RFA-DK-00-012: HEMODIALYSIS VASCULAR ACCESS CLINICAL TRIALS CONSORTIUM

Department of Health
and Human Services (HHS)

NIH... Turning Discovery Into Health^®

HEMODIALYSIS VASCULAR ACCESS CLINICAL TRIALS CONSORTIUM Release Date: December 14, 1999 RFA: DK-00-012 (Requesting competing applications from current awardees, see NOT-DK-05-010) National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: February 29, 2000 Application Receipt Date: March 28, 2000 PURPOSE The Division of Kidney, Urologic, and Hematologic Diseases (DKUHD) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has a longstanding and substantial interest in research on the care of patients with end-stage renal disease (ESRD). Among patients with ESRD, hemodialysis is the most common form of therapy. In 1996, about 60% of the approximately 280,000 patients with ESRD were treated with hemodialysis. Despite substantial advances in the care of hemodialysis patients over the past decade, the mortality and morbidity experienced by this patient population continues to be substantial. One important aspect that is essential to permit the treatment of hemodialysis patients, namely the establishment and maintenance of access to the central circulation, has recently received increasing attention. While a substantial number of clinical epidemiological studies have shown that arteriovenous (AV) fistulas are less prone to failure and complications than AV grafts, in 1996 only about 18 percent of ESRD patients had a functioning AV fistula 60 days after initiating hemodialysis. Although our knowledge about the factors that precipitate failure of both fistula and graft AV access is incomplete, there is a positive and strong relationship between the percentage of stenosis observed at the access site and the risk of thrombosis. Despite the substantial medical and economic impact of AV graft and fistula failure in the hemodialysis patient population there have been few randomized controlled clinical trials that have examined the effects of drugs and other therapies aimed at prolonging the survival of these types of vascular accesses. In order to identify effective therapies to reduce the rate of AV graft and fistula failure in hemodialysis patients, the NIDDK invites cooperative agreement applications for investigators to design and implement a series of multi-center, randomized, controlled, clinical trials. These cooperative agreements will support a collaborative network of Clinical Centers and a Data Coordinating Center to conduct well-designed clinical trials over a 5-year period. Because over 40 percent of the new cases of ESRD are attributed to diabetes mellitus and both AV fistulas and grafts are more likely to fail in these patients, special emphasis will be given to recruit at least 50% diabetic patients to permit adequate sub-group and comparative analyses. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Hemodialysis Vascular Access Clinical Trials Consortium, is related to the priority area of chronic disabling conditions and prevention services. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and Local governments, and eligible agencies of the Federal Government. Foreign institutions are not eligible to apply. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. An institution may apply for both a clinical center and the data coordinating center; however, separate applications are required and a specific plan of how the independent operation (i.e., confidentiality of the study-wide data) of each unit will be maintained is required in each application. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during 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. Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreements are discussed later in this document under the section "Terms and Conditions of Award." The total project period for applications submitted in response to the present RFA may not exceed five years. The anticipated award date is September 29, 2000. This is a one time solicitation for applications. The number of awards to be made and level of support to be provided depend on receipt of a sufficient number of applications of high scientific merit. 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 for this purpose. FUNDS AVAILABLE It is expected that approximately $2,000,000 total cost (direct plus Facilities and Administrative costs) will be available for each year over a five year period. It is anticipated that one award for the Data Coordinating Center will be made for approximately $625,000 total cost per year, and five awards for Clinical Centers will be made for $275,000 per year. RESEARCH OBJECTIVES Background End-stage renal disease is an important medical problem in the United States. The number of patients who reach ESRD has been steadily increasing. According to the United States Renal Data System, a national database including more than 95% of the treated ESRD patients in the United States, for the ten-year period from 1987 to 1996, the incidence rates for ESRD were increasing between 6 and 7 percent per year. Currently, approximately 280,000 patients are treated for ESRD in the U.S. and about 70,000 new patients start ESRD treatment annually. Over 60% of these patients receive in-center hemodialysis. Despite improvements in the technology and approaches to the medical management of hemodialysis patients during the past decade, the mortality and morbidity experienced by these patients is unacceptably high. In 1996, the adjusted one-year death rate for hemodialysis patients during the first year of ESRD was approximately 25 per 100 patient years. Of the numerous medical problems encountered by hemodialysis patients, the impact of failed vascular access has received increasing attention. It has been estimated that nearly 20% of the total expenditures for hemodialysis patients (in excess of $1 billion annually) is related to care of vascular access. The morbidity experienced by hemodialysis patients is also substantial; approximately 25% of all hospital stays for ESRD patients are related to problems with vascular access. The two