PROSPECTIVE COHORT STUDY OF CHRONIC RENAL INSUFFICIENCY Release Date: September 21, 2000 RFA: DK-01-005 (Reissued as RFA-DK-07-502) National Institute of Diabetes and Digestive and Kidney Diseases Applicant Information Forum Date: December 11, 2000 Letter of Intent Receipt Date: February 28, 2001 Application Receipt Date: March 28, 2001 PURPOSE The Division of Kidney, Urologic, and Hematologic Diseases (DKUHD) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has a longstanding interest in supporting epidemiological studies of end-stage renal disease (ESRD) patients. A substantial number of these studies, many emanating from the United States Renal Data System (URSRDS), has led to significant improvements in the treatment and quality of life of ESRD patients. In contrast, our understanding of the epidemiology of chronic renal disease prior to ESRD, during a period of reduced renal function or chronic renal insufficiency, is far less advanced. The NIDDK invites cooperative agreement applications for investigators to establish Clinical Centers to conduct a seven-year prospective cohort study of patients with chronic renal insufficiency. This Request for Applications (RFA) also seeks a Data Coordinating Center to assist the Clinical Centers in carrying out this cohort study. The primary goals of the cohort study in persons with chronic renal insufficiency with mild to moderately reduced levels of renal function are two-fold, to determine the risk factors for accelerated decline in renal function, and to determine the incidence and identify risk factors for cardiovascular disease. Because of the relative and increasing importance of diabetes as a cause of ESRD, approximately one-half of the study participants in the cohort study will be diabetic. 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, Prospective Cohort Study of Chronic Renal Insufficiency , is related to one or more of the priority areas. Potential applicants may obtain a copy of Healthy People 2010 at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, for-profit and non-profit institutions, public and private organizations, such as universities, colleges, hospitals, units of State and local government, and eligible agencies of the Federal government. Foreign institutions are not eligible to apply. Racial/ethnic minorities, women, and persons with disabilities are encouraged to apply as Principal Investigators. An institution or organization may apply for both a Clinical Center and a Data Coordinating Center. However, separate applications are required for each of these study components. The same person may not serve as the Principal Investigator of a Clinical Center and the Data Coordinating Center. MECHANISM OF SUPPORT The administrative and funding instrument to be used for these awards will be the cooperative agreement (U01). The cooperative agreement is an assistance mechanism in which substantial NIDDK scientific and programmatic involvement is anticipated during the performance of the activity. Under the cooperative agreement, the NIDDK’s purpose is to support and encourage the recipient’s activities by working jointly with the awardees in a partnership role, but not to assume direction, prime responsibility, or dominance. Details of the responsibilities, relationships, and governance of a study funded under a cooperative agreement are described under the section entitled Terms and Conditions of Award. The total project period for applications submitted in response to this RFA is seven years. The anticipated award date is September 30, 2001. At this time, the NIDDK has not determined whether or how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE The NIDDK plans to make six awards for Clinical Centers and one award for a Data Coordinating Center. Approximately $4,000,000 total cost (direct plus facilities and administrative costs) is expected to be available during year one of the study. In all subsequent years $6,000,000 will be available under this RFA. It is anticipated that the award for each Clinical Center will be about $500,000 total cost in year one and $650,000 total cost in all subsequent years. The award for the Data Coordinating Center will be about $1,000,000 total cost in year one and approximately $2,100,000 total cost in all subsequent years of the program. If the budget for either a Clinical Center or Data Coordinating Center exceeds the amount specified above the applicant must contact the Clinical Trials Program Director (contact information in the section, INQUIRIES), DKUHD, NIDDK, prior to submitting the grant application. The number of awards to be made is dependent on the receipt of a sufficient number of applications of high scientific merit and availability of funds. Although this program is provided for in the financial plans of the NIDDK, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. RESEARCH OBJECTIVES Background End-stage renal disease is an important medical and public health problem in the United States that disproportionately affects racial and minority populations. According to the USRDS, at the end of 1997 over 300,000 patients were receiving treatment for ESRD and nearly 80,000 new patients started ESRD treatment during the same year. The number of ESRD patients is steadily increasing. The absolute number of ESRD patients has more than doubled and the incidence rate has doubled from 1988 to 1997. Two important factors associated with this dramatic rise are the increasing prevalence of diabetes and the continuing high rates of uncontrolled high blood pressure observed in this country. Despite the prominence of diabetes and hypertension in increasing the risk of developing chronic renal disease the factors responsible for accelerating decline in renal function once chronic renal disease has been established are considerably less well defined. While there has been substantial interest during the past two decades to better understand the risk factors for progression of chronic renal disease (i.e., accelerated decline in renal function), there have been only a small number of epidemiological studies examining this issue. Of the studies conducted, all of them have had important shortcomings. Their major limitations include retrospective study design, small sample size, short-term follow-up, use of select populations such as clinical trial participants, lack of ethnic and racial diversity of the study populations, exclusion or low rates of participation of women, use of crude measures of renal function, limited assessment of potential risk factors, and inclusion of only select causes of renal disease, among others. Therefore, it is not surprising that the demographic, clinical, and laboratory factors examined in these studies explain only a small percentage of the variability in renal function decline between patients. This suggests that there remains a significant number of important but as of yet unidentified patient, genetic, environmental, and health care utilization related risk factors for rapid loss of renal function in persons with established chronic renal disease. The survival of ESRD patients is significantly poorer when compared to patients with other major illnesses