MULTICENTER CLINICAL TRIAL OF FOCAL GLOMERULOSCLEROSIS IN CHILDREN AND YOUNG ADULTS Release Date: June 28, 2001 RFA: RFA-DK-02-013 National Institute of Diabetes and Digestive and Kidney Diseases Applicant Information Forum Date: October 8, 2001 Letter of Intent Receipt Date: February 15, 2002 Application Receipt Date: March 15, 2002 PURPOSE The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites cooperative agreement (U01) applications for Regional Clinical Coordinating Centers and a Data Coordinating Center to conduct a randomized clinical trial of cyclosporin or novel immunomodulatory agents in children and young adults with Focal Segmental Glomerulosclerosis (FSGS). 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 Request for Applications (RFA), Multicenter Clinical Trial Of Focal Glomerulosclerosis In Children And Young Adults, 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. Only institutions located in North America are eligible to apply. Racial/ethnic minorities, women, and persons with disabilities are encouraged to apply as Principal Investigators. An institution may apply to serve as both a Regional Clinical Coordinating Center and a Data Coordinating Center. However, separate applications are required for each of these components. The same applicant may not serve as the Principal Investigator of a Regional Clinical Coordinating Center and the Data Coordinating Center, and other key staff cannot be shared by these two centers. 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 clinical trial 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 five years. The anticipated award date is September 2002. At this time, the NIDDK has not determined whether or how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE (ICs should modify as necessary) The NIDDK plans to make four awards for Regional Clinical Coordinating Centers and one award for a Data Coordinating Center. Approximately $1,000,000 total cost (direct plus facilities and administrative costs) is expected to be available during year one of the study. In each subsequent year $ 2,000,000 will be available under this RFA. It is anticipated that the award for each Regional Clinical Coordinating Center will be about $200,000 total cost in year one and $400,000 total cost in each subsequent year. The award for the Data Coordinating Center will be about $200,000 total cost in year one and approximately $400,000 total cost in each subsequent year of the program. 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 Most children and young adults who present with nephrotic syndrome have renal biopsy findings consistent with the diagnosis of minimal change disease, typically such patients will have remission of clinical symptoms with treatment with a course of high dose prednisone, progression to renal failure in this patient group is unusual. There is however a sub-group of nephrotic children and young adults for whom the long-term prognosis is substantially poorer, risk factors include steroid-resistant or steroid-dependent nephrotic syndrome and evidence of focal glomerulosclerosis on renal biopsy. No satisfactory treatment exists for this high-risk patient group. In the long term, patients with FSGS face a high risk of renal failure. In the shorter term, patients encounter the symptoms and complications of nephrotic syndrome including edema, ascites, hyperlipidemia and thromboembolism. The goal of this initiative is to develop and conduct a multi-center clinical trial that will address the treatment of nephrotic syndrome and reduction in residual proteinuria in patients with FSGS. While the long-term goal in these patients has to be protection of renal function, proteinuria provides a valuable surrogate marker that is both a measure of the severity of the nephrotic syndrome and a strong correlate of the risk of progressive loss of renal function. Focal glomerulosclerosis is also called focal segmental glomerulosclerosis, it is a pathological entity first described by Rich in 1957 characterized by the presence in some glomeruli, but not all, of areas of mesangial sclerosis. Although it is often secondary to other disorders such as HIV nephropathy, heroin use, or certain malignancies, it also appears as a primary, idiopathic condition, it is typically diagnosed on renal biopsy in nephrotic patients whose nephrotic syndrome has failed to respond to steroid therapy. Secondary forms are more common among older adults while the primary form is more common among children and young adults. FGS is also among the most common renal disease to recur post renal transplants, often resulting in allograft injury (20 to 30%) or graft loss (40-50%). The disease appears to be more prevalent and more severe in African-American and perhaps Hispanic-American children. Although steroid therapy is commonly used in the treatment of children with FSGS, approximately 75% of patients do not respond to therapy, relapse while on therapy or relapse rapidly when therapy is stopped. The overall outcome remains unpredictable, with some patients progressing to end-stage renal disease (ESRD) within a period of two years, while others reach that point after an average of ten years. In some children the heavy proteinuria may improve with steroid therapy, but at the cost of significant adverse effects. A number of strategies have been employed to treat FSGS. Converting enzyme inhibitors are one established strategy to slow the progression of certain forms of renal disease. However, the effects