FREQUENT HEMODIALYSIS CLINICAL TRIALS RELEASE DATE: December 4, 2002 RFA: DK-03-005 (Reissued as RFA-DK-07-503) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov) LETTER OF INTENT RECEIPT DATE: February 14, 2003 APPLICATION RECEIPT DATE: March 14, 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) invites cooperative agreement applications for a Data and Analysis Coordinating Center (DACC) and two Coordinating Clinical Centers (CCCs) to design, develop and implement clinical treatment trials of frequent hemodialysis for patients with end stage renal disease (ESRD). The DACC and CCCs will propose trial designs for the studies. It is anticipated that two trials will be initiated, one comparing short daily hemodialysis with conventional dialysis and one comparing long nocturnal dialysis with conventional dialysis. The goal of the RFA is to test the feasibility of randomizing a representative sample of dialysis patients into either (a) conventional three times per week dialysis, or (b) one of the two forms of frequent dialysis named above and to obtain preliminary data on the impact of these modalities on patient well-being. It is expected that patients will be followed for a minimum of six months and that intermediate outcomes will be tracked such as anemia, nutritional status, blood pressure, left ventricular hypertrophy, exercise tolerance, medication use, hospitalizations, etc. Based on the results of these trials, NIDDK will determine the advisability of continuing with a large scale trial of daily dialysis, powered to measure the impact of more frequent dialysis on hard endpoints, such as mortality and/or cardiovascular outcomes. The structure of the trials will be determined in part by the proposals. However, it is expected that the DACC will be responsible for coordinating the project design, monitoring data collection, and statistical analyses. Each CCC will be responsible for enrolling patients into the trials, monitoring the dialysis interventions, and data collection. It is not necessary that a CCC be able to enroll the entire patient cohort at a single site. A CCC may work out cooperative arrangements with a network of dialysis providers to reach enrollment goals. It is expected that CCCs will be given a fixed payment for the infrastructure for the trial and variable payments based on attaining enrollment goals. RESEARCH OBJECTIVES A. Background End stage renal disease afflicts approximately 380,000 Americans. Most are receiving hemodialysis three times per week. This frequency of hemodialysis, while conventional and capable of sustaining life, has no solid scientific basis. Although this schedule is compatible with prolonged survival for some patients, the annual mortality rates are quite high for the entire population of ESRD patients. More frequent hemodialysis has been employed by some centers in small numbers of selected patients. The modalities have included home and in- center hemodialysis delivered four to seven times per week with standard blood and dialysate flow rates. Some centers have employed a day time therapy of shorter duration per dialysis session than with the thrice weekly schedule. Alternatively, in the nocturnal version, lower than standard flow rates have been used but for longer periods of time than the usual, often 8 hours per night. The results of these approaches to increased frequency have been reportedly good. Reductions in blood pressure, serum phosphate levels and erythropoietin requirements have been noted. Improved patient well being has also been reported. However, these observations derive from small groups of selected patients in a few centers. Large numbers of subjects (N = 1,000 or more) are generally required to assess the effect of any change in ESRD therapy on mortality and cardiovascular events, e.g. stroke, myocardial infarction and heart failure, all of which often complicate ESRD. Based on previous studies of small numbers of daily dialysis patients, and the uncertain ability to randomize patients into daily versus conventional frequency, the trials conducted under this RFA will focus on intermediate outcomes. These outcomes include blood pressure, LVH, nutritional status, anemia quality of life, and vascular access. B. Research Goals and Scope The goal of this research initiative is to establish two clinical centers to conduct a trial of more frequent hemodialysis. It is the intent of this solicitation to invite applications from investigators who wish to apply their expertise to the testing of more frequent hemodialysis. This RFA solicits applications from investigators proposing to serve as a Coordinating Clinical Center or a Data and Analysis Coordinating Center to develop and conduct such a trial. It is anticipated that the studies to be conducted by this consortium in this RFA will take place in two CCCs over a period of four years. It is envisioned that each CCC will need to enroll a total of between 150 and 200 patients on dialysis. As stated above, the CCCs may chose to work out cooperative arrangements with a network of dialysis providers in order to reach enrollment goals. The data collection activities of the CCCs will be supported by a single DACC. C. Study Design Applicants for both the CCC and the DACC should respond with research protocols involving clinical trials to address the objectives of the study and to reach the study goals described in this RFA, and include detailed plans regarding their participation in clinical trials. Applicants should outline the rationale and background of the proposed study, study design and protocols, eligibility and exclusion criteria, and type of patients to be included in the protocols, and baseline and outcome measures to be assessed, in their applications. For each of the clinical protocols, the CCC applicants should discuss the characteristics and number of potential participants that would be available from their own geographic region. Provision of recruitment data regarding previous studies in patients with ESRD is required. Study Phases The program will be carried out in three phases over a four-year period. Phase I (Months 1-12): Protocol Development. Work to be performed during this phase includes the development of the interventional protocols, including procedures and forms for data collection, by the Steering and Planning Committee (see Cooperative