such as prostate and colon cancer. In 1996 the adjusted (for age, race, sex, and primary cause of ESRD) death rate for all incident ESRD patients was 19.8 per 100 patient years at risk for patients in the first year of ESRD therapy. The death rate for ESRD patients with renal disease due to diabetes is even higher. Strikingly, cardiovascular disease mortality rates among all ESRD patients are approximately 10 to 20 times those in the general population with cardiac arrest of unknown cause, acute myocardial infarction, and all other cardiac causes accounting for nearly one-half of the deaths in hemodialysis patients greater than 20 years of age. In contrast to the many studies of cardiovascular disease in ESRD patients, most notably in those undergoing hemodialysis, there is a noticeable lack of epidemiological studies documenting the occurrence of and risk factors for cardiovascular disease in persons with chronic renal insufficiency in the U.S. However, several small retrospective and prospective studies conducted in Europe suggest that the incidence rate of cardiovascular disease is at least three times more frequent among patients with chronic renal insufficiency resulting primarily from non-diabetic renal disease compared to the general population. In contrast, a recent report from the Framingham Heart Study found that among women, mild chronic renal insufficiency was not associated with an increased risk for cardiovascular events or all-cause mortality in men and in women, whereas in men there was an increase in all-cause mortality but not cardiovascular events. The impact of chronic renal disease on morbidity and mortality in diabetic patients is especially striking. For example, in insulin-dependent diabetic patients with overt nephropathy, the excess mortality may be up to one hundred times that of an otherwise matched normal population. Much of this mortality burden is due to an excess of cardiovascular deaths, which is over several hundred times higher in young insulin-dependent diabetic patients on renal replacement therapy compared with a normal population. Likewise, the impact of cardiovascular disease among non- insulin dependent diabetics with nephropathy is substantial. The reasons for the increased risk for cardiovascular disease among diabetic and non-diabetic patients with nephropathy are unclear. Although traditional risk factors such as hypertension, hyperlipidemia, hyperglycemia, tobacco use, and physical inactivity are considered important risk factors for cardiovascular disease in patients with chronic renal insufficiency, the relative importance of each of these risk factors compared to nontraditional risk factors (i.e., chronic inflammation, infection, oxidative stress, elevated homocysteine levels, fibrinogen, etc.), is not known. Thus, further studies are needed to determine the risk factors for cardiovascular disease and the relative magnitude of their effects in persons with chronic renal insufficiency and to evaluate the contribution of uremia to the pathophysiology of cardiovascular disease. These studies, however, must include ethnically and racially diverse populations with chronic renal diseases representing the major causes of ESRD in the United States. Research Goals and Scope of the Activity The purpose of this RFA is to solicit applications from investigators proposing to serve as a Clinical Center or a Data Coordinating Center to develop and conduct a multi-institution, prospective cohort study of patients with chronic renal insufficiency. Investigators will collaborate to develop a protocol with primary emphasis on assessing risk factors for both the accelerated loss of renal function and the occurrence of cardiovascular disease. Patients with chronic renal disease and decreased renal function are most likely to be identified in a time-efficient and cost-effective manner from established sources of medical care such as outpatient clinics and health maintenance organizations where information on serum creatinine is readily available. This RFA does not intend to support large-scale screening programs utilizing tests of renal function (i.e. serum creatinine) to recruit cohort study participants. However, there may be certain circumstances where specialized screening may be performed by the Clinical Centers to recruit minority or other participants at high risk for accelerated decline in renal function into the cohort study that otherwise would not be identified via traditional sources of medical care. Potentially eligible participants with a serum creatinine value suggesting that they would meet the glomerular filtration rate (GFR) eligibility range (see below) will be further assessed during a period of baseline screening. Upon entry into the cohort study, participants will be regularly followed and assessed by Clinical Center staff for a period, on average, of approximately 5 years. Baseline and follow-up measurements will be standardized across the Clinical Centers. Central Laboratories and Central Reading Centers will be utilized to maintain strict quality control of selected tests and procedures. A Central Repository will be established by the NIDDK to genetic and other material. The two primary goals of this solicitation are as follows: To determine risk factors for rapid progression of chronic renal disease. To determine the incidence of and risk factors for cardiovascular disease. The following are examples of the types of secondary goals that should be planned for the cohort study. To describe the relationship between baseline and follow-up levels of microalbuminuria (urinary albumin excretion > 30 mg/24 hours), proteinuria (urinary albumin excretion > 1g/24 hours) and subsequent loss of renal function, treatment for ESRD, cardiovascular disease morbidity, and cardiovascular disease mortality in different gender and ethnic groups. To examine factors associated with worsening of cardiovascular disease. To plan and conduct gender and racial/ethnic subgroup analyses as warranted by the evidence. To describe patterns of nutrition and the development of malnutrition. To assess the rates and causes of hospitalization, and the prevalence and incidence of other important co-morbid events and diseases. To document overall and cause-specific mortality rates. To describe patterns and levels of use of health services resources. To measure quality of life and psychological factors that may be associated with decline in renal function and the development of cardiovascular disease. To identify practice patterns of physicians with respect to chronic renal insufficiency patients. To obtain biological specimens (to be maintained in a central repository) for concurrent and future evaluation of genetic and biochemical risk factors for accelerated decline in renal function and development/progression of cardiovascular disease and other diseases. To collect and evaluate information on family members of the cohort study participants that may be useful in studies of genetic factors associated with increased susceptibility to chronic renal disease and cardiovascular disease. To determine the incidence of cardiovascular disease, other co-morbid medical conditions, hospitalization, and