most common methods of gaining repetitive access to the central circulation are arteriovenous (AV) fistulas and AV grafts. While the failure and complication rates for AV fistulas are generally considered to be lower than for AV grafts, less than 20 percent of the patients 60 days after initiating hemodialysis have a mature AV fistula. A substantial number of clinical epidemiological studies, utilizing a variety of methods to monitor the early events associated with vascular access dysfunction, have been conducted. These studies have shown that both AV fistula and AV graft failure is most often attributed to development of stenotic lesions resulting from neointimal hyperplasia which places the patient at high risk for developing access-related thrombosis. Despite the substantial impact of complications from vascular access failure, few intervention studies have been performed to evaluate pharmacologic therapies to improve this aspect of hemodialysis patient care. Of the small number of clinical trials conducted to date, many were carried out over a decade ago. This was prior to the introduction of other therapies for ESRD patients that may impact on the survival and functioning of AV grafts and fistula such as the use of erythropoietin and the increased use of high-flux dialysis membranes. The patient population in these older clinical trials was also different than the current hemodialysis patient population since the proportion of patients with ESRD due to diabetes (and other co- morbid medical conditions) has rapidly escalated during the past ten years. Importantly, novel anti-thrombotic agents and drugs to inhibit cytokines that have been developed over the past several years have not been systematically and rigorously evaluated for their effect on the rate of access survival and complications in hemodialysis patients. The few trials that have been performed more recently have suffered from numerous methodological shortcomings, including small sample sizes. A workshop on the Critical Issues in the Care of the Dialysis Patient, sponsored by the NIDDK, was held in September 1998. Among the recommendations from the workshop, the initiation of randomized controlled clinical trials to reduce both AV graft and fistula complications in hemodialysis patients was rated as having the highest priority. Objectives and Scope The intent of this Request for Applications is to solicit applications from investigators proposing to serve as Clinical Centers or the Data Coordinating Center to conduct collaborative studies among hemodialysis patients. These centers will design and conduct a series of multi-center, randomized, placebo-controlled clinical trials of drug therapies to reduce the failure and complication rate of AV grafts and fistulas in hemodialysis patients over a 5-year period. In order to accumulate a sufficient sample size to test the effect of these interventions, a collaborative effort will be required by five Clinical Centers and one Data Coordinating Center. In this collaborative effort, participating institutions will agree to follow a uniform study protocol with standardized data collection procedures. While applicants for a Clinical Center are requested to propose a single clinical trial design for either AV fistulas or grafts, they must be willing to conduct one or more clinical trials for a type of vascular access not originally proposed in their grant application. Thus it is essential that applicants for Clinical Centers be able to recruit a sufficient number of hemodialysis patients to study both AV fistulas and grafts during the five-year period of this clinical trials consortium program. It is estimated that each Clinical Center will be required to randomize at least 125 individual hemodialysis patients for each of the trials to be carried out by the consortium. The collaborative protocols will be developed by the Steering Committee, composed of the awardees and the NIDDK Project Scientist. The protocols will be subject to peer review by an uninvolved expert group, the Data and Safety Monitoring Board. The studies will proceed only with the concurrence of both the awardees and the NIDDK. Applicants are encouraged to contact pharmaceutical manufacturers of agents proposed for their clinical trial to determine their interest in participating in protocol development and to provide both drug and placebo to the consortium. For those applicants proposing to monitor vascular accesses by Doppler ultrasound, ultrasound dilution techniques, or via some other method requiring specialized equipment, it is recommended that applicants communicate with manufacturers of these devices. Applicants are requested to determine the level of interest of these manufacturers in participating in the trials to be conducted by the consortium, including providing equipment to the investigators. The results of these discussions should be clearly described in the grant application. The intent of this Request for Applications is to provide for an infrastructure to conduct a series of clinical trials among hemodialysis patients. In cases where applicants have an existing clinical research program within their hemodialysis units, the economic implementation of the proposed clinical trial should be documented in the application. It is anticipated that a series of randomized, placebo-controlled clinical trials will be designed and completed over the 5-year period of this program. While the timetable noted below indicates that four clinical trials are scheduled for the 5-year period, the actual number of protocols implemented may vary depending upon the specific study designs agreed upon and implemented by the Steering Committee. Timetable Year I: o Protocol development for clinical trial #1 (first six months) o Patient recruitment (second 6-month period in year 1) o Protocol development for clinical trial #2 (second six-month period) Year II: o Complete patient follow-up for protocol #1 (end of year 2) o Begin recruitment for clinical trial #2 (beginning of year 2) o Complete recruitment for clinical trial #2 (midpoint of year 2) o Data analysis/reporting