Agreement Terms and Conditions of Award). A manual of operations including well-defined procedures for the studies and for the training and certification of clinical personnel in study procedures will be written. Parameters to be assessed in Central Laboratories will be outlined. The Data and Analysis Coordinating Center will begin computer programming to establish the database for the study. The collaborative protocols for the trials will be developed by the Steering Committee. Prior to implementation of the trials, the protocols and manual of operations will be reviewed, and must be approved by the External Advisory Committee (see Cooperative Agreement Terms and Conditions of Award). The study will move into operational phase (Phase II) only with the concurrence of the External Advisory Committee and the NIDDK. During this phase outlay of funds will be primarily for appropriate levels of salary support for investigators to develop the trial protocol(s) and manual of operations, and for travel to the Steering and Planning Committee meetings. Phase II (Months 13-36): Recruitment of Study Participants/Initiation of Interventional Trials At the beginning of this period, training of study staff will begin, to ensure uniform protocols and provide certification for study procedures. Over this period potentially eligible participants will be identified, invited to the CCCs for baseline assessment, and those found eligible will be asked to enter the appropriate trial. During this phase the full component of personnel will be included in the budget. Concurrent with recruitment, follow-up of all study participants will be conducted in a standardized fashion over regular intervals. The External Advisory Committee will review the progress of recruitment at 6 month intervals, review interim outcomes and recommend to the NIDDK whether the trial(s) should continue. The major activity during the first half of this phase will be the recruitment, assessment, enrollment and retention of patients in the trials. Manuscripts describing recruitment of the subjects, and baseline demographic and clinical characteristics of the participants will be prepared. Follow-up and data collection on study participants will continue throughout this phase, as determined by the study protocols. Manuscripts will be prepared and submitted for publication on the interim findings from the study. The last follow-up visit of study participants will be scheduled during the final two months of this phase. Phase III (Months 37-48): Final Data Analysis and Close-out of the CCCs and the DACC. During the final twelve months of the program, the activities include final data analyses and preparation of manuscripts on the findings from the trials. The Coordinating Clinical Centers, the Data and Analysis Coordinating Center, and all central facilities will be closed-out in the last two months of this phase of the study. Study Organization The Study organization will include Coordinating Clinical Centers, a Data and Analysis Coordinating Center, a Steering and Planning Committee, and an External Advisory Committee (see descriptions under Cooperative Agreement Terms and Conditions of Award). MECHANISM OF SUPPORT This RFA will use the NIH U01 award mechanism(s). As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA uses just-in-time concepts. 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 total project period for applications submitted in response to this RFA is four years. The anticipated award date is September 1, 2003. FUNDS AVAILABLE The NIDDK plans to make two awards for Coordinating Clinical Centers and one award for a Data and Analysis Coordinating Center. Approximately $1,000,000 total cost (direct plus facilities and administrative costs) is expected to be available during the first year of the study and $3,000,000 for each of the remaining three years of the study. It is anticipated that the award for each Coordinating Clinical Center will be about $250,000 total cost in year one, $1,250,000 total cost in the second and third years, and $1,000,000 total cost in the fourth year. The award for the Data and Analysis Coordinating Center will be about $500,000 total cost in years one, two, and three of the program, and $1,000,000 in the fourth year. As noted in the Purpose section above, payments to the CCCs will be dependent, in part, on obtaining enrollment goals. 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. To defray the costs of more frequent dialysis, the Centers for Medicare and Medicaid Services (CMS) has authorized one additional composite rate payment per week for the duration of the trials to cover the reasonable costs of the provision of the additional dialysis sessions. CMS will also permit additional home dialysis training payments at the composite payment rate plus $20 per training session. Payment would be made for each training session incurred for up to 5 weeks. These payments will not be paid through this U01 mechanism but will be paid through the normal Medicare payment billing system. More information about dialysis payment levels can be obtained from the persons listed in the Inquiries section at the end of this document. 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 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 the NIDDK Project Scientist. (1) Awardees' Rights and Responsibilities Awardees will have primary responsibility for the project as a whole, including protocol development, enrollment of study participants, data collection, data quality control, management of the trials, final data analyses and interpretation, and preparation of publications. 