of converting enzyme inhibitors has not been examined in children with FGS, and in adults the number of patients studied has been too small to allow meaningful subgroup analyses. Nonetheless, because the drugs are well tolerated and frequently result in some reduction in proteinuria, many nephrologists consider use of a converting enzyme inhibitor to be standard care, at least for patients who have both proteinuria and hypertension. The other important category of agents is immunomodulatory in nature. Both cyclophosphamide and chlorambucil have been used for treatment of FSGS for several decades. These agents have been studied in several clinical trials. A recent meta-anlysis summarizing experience with cyclophospahmide and chlorambucil (Latta K. et al. Pediatric Nephrology 16:271-282, 2001) notes an overall increased rate of relapse-free survival with increasing doses of either agent. Overall, however, the complication rate with these agents is not insignificant, response rates are not satisfactory, and even among patients who respond a substantial portion of patients do not remain in long- term remission. Results with cyclosporin are viewed by at least some nephrologists as more promising, although the overall experience is not extensive, and small, randomized trials have not established an advantage over the cytoxic agents. Goal The goal of this RFA is to conduct a collaborative, multi-center randomized controlled clinical trial of therapy to improve the clinical course of children and young adults with FSGS. The primary outcome of this clinical trial is a clinically significant reduction or remission of proteinuria. Each Regional Clinical Coordinating Center is expected to randomize at least 100 study participants over an 18-month period. This sample size will require Regional Clinical Coordinating Centers to develop cooperative arrangements with other institutions and practicing physicians for patient referral. A Central Repository will be established by the NIDDK as a result of a separate solicitation to store patient samples. This is a collaborative research program. Investigators are required to work closely together to develop the design of the trial, recruit participants, and collect uniform follow up data. Because the trial will involve a large number of physicians over a wide geographic region the trial design must be simple and the intervention readily acceptable by both physicians and trial participants. STUDY ORGANIZATION 1. Regional Clinical Coordinating Centers Because the number of patients with FSGS followed at any one medical institution is likely to be insufficient to meet the recruitment goal for an individual Regional Clinical Coordinating Center, these centers will consist of a central institution coordinating the recruitment, intervention, and follow-up of patients entered into the trial from other medical organizations and individual physicians. A Regional Clinical Coordinating Center should consist of an interdisciplinary team of clinical investigators and appropriate personnel, such as a research coordinator and clerical staff. Regional Clinical Coordinating Center investigators will have direct responsibility for developing the trial protocol and standardized forms for data collection, identifying potentially eligible study participants, assessing their eligibility to participate in the clinical trial, conducting baseline and follow-up visits, and obtaining blood, urine, and other biological samples, as defined in the trial protocol. The Regional Clinical Coordinating Centers must work closely with the Data Coordinating Center to implement procedures for uniform and timely data collection, transmittal of data, as well as data audits and other data quality control procedures as established by the trial protocol. Regional Clinical Coordinating Centers are required to obtain patient consent for the trial. The protocol must also be approved their Institutional Review Board. 2. Data Coordinating Center The Data Coordinating Center will be responsible for assisting the Regional Clinical Coordinating Center investigators to develop the trial protocol, including providing sample size estimates and statistical power calculations. The Data Coordinating Center will also have primary responsibility for collecting, editing, storing, and analyzing data generated by the Regional Clinical Coordinating Centers, and for establishing and implementing data audits and quality control procedures. The Data Coordinating Center will be responsible for establishing any Central Laboratories and coordinating the shipping of samples to a Central Repository. 3. 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 Regional Clinical Coordinating Centers and the principal investigator of the Data Coordinating Center, the Chairperson of the Steering and Planning Committee, and the NIDDK Project Scientists (described in detail under Terms and Conditions). They will meet initially to develop the clinical trial protocol and subsequently to discuss the progress of the trial and to consider problems arising during its conduct. The Steering and Planning Committee will develop policies for the trial pertaining to access to patient data and specimens, ancillary studies, performance standards, and publications and presentations. The Steering and Planning Committee may establish subcommittees on such topics as recruitment, quality control, and publications and ancillary studies. Small working groups may be established to prepare manuscripts and presentations. 