mortality in patients after treatment for ESRD has been initiated. To describe the patterns of access to chronic renal insufficiency and ESRD therapy. To conduct subgroup analyses by cause of renal disease, gender, and ethnicity for renal disease progression and cardiovascular disease. The purpose of this RFA is to establish a cohort of patients with chronic renal insufficiency whose distribution of clinically and pathologically diagnosed causes of renal disease represents, as much as feasible, the major causes of ESRD found in the U.S. The goal of this RFA is to recruit a cohort of study participants whose racial, ethnic, and gender composition reflects the United States end-stage renal disease patient population. It is envisioned that diabetic patients will comprise approximately 50% of the cohort. The total sample size for the cohort study is projected to be approximately 3,000. It is anticipated that this number of participants will permit subgroup analyses of the major outcomes (renal function decline, ESRD, incidence of cardiovascular disease) of the study among diabetic compared to non- diabetic patients and by other primary causes of renal disease. Currently there are no widely accepted and standardized definitions for mild and moderate chronic renal insufficiency. For the purposes of this RFA and to provide guidelines for targeting populations for further screening for entry into the cohort study, the lower value for serum creatinine in women and men with mild chronic renal insufficiency is suggested as 1.4 mg/dl and 1.7 mg/dl, respectively. It is envisioned that the range of renal function as assessed by the glomerular filtration rate (GFR) will be approximately 30 70 ml/min/1.73m2. It is anticipated that GFR will be measured twice during baseline and once annually during follow-up. Although levels of serum creatinine to be considered for initial screening and a study eligibility GFR range are suggested in this RFA, investigators may wish to propose their own criteria for these renal function parameters. However, it is important to note that any recommendations for study entry based on GFR must be accompanied by evidence from the published literature that a sufficient number of cohort study participants will not only have renal function decline at an accelerated rate but also experience the necessary number of cardiovascular disease events during the period of time specified in this RFA to achieve the goals of the study. Because cardiovascular disease imposes such a significant burden on ESRD patients, a major emphasis of the cohort study will be observing the treated natural history of cardiovascular disease. Evidence of cardiovascular disease will be carefully assessed during baseline and during follow-up. A major effort will be placed on identifying risk factors for incident cases of cardiovascular disease and worsening of established disease. To that end the following tests and procedures to assess cardiovascular disease status may be considered in the design of the cohort study protocol: electrocardiogram, echocardiography, ultrasound measurement of the carotid arteries, and electron-beam computed tomography of the heart. Other measurements of cardiovascular disease may also be proposed for implementation in the entire cohort study population or 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. Because little is known about the natural history of cardiovascular disease in patients undergoing renal replacement therapy, the cohort study will continue to follow participants after they reach end-stage renal disease. The information obtained from this prospective cohort study of chronic renal insufficiency will serve to identify the point at which promising interventions could be evaluated in clinical trials. In addition, professional and public education programs to prevent ESRD and to reduce the burden of cardiovascular disease in patients with chronic renal insufficiency and ESRD in the U.S. will benefit from these findings. Study Phases The timetable for the cohort study may be subdivided into four phases over a seven-year period. Phase I (Months 1-6): Protocol Development. Work to be performed during this phase includes the development of the study protocol, including forms for data collection, for the cohort study by the Steering and Planning Committee. Central Laboratories, and Reading Centers. A Central Repository for genetic and other material will be established and supported directly by the NIDDK. The Data Coordinating Center 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 external advisors. Phase II (Months 7-24): Recruitment of Cohort Study Participants/Initiate Follow-up and Clinic Visit Assessment. Over this period of 18 months potentially eligible participants will be identified, invited to the Clinical Centers for baseline assessment, and those found eligible will be asked to enter into the cohort study. Concurrent with recruitment, follow-up of all study participants will be conducted in a standardized fashion over regular intervals. The external advisors will review the progress of recruitment at its mid- point (about Month 16 in Phase II) and recommend to the NIDDK whether the cohort study should continue. Preparation of manuscripts describing recruitment of the cohort, baseline demographic and clinical characteristics of the participants, and the cross-sectional relationships between level of renal function and cardiovascular disease status using clinical, demographic, and laboratory measurements will begin to be developed in the latter months (Months 18 to 24) of this phase. Phase III (Months 25-78): Follow-up of Cohort Study Participants and Participants Post-ESRD Treatment. The major activity during this period will be follow-up clinic visits. Questionnaires will be administered to assess various demographic, nutritional and quality of life factors, renal function will be measured, cardiovascular studies will be performed, and will be laboratory tests performed in all cohort study participants. Follow-up and data collection on cohort study participants who reach ESRD will be performed after initiation of renal replacement therapy (renal transplantation, hemodialysis, peritoneal dialysis) with modification of data collection, measurements, and follow-up visit schedule, as necessary and described in the study protocol. Follow-up assessment of patients who have reached ESRD includes determining the incidence of cardiovascular disease, other co- morbid medical conditions, frequency and cause of hospitalization, overall and cause-specific mortality, selected laboratory measurements and procedures to evaluate cardiovascular disease. Manuscripts will be prepared and submitted for publication on the cross-sectional and initial longitudinal findings from the study. The last follow-up visit of cohort study participants will be scheduled during the final four months of this phase. Data collection for persons who previously reached ESRD will also be terminated at that time. Phase IV (Months 79-84): Final Data Analysis and Close-out of the Clinical Centers and the Data Coordinating Center. 