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. Coordinating Clinical Centers The Coordinating Clinical Center investigators will have direct responsibility for developing the study protocol(s) and uniform data collection forms, identifying potentially eligible study participants, assessing their eligibility to participate in the clinical trials, conducting baseline and follow-up visits, obtaining blood, urine, and other biological samples, performing measures of dialysis delivery and other measurements, collecting data (both clinical and cost related), and transmitting it in a timely fashion to the Data and Analysis Coordinating Center. They, along with staff from the Data and Analysis Coordinating Center, will also be responsible for making presentations at scientific meetings and writing and publishing manuscripts on the findings of their studies. A CCC will work collaboratively with the other CCC and the DACC, and will follow study protocols. Data and Analysis Coordinating Center The Data and Analysis Coordinating Center will be responsible for assisting the CCC investigators, through the Steering and Planning Committee, in developing the trial protocol(s) during Phases I and II. The Data and Analysis Coordinating Center will create data collection forms based on input from the Steering and Planning Committee. The Data and Analysis Coordinating Center will be responsible for establishing a database to accommodate data sent by the Coordinating Clinical Centers, developing a web-based data communication system, assessing data quality and completeness throughout the study, and providing general assistance to the Coordinating Clinical Centers to maintain long-term participation of the study subjects and their adherence to the study protocols. The Data and Analysis Coordinating Center will also create a web site for study information available to the public. The Data and Analysis Coordinating Center will also perform analyses as suggested by the Coordinating Clinical Centers, as well as propose original analyses to the collaborative group for their consideration. The Data and Analysis 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 External Advisory Committee. The DACC will be responsible for coordinating transfer of biologic samples and, to a repository to be established by the NIDDK. The Data and Analysis Coordinating Center will be responsible for arranging meetings and conference calls of the Steering and Planning Committee and will perform other administrative functions necessary to coordinate the efficient operation of the Frequent Hemodialysis Clinical Trial Network. The Data and Analysis Coordinating Center will establish, via subcontracts, Central Laboratories and other necessary adjuncts to the study, as necessitated by the study protocol(s). The DACC will be expected to provide the NIDDK and CMS with data (both clinical and cost related) in a uniform, usable platform throughout the course of the studies and after the termination of the studies supported by this RFA. (2) NIDDK Staff Responsibilities The NIDDK will name a Program Director and a Project Scientist to the project from within the Division of Kidney, Urologic and Hematologic Diseases. The Program Director will be responsible for the overall management of the project and will oversee all operational aspects of the project. The Program Director will assist the Steering and Planning Committee in carrying out the study and will serve as Executive Secretary of the External Advisory Committee. 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 have a voting membership on the Steering and Planning Committee. 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 study, maintaining high rates of follow-up and data collection/completion of participants' tests, in timely data reporting, achieving high levels of data quality, maintaining adherence to the study protocol(s), working cooperatively or other major breaches of the protocol(s), or human subject or ethical issues that may dictate a premature termination. The study will progress from one phase to the next only with NIDDK approval. (3) Centers for Medicare and Medicaid Services (CMS) Staff Responsibilities The CMS will name one project liaison representative to participate in these trials and assist the NIDDK in carrying out the study. The liaison representative will have experience in Medicare ESRD program and payment policy. The liaison representative will serve as a voting member of the steering and planning committee and will attend meetings of the EAC. The project liaison representative will have substantial involvement in the development of cost data collection design, collection and analysis. The DACC and CCCs will cooperate with the Centers for Medicare and Medicaid Services (CMS) in the design and collection of cost data relevant to the provision of daily dialysis. This will include the costs of training patients as well as the weekly maintenance costs of providing daily dialysis. (4) Collaborative Responsibilities The Steering and Planning Committee, composed of each of the Principal Investigators of the CCCs, the Principal Investigator of the DACC, the NIDDK Project Scientist, the Chairperson of the Steering and Planning Committee, and the CMS liaison representative will be the main governing board of the study. NIDDK may supplement the Steering and Planning Committee with experts in the fields of nephrology, clinical trials, and statistics as deemed necessary. This committee will have the primary responsibility for developing the study protocol(s), facilitating the conduct of participant follow-up and testing, monitoring completeness of data collection adherence to protocol(s), and timely transmission to the Data and Analysis 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, 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 one of the NIDDK or CMS representatives). An independent External Advisory Committee (EAC), selected by the Director, NIDDK, will review periodically the progress of the study to ensure patient safety during the conduct of the trial(s). This group will include experts in the relevant medical, epidemiological, radiological, statistical, and ethics fields, as well as lay representatives, who are not otherwise involved in the study. The EAC will review the study protocol(s) as developed during Phases I and II, 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 representatives will serve as Executive Secretary of the External Advisory Committee. The members of the EAC will review the trials' progress and report to the NIDDK at least once each year, or more often if necessary. (5) 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. 