4. Data and Safety Monitoring Board An independent group of experts in areas such as pediatric nephrology, nephrology, pathology, biostatistics, clinical trials and ethics, who are not otherwise involved in the study, as well as lay persons, will be selected by the NIDDK to evaluate the protocol prior to implementation, to review periodically the progress of the trial (described in detail under Terms and Conditions), and to ensure patient safety. 5. Project Scientists The NIDDK will identify two Project Scientists for the trial. The Project Scientists will assist the Steering and Planning Committee in carrying out the trial (described in detail under Terms and Conditions). Study Phases The clinical trial will be carried out in three phases over a five-year period. Phase I (6 Months): Development of the Clinical Trial Protocol, Manual of Operations, Data Forms and Data Base Work to be performed during this phase will be the development of a single clinical trial protocol and a detailed Manual of Operations specifying the procedures to be performed. If necessary, Central Laboratories will be established. 2. Phase II (51 months): Trial Implementation: Recruitment, Intervention and Follow-up Patients will be recruited into the trial and followed-up. It is anticipated that recruitment will be conducted over an 18 month period. Phase III (3 months): Final Data Analysis and Close-out of the Trial The last follow-up visit will be conducted at the beginning of Phase III. In addition, final data analysis will be performed and manuscripts written on the primary and secondary outcomes of the trial. The Regional Clinical Coordinating Centers, Central Laboratories (if required) and the Data Coordinating Center will be closed-out. SPECIAL REQUIREMENTS Terms and Conditions of Award 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 Scientists. 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. (1) Responsibilities of the Regional Clinical Coordinating Centers: The Regional Clinical Coordinating Centers will have primary responsibility for developing the trial protocol, recruiting a sufficient number of study participants, maintaining high rates of follow-up and data collection, ensuring adherence to the trial protocol, obtaining high quality data, transmitting it accurately and expeditiously to the Data Coordinating Center, and interpreting, presenting, and publishing findings from the trial. A Regional Clinical Coordinating Center will work collaboratively with the other Centers, the Data Coordinating Center, and the NIH. (2) Responsibilities of the Data Coordinating Center: The Data Coordinating Center will assist the Regional Clinical Coordinating Centers in protocol development and will have primary responsibility for collecting, editing, storing and analyzing data generated by the Regional Clinical Coordinating Centers, and in preparation of reports and scientific publications. The Data Coordinating Center has the major responsibility of creating the database and data collection systems. They will also be responsible for performing statistical analyses of the data, including sample size and power estimates of the final trial design. The Data Coordinating Center will arrange for the transfer of biologic samples to a repository to be established by the NIDDK. The repository will be supported through a mechanism separate from this RFA, and the samples will be available to FSG Consortium investigators and to other interested investigators. In addition, the Data Coordinating Center will supply logistical support for the meetings of the Steering and Planning Committee and the Data and Safety Monitoring Board. The Data Coordinating Center should be prepared to assume a key role in overseeing implementation and adherence to the trial protocol, and assuring quality control of the data collected. The Data Coordinating Center will be expected to provide the NIDDK with a well-documented and complete data set after termination of the trial. The Data Coordinating Center will also be expected to generate appropriately detailed reports to the Steering and Planning Committee and to the Data and Safety Monitoring Board at regular intervals, and will be responsible for the logistics and planning of the meeting of these committees and their subcommittees. (3) Awardees Rights and Responsibilities Awardees will have substantial and lead responsibilities in all tasks and activities. These include protocol development, enrollment of study participants, data collection, quality control of the data, management of the trial, final data analysis and interpretation, and preparation of publications. The awardees agree to work cooperatively with the other Regional Clinical Coordinating Centers and agree to follow the common protocol developed by the Steering and Planning Committee. The awardees agree also to transmit the trial data in a timely manner. Awardees will retain custody of and have primary rights to their data developed under these awards for the duration of the awards, subject to Government (e.g., NIDDK, NIH, or PHS) rights or access consistent with current HHS and NIH policies. Patient samples will be stored and retained in the Central Repository, and the samples will be available to FSG Consortium investigators and to other interested investigators. (4) 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 trial. The Project Scientists 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. One of the NIDDK Project Scientists will also serve as Executive