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, including the morbidity and mortality experience in persons treated for ESRD. The Clinical Centers, the 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 National Institutes of Health will maintain the Central Repository for genetic and other material beyond the seven years of this program. Study Outline STUDY COMPONENTS Clinical Centers The Clinical Center investigators will have direct responsibility for developing the study protocol and uniform data collection forms, identifying potentially eligible study participants, assessing their eligibility to participate in the cohort study, conducting baseline and follow-up visits, obtaining blood, urine, and other biological samples, performing renal function and other measurements, collecting data, and transmitting it in a timely fashion to the Data Coordinating Center. They, along with staff from the Data Coordinating Center and the various central laboratories and reading centers, will also be responsible for making presentations at scientific meetings and writing and publishing manuscripts on the findings of their studies. Data Coordinating Center The Data Coordinating Center will be responsible for assisting the Clinical Center investigators through the Steering and Planning Committee in developing the cohort study protocol. The Data Coordinating Center will create data collection forms based on input from the Steering and Planning Committee. The Data Coordinating Center will be responsible for establishing a database to accommodate data sent by the Clinical Centers, developing a web-based data transmission system, assessing data quality and completeness throughout the study, and provide general assistance to the Clinical Centers to maintain long-term participation of the cohort study subjects. The Data Coordinating Center will also perform analyses as suggested by the Clinical Centers, Central Laboratories and Central Reading Centers, as well as propose original analyses to the collaborative group for their consideration. The Data Coordinating Center will prepare periodic reports on the progress of the study, including data quality control, and interim and final results to the Steering and Planning Committee, the NIDDK and the group of external advisors. The Data Coordinating Center will be responsible for arranging meetings and conference calls of the Steering and Planning Committee, meetings of the external advisors, and will perform other administrative functions necessary to coordinate the efficient operation of the collaborative study group. The Data Coordinating Center will establish, via subcontracts, Central Laboratories and Reading Centers, as deemed necessary by the study protocol. They will also provide administrative coordination for the Central Repository to be established and directly supported by the NIDDK to store genetic material and other biological specimens obtained from cohort study participants. Steering and Planning Committee The primary governing body of the study will be the Steering and Planning Committee comprised of each of the Principal Investigators of the Clinical Centers and the Principal Investigator of the Data Coordinating Center, the Chairperson of the Steering and Planning Committee, and the NIDDK Project Scientist (described in detail under Terms and Conditions). The Steering and Planning Committee will develop policies for the study pertaining to access to patient data and specimens, ancillary studies, performance standards, and publications and presentations. They will meet initially to develop the study protocol and subsequently to discuss the progress of the study and to consider problems arising during its conduct. The Steering and Planning Committee may establish subcommittees on such topics as recruitment, measurement of renal function, risk factor assessment for renal disease and cardiovascular disease, cardiovascular studies, quality control, and publications and ancillary studies. Small working groups may be established to prepare manuscripts and presentations. External Advisors An independent group of experts in areas such as nephrology, cardiology, preventive medicine, epidemiology, nutrition, ethics, health economics, and biostatistics who are not otherwise involved in the study will be recruited by the NIDDK to evaluate the proposed protocol and review periodically the progress of the study (described in detail under Terms and Conditions). Project Scientists The NIDDK will identify two Project Scientists for the study. The Project Scientists will assist the Steering and Planning Committee and external advisors in carrying out the study (described in detail under Terms and Conditions). SPECIAL REQUIREMENTS 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. Responsibilities of the Clinical Centers: The participating Clinical Centers will have primary responsibility for developing the study protocol, recruiting a sufficient number of study participants, maintaining high rates of follow-up and data collection, obtaining data of high quality, and interpreting, presenting, and publishing findings from the study. Responsibilities of the Data Coordinating Center: The Data Coordinating Center will assist in protocol development and preparation of scientific publications. The Data Coordinating Center has the major responsibility of creating a database and data collection systems for the Clinical Centers, ongoing evaluation of data quality and performance monitoring of the Clinical Centers, and statistical analyses of the data. (1) 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, data quality control, final data analysis and interpretation, and preparation of publications. The awardees agree to work cooperatively with the other Clinical Centers and agree to follow the common protocol developed by the Steering and Planning Committee. The awardees agree also to transmit the agreed upon study data in a timely manner according to study protocol to the Data Coordinating Center for combination and analysis. 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. (2) NIDDK Staff Responsibilities The NIDDK will name two Project Scientists from within the Division of Kidney, Urologic and Hematologic Diseases whose function will be to assist the Steering and Planning Committee in carrying out the study. The Project Scientists will have experience in nephrology and the development and conduct of multi-center clinical studies. The Project Scientists will have substantial scientific-programmatic involvement in protocol development, quality control, interim data analysis, final data analysis and interpretation, preparation of publications, and coordination and performance monitoring. The NIDDK Project Scientists will have voting membership on the Steering and Planning Committee and will have one vote. One of the NIDDK Project Scientists will also serve as Executive Secretary of the external advisors. The NIDDK reserves the right to terminate or curtail the study (or an individual award) in the event of difficulties in recruiting participants to the cohort study, maintaining high rates of follow-up and data collection/completion of participants tests, in timely data reporting, achieving high levels of data