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: Paul Eggers, Ph.D, Division of Kidney, Urologic, and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 617 MSC 5458 Bethesda, Maryland 20892-5458 (for express or courier service use 20817) Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: pe39h@nih.gov Thomas Hostetter, M.D. Division of Kidney, Urologic, and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 647 MSC 5458 Bethesda, Maryland 20892-5458 (for express or courier service use 20817) Telephone: (301) 594-8864 FAX: (301) 480-3510 Email: th192u@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 and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 752 MSC 5452 Bethesda, MD 20892 Telephone: (301) 594-8897 FAX: (301) 480-3505 Email: fc15y@nih.gov o Direct your questions about financial or grants management matters to: Ms. Helen Ling Senior Grants Management Specialist Grants Management Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Room 732 MSC 5456 Bethesda, MD 20892-5456 (For Express Mail Use Zip Code 20817) Telephone: (301) 594-8857 Fax: (301) 480-3504 Email: hl12d@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: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 752 MSC 5452 Bethesda, MD 20892 (Courier use ZIP 20817) 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 https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. 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: https://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 and any appendices must be sent to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 752 MSC 5452 Bethesda, MD 20892 (Courier use ZIP 20817) Telephone: (301) 594-8897 FAX: (301) 480-3505 Email: fc15y@nih.gov 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 applications will be returned to the applicant without further consideration. And, if the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. 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 National Diabetes and Digestive and Kidney Diseases Advisory Council. REVIEW CRITERIA REVIEW CRITERIA FOR COORDINATING CLINICAL CENTERS General: The ability to regionally recruit sufficient numbers of subjects for randomization, to provide the proposed frequent hemodialysis therapy, to provide cost data, and to document adherence to the protocol in a large number of dialysis sites will be key review criteria. 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 sound approaches to achieve the aims of the RFA? Is the potential pool of 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 studies? 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 study participants been adequately described, and plans described for appropriate analyses? What plans have been presented to ensure the high rates of follow-up and high rates of adherence mandated by the study protocol? 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 and Analysis Coordinating Center. Knowledge of the possible problems associated with the conduct of clinical trials 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 pilot and feasibility studies and to long- term interventional studies? Does the Principal Investigator and the proposed study team possess experience in clinical trial design to ensure meaningful participation in design of the trial? Staff Qualifications: Documented specific competence and relevant experience of professional, technical, and administrative staff pertinent to the operation of a Coordinating Clinical Center are required. Documented experience in nephrology, and specifically in the field of ESRD and clinical trial methodology is 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 Number of Eligible Patients and Ability to Recruit Large Numbers of Patients in Clinical Trials: Evidence of the ability to access sufficient numbers of appropriate patients from which potential study participants will be recruited is necessary. Documentation must be provided on the ability to contact patients identified in order to invite them to more detailed, clinical assessments of their eligibility to participate in the trial(s). Provisions must be made to ensure subject confidentiality and ethical standards. REVIEW CRITERIA FOR A DATA AND ANALYSIS 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: Does the applicant acknowledge potential problem areas and consider alternative tactics in the implementation and performance of the trials necessary to achieve the goals of this RFA? What is the approach to handle missing follow-up data and patient non-adherence? How does the applicant propose to collect and analyze dialysis cost data? Experience in developing protocols, developing web-based technology for data collection, establishing and maintaining large databases for data from the Coordinating Clinical Centers, plans for analysis of the combined data, and efforts to ensure high quality data collection, and ensuring study participant adherence and confidentiality will be evaluated. 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, clinical trial methodology and biostatistics is required. Does the applicant have expertise in longitudinal data analysis? The level of expertise of consultants in nephrology will be considered. Experience in database development, data management, and statistical analysis is required. The ability of the investigators from the Data and Analysis Coordinating Center to take the lead in developing a cooperative relationship among the Coordinating Clinical Centers and the Central Laboratories, and to exercise appropriate leadership in matters of study design, data acquisition, data management, data quality, data analysis, repository function, and administration and coordination of Steering and Planning Committee meetings 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? 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. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: February 14, 2003 Application Receipt Date: March 14, 2003 Peer Review Date: June/July 2003 Council Review: September 2003 Earliest Anticipated Start Date: September 30, 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. 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: https://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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://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 https://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 https://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 https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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 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 https://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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