Secretary of the Data and Safety Monitoring Board. The NIDDK reserves the right to terminate or curtail the trial (or an individual award) in the event of difficulties in recruitment, or other shortcomings in carrying out the trial protocol, or human subject or ethical issues that may dictate a premature termination. (5) Collaborative Responsibilities The Steering and Planning Committee, composed of each of the Principal Investigators of the Regional Clinical Coordinating Centers, the Principal Investigator of the Data Coordinating Center, the NIDDK Project Scientists, and the Chairperson 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 adherence to the protocol, timely transmission of the data to the Data Coordinating Center, and reporting the trial results. It will also be responsible for establishing trial 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 one of the NIDDK Project Scientists) or alternatively, from among experts in nephrology who are not participating directly in the trial. An independent Data Safety and Monitoring Board will be selected by the NIDDK. This group will include experts in pediatric nephrology, nephrology, biostatistics, pathology, and lay representatives, who are not otherwise involved in the trial. The Data Safety and Monitoring Board will review the trial protocol prior to implementation and evaluate interim and final results, monitor data quality, participant safety, and provide operational and policy advice to the Steering and Planning Committee and to the NIDDK. One of the NIDDK Project Scientists will serve as Executive Secretary of the Board. The members of the Board will review progress and report to the NIDDK at least once each year, or more often if necessary. Approval of the protocol by the Board is necessary prior to implementation. (6) 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. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of 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. 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 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/not98-024.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. REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS All investigators proposing research involving human subjects should read the policy that was published in the NIH Guide for Grants an Contracts, June 5, 2000 (Revised August 25, 2000), and is available at the following URL address http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm Applicants may wish to place data collected under this 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. INFORMATION FOR PROSPECTIVE APPLICANTS Open Forum A one-day open information forum will be held for prospective applicants on October 8, 2001 from 1 p.m. to 4 p.m. (E.S.T.) in Conference Room 701A, 6707 Democracy Boulevard (Two Democracy Plaza), Bethesda, Maryland. At this forum NIDDK program staff will answer 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. Applicants may also contact Dr. Kusek to obtain a summary of the forum. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent by February 15, 2002 that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the 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 that it contains allows 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 752, MSC 5452 Bethesda, Maryland 20892-5452 Bethesda, Maryland 20827 (for courier service) Telephone: (301) 594-8897 Fax: (301) 480-3505 Email: fc15y@nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov. Applicants for Regional Clinical Coordinating Centers should describe their plans for participating in a multi-center clinical trial to address the goals as stated in the RFA. The design for a single clinical trial must be included in the application. The design should include primary and secondary outcomes, entry and exclusion criteria, a comparison or usual care group-specifying treatment regimens for that group, a proposed follow-up visit schedule, and tests to be performed. Sample size estimates and power calculations are not required. Applicants should provide detailed information regarding the size of the potential pool of FSGS patients who will be willing to come to the Regional Clinical Coordinating Center to participate for screening visits to assess study eligibility, and a reasonable projection of the proportion of patients screened and found eligible that would be willing to participate in a long-term clinical trial as outlined in this RFA. A detailed description of the patient database from which patients targeted for this intervention will be selected, as well as a comprehensive plan to recruit patients, must be provided. Realistic rates of study drop-outs, out-migration, and intervention non-adherence should be proposed. Efforts to maintain follow-up of study participants and to collect data from participants recruited from distant locations should be specified. Applications for the Data Coordinating Center must also include a design for a single clinical trial, specifying primary and secondary outcomes, possible entry and exclusion criteria, use of a comparison or control group, a follow- up visit schedule and test measurements. Power calculations using clinically significant reduction of proteinuria or remission of proteinuria as the primary outcome should be provided. The application should also include plans for data collection, and overall quality control of the trial. An administrative plan to coordinate the activities of the Central Laboratories (if required), including quality control and data transmission to the Data Coordinating Center should be included in the application. The experience of the Data Coordinating Center in developing and maintaining web-based data collection systems for multi-center studies, including clinical trials should be documented. Plans for transferring biologic samples to a repository to be established by the NIDDK should be outlined. A description of anticipated problems in carrying out this study and their proposed solutions must be included in the application. Institutional Support: There should be evidence of strong institutional support for the study, including adequate space in which to conduct participant follow-up (Regional Clinical Coordinating Centers) and data analysis/management (Data Coordinating Center) activities. An organizational structure for the trial should be set forth in the application, delineating lines of authority and responsibility for dealing with anticipated problems in all general areas as well as stated willingness to follow the commonly agreed- upon protocol. Previous Experience: The applicant should include a succinct discussion of previous relevant research efforts in multi-center 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 (Regional Clinical Coordinating Centers only). 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 Regional Clinical Coordinating Centers, expertise in pediatric nephrology, clinical research study management, and clinical trials is required. Personnel may be full-time or part-time and may serve in more than one capacity. A suggested Regional Clinical Coordinating Center study team might include, besides a Principal Investigator, a co-investigator (M.D. or Ph.D.), study coordinators, appointment-scheduler or administrative assistant and data entry clerk. Personnel for the Data Coordinating Center must have training and experience in biostatistics, 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. Budget Preparation by Year Applicants for the Regional Clinical Coordinating 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. Phase I (First 6 months). The budget will be for development of the trial protocol. The Data Coordinating Center will establish the database necessary to accommodate the data transmitted by the Regional Clinical Coordinating Centers. A web-based technology for data transmission will be established in Phase I that will be efficient, and will protect study participant privacy. The Data Coordinating Center will identify and establish subcontracts with Central Laboratories (if required by the trial protocol) and other support centers as necessitated by the protocol. It is expected that the Data Coordinating Center will purchase all the necessary hardware and software for data transmission. The budget for this period should include only those personnel actively involved in protocol development. The travel budget for Phase I should be estimated based on travel for two key investigators to attend two-day, monthly meetings of the Steering and Planning Committee in the Washington, D. C. area. Phase II (Months 7 through 57). The budget for the Regional Clinical Coordinating Centers should include the full complement of personnel required to recruit the study participants, implement the intervention(s), and perform baseline and follow-up measurements and data collection. Regional Clinical Coordinating Center personnel could include a principal investigator, co- investigator, study coordinator, appointment scheduler/administrative assistant, and data entry clerk. The budget for the Data Coordinating Center should also include the full complement of personnel for trial implementation. 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 include costs associated with necessary Central Laboratories. This phase of the program will require meeting approximately every four months in the Washington, D.C. area. The travel budget should be estimated based on travel for the Principal Investigator and the Study Coordinator as well as any other key personnel for both the Regional Recruiting Centers and the Data Coordinating Center. Budgets for the Data Coordinating Center should include travel for any consultants. Travel for key staff at the Regional Clinical Coordinating Centers and the Data Coordinating Center should be budgeted each year for centralized training and re-certification of Regional Clinical Coordinating Center staff. Travel by Data Coordinating Center staff to Washington, D.C. for a meeting with the Data Safety and Monitoring Board should be planned and budgeted for annually. Phase III (3 months). Final data analysis and close-out of the Regional Clinical Coordinating Centers, the Data Coordinating Center, and Central Laboratories (if required) will take place over a three-month period. The major activity during this phase will include final data analysis and conducting close-out visits of the study participants. Manuscripts describing the primary and secondary results will be prepared and submitted to peer- reviewed scientific journals for publication. The Regional Clinical Coordinating Centers, the Data Coordinating Center and the Central Laboratories (if required) will be closed-out. One meeting of the Steering and Planning Committee and one meeting of the Data and Safety Monitoring Board will be held. The RFA label available in the PHS 398 (rev. 4/98) 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 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 752 MSC 5452 Bethesda, Maryland 20892-5452 Bethesda, Maryland 20817 (for express/courier service) Applications must be received by March 15, 2002. 