of results for clinical trial #1(second half of year 2) Year III: o Complete follow-up for clinical trial #2 (midpoint of year 3) o Develop protocol for clinical trial #3 (first half of year 3) o Data analysis/reporting of results for clinical trial #2 (second half of year 3) o Recruitment for clinical trial #3 (second half of year 3) Year IV: o Data analysis/reporting of results for clinical trial #2 (first half of year 4) o Develop protocol for clinical trial #4 (first half of year 4) o Complete follow-up for clinical trial #3 (end of year 4) o Recruitment for clinical trial #4 (second half of year 4) Year V: o Data analysis/reporting of results for clinical trial #3 (first half of year 5). o Complete follow-up for clinical trial #4 (end of year 5) o Data analysis/reporting of final results for clinical trial #4 (end of year 5) o Close-out of Clinical Centers SPECIAL REQUIREMENTS A. Participation in a Collaborative Program To promote the development of a collaborative program among the awardees, the applicant should present evidence of experience in working cooperatively with other Clinical and Data Coordinating Centers and of ability to follow common protocols that are collaboratively developed. Clinical Centers will be expected to communicate with the Data Coordinating Center and the NIDDK Project Scientist on a regular basis. All Clinical Centers in the consortium must agree to implement the protocols and manual of operations that will be developed cooperatively and agree to electronically transmit all study data in a timely fashion to a central Data Coordinating Center for combination and analysis. An explicit statement of willingness to cooperate in a collaborative program should be included in the application. Willingness to study both AV fistulas and grafts must be indicated. The Data Coordinating Center will be involved in collaborations with the NIDDK and the Clinical Centers during all phases of the trials. Thus the applicant for the Data Coordinating Center is expected to demonstrate experience in working cooperatively with Clinical Centers and sponsoring organizations in a multi-center clinical trial or clinical research study and overseeing the implementation of and adherence to a common protocol, as well as assuring quality control of the data collected. An explicit statement of the willingness to participate in a collaborative program should be included in the application. In addition to organizing and attending regular meetings, the Data Coordinating Center will be expected to maintain close communications with the NIDDK Project Scientist and the Clinical Centers. B. Study Components 1) Clinical Centers. Clinical Centers in the consortium will be expected to: a) Design the study protocols and write the manual of operations for each of the clinical trials b) Develop operational plans for the recruitment, treatment, and follow-up of patients c) In collaboration with the Data Coordinating Center, suggest approaches to data analysis and participate in writing of manuscripts for publication in peer-reviewed scientific journals. A Clinical Center is an institution that is actively involved in the recruitment, evaluation, treatment, and follow-up of study participants. For these trials it will consist of a core team of researchers who are skilled in nephrology, delivery of hemodialysis, the care and management of vascular accesses, and have experience in collaborative clinical investigation. An important goal of this consortium is to conduct clinical trials among an overall patient population that at least reflects the gender and racial/ethnic composition of the U.S. hemodialysis patient population. Thus individual Clinical Centers will be required to target recruitment of a sufficient number of women, African American, Hispanic, and Native American hemodialysis patients. Clinical Centers that are able to enhance recruitment in one or more these populations are encourage to indicate this capability in the grant application. Clinical Centers must work in concert with the Data Coordinating Center and must be willing to submit to data audits and other data quality control procedures as established by the study protocol. 2) Data Coordinating Center. The Data Coordinating Center will have the primary responsibility for collecting, editing, storing, and analyzing data provided by the Clinical Centers. It should be prepared to assume a key role in providing guidance and assistance on development of the design of the trials, developing the manual of procedures for each of the individual trials, overseeing implementation and adherence to the protocols, and assuring quality control of the data collected. The Data Coordinating Center will be expected to provide appropriate biostatistical, data management, and coordination expertise. Expertise in nephrology with particular emphasis on hemodialysis and vascular access is beneficial. Applicants for the Data Coordinating Center must provide a detailed description of prior experience in multi-center studies, and should address the aspects of the Data Coordinating Center described below. The Data Coordinating Center will have a central role in statistical aspects of the trials, including final sample size determinations, estimation of event rates, interim analyses for quality control, analyses of trial outcomes, and full statistical oversight. The application should include a discussion of statistical issues and potential problems likely to arise in the design and conduct of these clinical trials. The Data Coordinating Center will provide the support and guidance necessary to maintain the scientific integrity of the trials through Coordinating Center staff or procurement of consultants as necessary. The Data Coordinating Center will have the primary responsibility for developing and implementing computer systems for intra-study communications. The Data Coordinating Center will facilitate the design and refinement of all protocols, manuals of operations, and forms. The Data Coordinating Center will establish a state-of-the- art system for electronic submission of data in a standard