quality, working cooperatively or other major breaches of the protocol, or human subject ethical issues that may dictate a premature termination. The NIDDK Project Scientists will establish the Central Repository for genetic and other material. (3) Collaborative Responsibilities 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. The Steering and Planning Committee, composed of each of the Principal Investigators of the Clinical Centers, the Principal Investigator of the Data Coordinating Center, the NIDDK Project Scientists, and the Chairman of the Steering and Planning Committee, 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 and timely transmission to the Data Coordinating Center, 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 and Planning 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 and Planning Committee. A Chairperson will be chosen by the NIDDK from among the Steering and Planning Committee members (but not the NIDDK Project Scientist) or alternatively, from among experts in the field of nephrology, cardiology, preventive medicine, nutrition, or epidemiology who are not participating directly in the study. An independent group of external advisors, selected by the Director, NIDDK, will review periodically the progress of the study. This group will include experts in the relevant medical, epidemiological, statistical, and ethics fields who are not otherwise involved in the study. The external advisors will review the study protocol and evaluate results, monitor data quality, participant safety, and provide operational and policy advice to the Steering and Planning Committee and to the NIDDK regarding the status of the study. One of the NIDDK Project Scientists will serve as Executive Secretary of the group. The members of the group will review progress and report to the NIDDK at least once each year, or more often if necessary. (4) Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award) between recipients and the NIDDK may be brought to arbitration. An arbitration panel will be composed of three members, one selected by the Steering and Planning 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. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. Investigators should consider the available evidence and discuss the NIH Phase III Clinical Trial requirements for planning analyses of gender or subgroup differences in their applications and protocols, and conducting and reporting on these analyses in reports to NIH and in manuscripts for publication. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. All investigators proposing research involving human subjects should read the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-025.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLS) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. INFORMATION FOR PROSPECTIVE APPLICANTS Open Forum A one-day open information forum will be held for prospective applicants on December 11, 2000, from 1 p.m. to 4 p.m. (EST) in Building 1, Room 151, on the campus of the National Institutes of Health. At this forum NIDDK program staff will address any questions that prospective applicants might have regarding the clinical/scientific concepts of the RFA. Attendance is not required and is not a pre-condition for submission of an application. Applicants planning to attend this meeting should submit their questions in writing (electronic mail is acceptable) to John W. Kusek, Ph.D. at the address listed under INQUIRIES at least two weeks in advance of the forum. Information on the Web For those who cannot attend the December 11 forum, a website will contain a summary of that meeting. It will also contain questions of general interest asked by prospective applicants and their answers. Prospective applicants are encouraged to check this website frequently while preparing an application. The website can be reached through the following URL: http://www.niddk.nih.gov/fund/crfo/rfas.htm. LETTER OF INTENT Prospective applicants are asked to submit, by February 28, 2001, a letter of intent that includes a descriptive title of the proposed research, name, address, and telephone number of the Principal Investigator, identities of other key personnel and participating institutions, and number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information it contains allows the NIDDK staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes, Digestive, and Kidney Diseases 6707 Democracy Boulevard Room 653, MSC 5452 Bethesda, Maryland 20892-5452 (for courier service use 20817) Telephone: (301) 594-8885 Fax: (301) 480-3505 Email: hagana@extra.niddk.nih.gov APPLICATION PROCEDURES Applications must be submitted on the standard research grant application form PHS 398 (rev. 4/98). Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, Maryland 20892-7910, telephone (301) 710-0267, E-mail: GrantsInfo@nih.gov. The RFA label available in the form PHS 398 must be affixed to the bottom of the face page. 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. For purposes of identification and processing, item 2 of the face page of the application must be marked YES and the RFA number and the words Prospective Cohort Study of Chronic Renal Insufficiency must be typed in. The RFA label and line 2 of the application should both indicate the RFA number. The RFA label must be affixed to the bottom of the face page. 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. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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 653 MSC 5452 Bethesda, Maryland 20892-5452 (For express/courier service, use 20817) Applications must be received by March 28, 2001. If an application is received after this 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 a substantial revision of an application already reviewed, but such an application must follow the guidance in the PHS 398 applications instructions for the preparation of revised applications, including an introduction addressing the previous critique. Information to be Included in Applications Details of the Proposed Study Protocol: Applicants for a Clinical Center should describe a research plan involving multi-center participation to address the objectives of the study and to reach the study goals. Applicants should outline the rationale and background of the proposed prospective cohort study and follow-up data collection of participants after they have reached ESRD. Major entry and exclusion criteria, including measures of renal function, should be described and justified. The type of laboratory and medical tests, questionnaires, and other data collection should be specified and the frequency of assessment during follow-up must be specified. Particular emphasis should be given to measurement of renal function and tests to determine prevalence of cardiovascular disease at baseline and its incidence and/or progression during follow-up. An application for a Clinical Center must provide credible evidence of the size of the potential pool of participants based on an objective measure of renal function, an estimate of the proportion of persons with mild to moderate chronic renal insufficiency who will be willing