support for the minimum number of full and/or part-time staff to successfully carry out the proposed cohort study. A Clinical Coordinating Center personnel list could include a principal investigator, co-investigator, study coordinators, appointment scheduler / administrative assistant, and data entry clerk. For applications for the Data Coordinating Center, the budget should include the time and effort of key personnel for database management, programming, data analysis, and administrative functions to support the collaborative group. The budget should also include subcontracts for a Central GFR Laboratory and Central Biochemistry Laboratory. As noted previously, funding for the Central Repository will be directly from the NIDDK. Travel by Data Coordinating Center staff to Washington, D.C. for a meeting with the group of external advisors should be planned and budgeted for annually. Phase IV (Months 55-60). Final Data Analysis and Close-out of the Clinical Coordinating Centers, the Data Coordinating Center, Central Biochemistry Laboratory and the Central GFR Laboratory. The major activities include final data analysis of the cohort study. Manuscripts describing these findings will be prepared and submitted to peer- reviewed scientific journals for publication. The Clinical Centers, the Data Coordinating Center and the Central Laboratories will be closed-out during the last two months of this phase of the program. Two meetings of the Steering Committee and one meeting of the group of external advisors will be held in Phase IV. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center For Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes, Digestive, and Kidney Diseases 6707 Democracy Boulevard Room 752 MSC 5452 Bethesda, Maryland 20892-5452 Bethesda, Maryland 20817 (for express/courier service) APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDDK in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the NIDDK National Advisory Council REVIEW CRITERIA Criteria for Clinical Coordinating Centers and Data Coordinating Center: The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. o OTHER REVIEW CRITERIA: Applicants are expected to address issues identified under the following sections in this RFA: SPECIAL REQUIREMENTS, SUBMITTING AN APPLICATION/SUPPLEMENTAL INSTRUCTIONS as well as the OBJECTIVES OF THE RESEARCH PROGRAM. All applications will be reviewed according to the criteria listed below. Clinical Coordinating Centers: o Patient access and study population: The ability to access a large number of potentially eligible pediatric patients with chronic kidney disease is a critical element of the application. Realistic estimates must be made regarding the number of patients who may prove eligible for the study. o Willingness to participate in a collaborative study: The Clinical Coordinating Centers and the Data Coordinating Center must participate in a collaborative and interactive manner to develop the study protocol and carry out the study. There should be evidence of prior experience in working collaboratively in carrying out a developed protocol. Data Coordinating Center: o Understanding of the scientific, statistical, logistical, and technical issues underlying multicenter studies. o Evaluation of the comprehensiveness, stability, adaptability and accessibility of the database. o Adequacy of the proposed plans for acquisition, transfer, management and analysis of data, quality control of data collection and monitoring and overall coordination of the collaborative effort. o The administrative, supervisory, and collaborative arrangements for achieving the goals of the program, including willingness to cooperate with the principal investigators of the Clinical Coordinating Centers and the NIDDK. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: January 21, 2003 Application Receipt Date: February 21, 2003 Peer Review Date: July 2003 Council Review: September 2003 Earliest Anticipated Start Date: October 1, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. o Geographic Distribution (Clinical Coordinating Centers only) REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub- populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH- defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.849, 93.864, 93.853 and 93.865 and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284)and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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