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDDK in accordance with the review criteria stated below. As part of the initial merit review, all applications will 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 NIDDK National Advisory Council or Board. 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 Regional Clinical Coordinating Centers Recruitment: The ability to access a large number of potentially eligible patients with FSGS is a critical element of the application. Realistic estimates must be made regarding the number of patients who may prove eligible for the trial and are willing to be randomized and followed-up. Significance: The proposed trial protocol must appropriately address the issue of improving the clinical course of patients with FSGS as described in this RFA. Trial Design: Does the applicant propose a reasonable trial design and methods to achieve the aims of the RFA? Are entrance and exclusion criteria clearly defined and reasonable to permit recruitment of a sufficient number of patients? Is the proposed comparison or control group feasible and ethically acceptable? Are clinically meaningful primary and secondary endpoints described? Will the intervention(s) proposed likely to be accepted by practicing physicians and patients alike? Are plans presented to ensure patients follow-up and adherence to the study protocol? Investigators: Is the Principal Investigator appropriately trained and well suited to carry out the work? Is the work proposed appropriate to the experience level of the Principal Investigator and other key personnel? 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 clinical trials? Necessary Expertise: Documented experience in pediatric nephrology is required. Staff Qualifications: Documented specific competence and relevant experience of professional, technical, and administrative staff pertinent to the operation of a Regional Clinical Coordinating 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? Recruitment of Minority Participants: Has the applicant described in detail the distribution of minority participants to be recruited? Review Criteria for a Data Coordinating Center: Significance: Will the trial design answer the important clinical issues of patients with FSGS? Is the trial design feasible and practical, with appropriately justified primary and secondary outcomes? Approach to Conduct of the Trial: Does the applicant acknowledge potential problem areas and consider alternative tactics in the implementation and performance of a clinical trial necessary to achieve the goals of this RFA? What is the approach to handle missing follow-up data and patient non- adherence? Experience in developing protocols, developing web-based technology for data collection, establishing and maintaining large databases for data from the Regional Clinical Coordinating 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? Experience in database development, data management, and statistical analysis is required. The ability to exercise appropriate leadership in matters of trial design, the acquisition, management and quality of the data, data analysis, and administration and coordination of Steering and Planning Committee meetings are important elements of the application. 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: October 8, 2001 Letter of Intent Receipt Date: February 15, 2002 Application Receipt Date: March 15, 2002 Special Review Committee: June/July 2002 NDDK Advisory Council: September 18-19, 2002 Anticipated Award Date: September 30, 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit as determined by peer review o Ability to achieve the recruitment goals, including racial and ethnic minority participants o Geographic distribution (Regional Clinical Coordinating Centers only) o Cost INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Gladys H. Hirschman, M.D., or John W. Kusek, Ph.D. Division of Kidney, Urologic, and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Room 630 (Dr. Hirschman) MSC 5458 Room 617 (Dr. Kusek)MSC 5458 6707 Democracy Boulevard Bethesda, Maryland 20892-5458 (for express or courier service use 20817) Telephone: (301) 594-7717 (Dr. Hirschman) (301) 594-7735 (Dr. Kusek) FAX: (301) 480-3510 (for both Drs. Hirschman and Kusek) Email: Dr. Hirschman: gh24q@nih.gov Dr. Kusek: jk61x@nih.gov Direct inquiries regarding review issues to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities National Institute of Diabetes, Digestive, and Kidney Diseases 6707 Democracy Boulevard Room 752, MSC 5452 Bethesda, Maryland 20892-5452 Bethesda, Maryland 20827 (for courier service) Telephone: (301) 594-8897 Fax: (301) 480-3505 Email: fc15y@nih.gov Direct inquiries regarding fiscal matters to: Teresa Farris Grants Management Specialist Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Room 728MSC 5456 6707 Democracy Boulevard Bethesda, Maryland 20892-5456 (for express/courier service use 20817) Telephone: (301) 594-7682 FAX: (301) 480-3504 Email: tf102y@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.849. 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 and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace 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 PHS mission to protect and advance the physical and mental health of the American people.


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