to come to the Clinical Center to participate in a screening visit to assess cohort study eligibility, and a reasonable projection of the proportion who were screened and found eligible that would be willing to commit to participation in a long-term follow-up study as described in this RFA. A detailed description of the gender and racial/ethnic composition of the population of chronic renal insufficiency patients targeted for recruitment as well as a comprehensive plan to recruit a cohort of patients reflecting the make-up of the U.S. end-stage renal disease patient population must be provided. Realistic rates of study drop- outs and out migration from the study should be proposed. Efforts to maintain follow-up of cohort study participants must also be described. Applicants must consider the sample size proposed in this RFA and include a discussion of event rates (ESRD, incident cardiovascular disease), the expected rate of decline in renal function (GFR) anticipated in the cohort, and the statistical power of the study for subgroup analyses (diabetics vs. non-diabetics, within major causes of renal disease, gender, and racial/ethnic subgroup). Recommendations for serum creatinine values for screening and GFR eligibility range for the cohort study differing from those included in the RFA must be justified with published information. Applications for the Data Coordinating Center should also include a proposed design for a prospective cohort study of chronic renal insufficiency patients as described in this RFA, a plan for the study of cohort study participants post-initiation of renal replacement therapy, plans for data collection, and overall quality control of the study. Information on proposed plans for study-wide data analysis should be included, including the analysis of the cohort study phase and the post-ESRD treatment follow-up phase. Applicants must also consider the sample size proposed in this RFA and include a discussion of event rates (ESRD, incident cardiovascular disease), the expected rate of decline in renal function (GFR) anticipated in the cohort, and the statistical power of the study for subgroup analyses (diabetics vs. non-diabetics, within major causes of renal disease). An administrative plan to coordinate the activities of the Central Laboratories and Central Reading Centers, including quality control and data transmission to the Data Coordinating Center must be included in the application. The identification and access of genetic material and other biological specimens stored in the Central Repository must also be delineated. A description of anticipated problems in carrying out this study and their proposed solutions should be included in the application. Institutional Support: There should be evidence of strong institutional support for the study, including adequate space in which to conduct participant follow-up (Clinical Centers) and data analysis/management (for the Data Coordinating Center) activities. 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 epidemiological population studies, multi-center clinical trials, 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 Centers, expertise in nephrology, cardiology, and epidemiology is required. Personnel may be full-time or part-time and may serve in more than one capacity, as appropriate. A suggested Clinical Center study team may include besides a Principal Investigator, a co-investigator (M.D. or Ph.D.), study coordinators, GFR technician, appointment scheduler/administrative assistant and data entry clerk. Expertise required for the Data Coordinating Center must also include expertise in biostatistics, epidemiology, data management, computer programming and database development. Experience in the use of web-based data collection systems in a multi-center study setting is also necessary. Consultants in nephrology, cardiology, nutrition, quality of life, and health resource utilization assessment are also advisable. Budget Preparation by Year Applicants for the Clinical Centers and the Data Coordinating Center 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. Also note that the Central Repository established for the cohort study will be supported directly by the NIDDK and not via a subcontract to the Data Coordinating Center. Phase I (First 6 months of Year 1). The budget will be for development of the protocol by the Clinical 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 Centers. A web-based technology for data transmission will be established in Phase I that will protect study participant privacy. The Data Coordinating Center will identify and establish subcontracts with Central Laboratories and Central Reading Centers as specified by the study protocol. It is expected that the Data Coordinating Center will purchase the hardware and software necessary for data transmission from the Clinical Centers. The proposed study protocol will also be reviewed by the external advisors and must be approved prior to its implementation. The travel budget for Phase I should be estimated based on travel for two key investigators to attend two-day, every two months meetings of the Steering and Planning Committee in the Washington, D. C. area. Phase II (Months 7-24). The budget for the Clinical Centers should reflect the level of effort necessary to recruit the entire study cohort and perform baseline and follow-up studies. Follow-up data will also be collected by the Clinical Centers. Costs should be included for specialized studies of renal function (GFR measurement) and cardiovascular studies (echocardiography, carotid ultrasound, electron beam computed tomography). The Data Coordinating Center will receive and store the data transmitted by the Clinical Centers, assess its completeness, provide feedback to the Clinical Centers regarding data quality, and prepare progress reports for the Steering and Planning 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, a Central GFR Laboratory, and central facilities for reading the echocardiography, carotid ultrasound, and electron beam computed tomogaphy). Costs associated with a Central Repository for genetic and biochemical material will be borne directly by the NIDDK. 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 25-78). The major activities in this phase are follow-up and assessment of cohort study participants. Initially, data analysis of the recruitment experience and baseline characteristics of the cohort study participants will be undertaken. The first manuscripts will focus on cross-sectional findings. Subsequently, the manuscripts will deal with longitudinal changes in renal function and occurrence of cardiovascular disease in the cohort and other outcomes of interest. Data analysis will be conducted and papers addressing the secondary goals of the cohort study will also be prepared. Renal function measurements and studies of cardiovascular disease will continue during follow-up. A Central Biochemistry Laboratory, Central GFR Laboratory, and Central Reading Facilities for echocardiography, ultrasound, and electron beam computed tomography 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, including those followed post-ESRD treatment, 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 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 Center personnel list could include a principal investigator, co-investigator, study coordinators, GFR technician, 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, Central Biochemistry Laboratory, Echocardiography Reading Center, Ultrasound Reading Center, and Electron Beam Computed Tomography Reading Center. 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 79-84). Final Data Analysis and Close-out of the Clinical Centers, the Data Coordinating Center, Central Biochemistry Laboratory, the Central GFR Laboratory and Central Reading Facilities for Echocardiography, Ultrasound, and Electron Beam Computed Tomograpghy. The major activities include final data analysis of the cohort study. Final data analysis will also be conducted on the post- ESRD treatment experience of the cohort study participants. Manuscripts describing these findings will be prepared and submitted to peer-reviewed scientific journals for publication. The Clinical Centers, the Data Coordinating Center, the Central Laboratories, and Central Reading Centers will be closed-out during the last two months of this phase of the program. Two meetings of the Steering and Planning Committee and one meeting of the group of external advisors will be held in Phase IV. The following is a list of yearly major activities to assist in the preparation of budgets for each of the five years of the program. Year 1 (Months 1-6). Develop the study protocol and data collection forms for the collaborative studies by means of meetings every two months. The database will be established by the Data Coordinating Center. A web-based data transmission system will also be developed by the Data Coordinating Center. Central Laboratories, and Reading Centers will be identified and established by the Data Coordinating Center. Recruitment plans are further developed by the Clinical Centers. Computer hardware and software will be purchased by the Data Coordinating Center for use by the Clinical Centers. The Central Repository will be identified by the NIDDK. Year 1 (Months 7-12): The Clinical Centers begin recruitment and screening of cohort study participants. Participant follow-up assessment begins. Database development is continued by the Data Coordinating Center. The Central Biochemistry Laboratory, the Central GFR Laboratory, the Central Repository, and Central Facilities for Echocardiography, Ultrasound, and Electron Beam Computed Tomography will begin functioning. The Central Repository will become operational. Year 2 (12 months): Recruitment of cohort study participants continues and is completed at the end of year two. Participant follow-up assessment by the Clinical Centers continues. Reports on recruitment rates, data quality, and baseline characteristics of study participants prepared by the Data Coordinating Center. Plans for data analysis on the recruitment experience and baseline findings are established by the Data Coordinating Center. Year 3 (12 months): Participant follow-up assessment by the Clinical Centers continues. Reports on data quality, and follow-up studies generated by the Data Coordinating Center. Manuscripts describing the recruitment experience, baseline clinical and demographic characteristics of the participants, and unique aspects of this cohort study are prepared based on analyses from the Data Coordinating Center. Year 4 (12 months): Participant follow-up by the Clinical Centers continues. Manuscripts describing short-term changes in renal function, changes in cardiovascular disease risk factors, and other findings from the study are prepared based on data analysis from the Data Coordinating Center. The Clinical Centers and the Data Coordinating Center, and whenever appropriate the Central Reading Centers and Central Laboratories, will participate in special epidemiological studies such as nested case-control studies of risk factors for renal disease progression and occurrence of cardiovascular disease. Year 5 (12 months): Participant follow-up assessment by the Clinical Centers continues. Data analysis and manuscripts prepared addressing secondary goals of the cohort study. Year 6 (12 months): Participant follow-up assessment by the Clinical Centers continues. Continued data analysis by the Data Coordinating Center and preparation of manuscripts by the Clinical Centers and investigators from the Central Reading Centers on primary and secondary goals of the study. Plans will be established for study close-out. Year 7 (First 6 months): Final follow-up clinic visit is conducted. Data collection for patients receiving treatment for ESRD is concluded. Plans will be established for final data analysis by the Data Coordinating Center and Clinical Centers. Year 7 (Last 6 months): Final data analysis will be performed and major reports and manuscripts prepared. The Data Coordinating Center, the Clinical Centers, the Central Laboratories, and the Central Reading Center, will be closed-out. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness by the NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDDK in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Diabetes and Digestive and Kidney Diseases Advisory Council. Review Criteria Applicants are encouraged to submit and describe their own ideas about how best to meet the goals of the cooperative study as outlined in this RFA, and are expected to address issues identified under INFORMATION TO BE INCLUDED IN APPLICATIONS. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. Review Criteria for Clinical Centers 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: Does the applicant propose a sound study design and methods to achieve the aims of the RFA? Is the potential pool of cohort study participants available to the investigator outlined clearly? Have realistic estimates been made regarding the number of participants who will prove to be eligible for the cohort study based on level of renal function? Among persons found eligible during screening have realistic participation rates been applied to meet the sample size goals stated in the RFA? Has the racial, ethnic, and gender composition of the proposed cohort been adequately described, and plans described for appropriate analyses? Has information on the distribution of renal disease of the population targeted for recruitment been discussed? What plans have been presented to ensure high rates of follow-up and high rates of participation in answering questionnaires and undergoing tests mandated by the study protocol? What risk factors (i.e., demographic, clinical, and laboratory measurements) are proposed to be included in the study protocol to explain decline in renal function and development of cardiovascular disease? What measurements will be used to assess cardiovascular disease status at baseline and during follow- up? Have the sample size and power calculations and proposed subgroup analyses been adequately addressed? What steps are planned for data quality control? The applicant must provide plans to ensure the complete, reliable, and timely transmission of study data to the Data Coordinating Center. Knowledge of the possible problems associated with the conduct of multi-center epidemiological studies and any potential issues of importance in this study should be described. Investigators: Is the Principal 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? Are the Principal Investigator and her/his co- investigators experienced in collaborating with other investigators in a multi-center study? Are the investigators willing to participate in establishing and conducting a common protocol? Does the Principal Investigator and the proposed study team possess experience in recruiting participants to long-term follow-up studies? Necessary Expertise: Documented experience in nephrology, cardiology, and epidemiology is required. Demonstrated knowledge of clinical aspects of chronic renal disease and cardiovascular disease is required. Staff Qualifications: Documented specific competence and relevant experience of professional, technical, and administrative staff pertinent to the operation of a Clinical Center are required. Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Documented adequacy of the proposed facility and space is necessary. Is there evidence of institutional support and commitment for the proposed program? Access to Large Patient Databases: Evidence of the ability to access large patient databases containing information on level of renal function and/or diagnoses of chronic renal disease from which potential cohort study participants will be recruited is necessary. Documentation must be provided on the ability to contact patients identified in these databases in order to invite them to a more detailed, in-clinic assessment of their eligibility to participate in the cohort study. The necessary administrative arrangements to access these databases and to contact individual patients must also be included in the application. Recruitment of Minority Participants: Has the applicant described in detail, the distribution of minority participants to be recruited? Is the racial and ethnic composition of the proposed recruited population similar to the U.S. end-stage renal disease patient population? Review Criteria for a Data Coordinating Center: Significance: Does the study address an important problem? If the aims of the applications 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: A design for a cohort study should be included in the application for a Data Coordinating Center. Is a sound design proposed for the cohort study and are the planned follow-up studies and examinations reasonable to achieve the goals of the RFA. Are the conceptual framework, design, and methods adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Experience in developing protocols, developing web-based technology for data collection, establishing and maintaining large databases for data from the Clinical Centers, plans for analysis of the combined data, and efforts to ensure high quality data collection, and ensuring study participant confidentiality will be evaluated. Have the sample size estimates and power calculations been described in detail? Have adequate statistical plans been included for subgroup analyses? What is the approach to handle missing follow-up data? Investigators: Is the Principal 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? Are the Principal Investigator and her/his co- investigators experienced in collaborating with other investigators in a multi-center study? Documented experience in epidemiology and biostatistics is required. Does the applicant have expertise in longitudinal data analysis, including renal function measurements? Demonstrated knowledge of clinical aspects of chronic renal disease and cardiovascular disease from either a co-investigator or consultant will be judged. The level of expertise of consultants in nephrology, cardiology, quality of life and health resource utilization will be considered. Experience in database development, data management, and statistical analysis is required. The ability of the investigators from the Data Coordinating Center to take the lead in developing a cooperative relationship among the participating Clinical Centers, the Central Laboratories, and the Central Reading Centers and exercise appropriate leadership in matters of study design, data acquisition, data management, data quality, data analysis, and administration and coordination of Steering and Planning Committee will be considered. Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Documented adequacy of the proposed facility and space is necessary. Is there evidence of institutional support and commitment for the proposed program? In addition to the above criteria, in accordance with NIH policy, all applications will be reviewed with respect to the following. The reasonableness of the proposed budget for each year of the program. The adequacy of the proposed protection for humans and the environment, to the extent they may be adversely affected by the studies described in this RFA. The scientific review group will also examine the safety of the research environment. Schedule Applicant Information Forum Date: December 11, 2000 Letter of Intent Receipt Date: February 28, 2001 Application Receipt Date: March 28, 2001 Special Review Committee: June/July 2001 NDDK Advisory Council: September, 2001 Anticipated Award Date: September, 2001 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 Cost o The distribution of the causes of renal disease, racial and ethnic composition of the population targeted for recruitment o Geographic distribution of the Clinical Centers INQUIRIES Written and telephone inquiries concerning this RFA are strongly encouraged. The opportunity to clarify any issues or questions form potential applicants is welcome. For information relating to the NIDDK, programmatic inquiries may be made to: John W. Kusek, Ph.D. or Paul L. Kimmel, M.D. Division of Kidney, Urologic, and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Room 617 (J. Kusek, Ph.D.) or Room 607 (P.L. Kimmel, M.D.) MSC 5458 6707 Democracy Boulevard Bethesda, Maryland 20892-5458 (for express or courier service use 20817) Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: kusekj@ep.niddk.nih.gov kimmelp@ep.niddk.nih.gov Fiscal and administrative inquiries may be directed to: Teresa A. Farris Grants Management Specialist Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Room 630 MSC 5456 6707 Democracy Boulevard Bethesda, Maryland 20892-5456 (for express/courier service use 20817) Telephone: (301) 594-7682 FAX: (301) 480-3504 Email: farrist@ep.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.849 and 93.864. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410), as amended by Public Law 99-158, 42 USC 241 and 285) and administered under Public Health Service grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service strongly encourages all grant and contract recipients to provide a smoke-free work place and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro- Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the Public Health Service mission to protect and advance the physical and mental health of the American people.


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