format from the Clinical Centers. They will also process all data transmitted, monitor the quality of the data and the performance of the Clinical Centers in the implementation of the protocols, and prepare periodic reports to Clinical Centers on recruitment, protocol adherence, and data quality. The Data Coordinating Center will be responsible for developing plans and interim analyses for the Data and Safety Monitoring Board. The Data Coordinating Center will perform analyses necessary for interim publications and presentations, and prepare appropriately detailed reports to the NIDDK, the Steering Committee and to the Data and Safety Monitoring Board. Shortly after each trial is completed, the Data Coordinating Center will prepare outcome analyses of the data and will collaborate with the investigators of the Clinical Centers and the NIDDK to prepare final reports of the trial for publication. Staff of the Data Coordinating Center will be required to travel to meetings during the planning phases for the development of study designs, protocols, manuals of operation, and forms. The Data Coordinating Center will be required to manage the logistics of all committee and sub-committee meetings during the course of the trials and will be responsible for taking minutes of the various meetings, including the Data and Safety Monitoring Board. The Data Coordinating Center also will make logistical arrangements for meetings of the Data and Safety Monitoring Board, but the NIDDK Project Scientist will serve as Executive Secretary of this group. The Data Coordinating Center will assist the NIDDK Project Scientist in written, telephone, and electronic communications with Clinical Centers and with various committees as requested. 3) Steering Committee. The primary governing body of the study will be the Steering Committee, which will have responsibility for overall trial design and policy decisions (described in more detail under Terms and Conditions) 4) Executive Committee. An Executive Committee also will be convened to facilitate the monitoring and conduct of the trials between meetings of the Steering Committee (described in more detail under Terms and Conditions). 5) NIDDK Project Scientist. The NIDDK will name an NIDDK Project Scientist whose function will be to assist the other components as appropriate in those aspects of the trials described in more detail under Terms and Conditions. The NIDDK Project Scientist will administer the cooperative agreements and will be responsible for the fiscal management of the program at the NIH. TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator(s) as well as the institutional official at the time of award. The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH grant administration policies. 1) Collaborative Responsibilities. The administrative and funding instrument used for this program is a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during 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 this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NIDDK Project Scientist. 2) Awardees Rights and Responsibilities. Clinical Centers The tasks or activities in which awardees for the Clinical Centers will have substantial and lead responsibilities are as follows: 1) Design the study protocols and write the manual of operations for each of the clinical trials 2) Develop operational plans and carry out patient recruitment, treatment, follow-up 3) Carry out complete and accurate data collection and timely transmission to the Data Coordinating Center 4) Suggest approaches to the analyses of data and participate in writing manuscripts of the interim and final results of the trials 5) Ensure adequate representation of women and racial/ethnic minority groups in the trials Willingness to adhere to a common study protocol for each of the trials is essential. Data Coordinating Center The tasks or activities in which awardees for the Data Coordinating Center will have substantial and lead responsibilities are as follows: 1) In conjunction with the Clinical Centers, develop the trial designs and manuals of operations 2) Collect, store, and evaluate the quality of the data transmitted by the Clinical Centers 3) Monitor performance of Clinical Centers in implementing the protocols 4) Provide interim reports on the progress of the Clinical Centers, including reports on recruitment and data quality 5) Provide analyses for the Steering Committee, Data and Safety Monitoring Board, the Executive Committee, and the National Institutes of Health 6) Conduct analyses of the data for publication in peer-reviewed scientific journals Willingness to follow a common protocol for each of the trials is mandatory. Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government policies regarding rights of access. 3) NIDDK Responsibilities. The NIDDK will name the Director, Clinical Trials Program, Division of Kidney, Urologic, and Hematologic Diseases, NIDDK, to be the NIDDK Project Scientist. The Project Scientist’s function will be to assist the Steering Committee, the Executive Committee, the Data and Safety Monitoring Board, and other subcommittees in carrying out the trials, including quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and coordination and performance monitoring. The NIDDK Project Scientist will have voting membership on the Steering Committee, the Executive Committee, and as appropriate, other subcommittees of the Steering Committee. The NIDDK Project Scientist will also serve as Executive Secretary of the independent Data and Safety Monitoring Board. The NIDDK Project Scientist will administer the cooperative agreements and will be responsible for the fiscal management of the program at the NIH. Other NIDDK scientists may, as appropriate, serve on study committees and work with awardees on issues coming before the Steering Committee or its subcommittees. However, in all cases, the NIDDK will have only a single vote on study committees, either of the whole or on subcommittees. The NIDDK reserves the right to terminate or curtail the study (or an individual award) in the event of (a) a major breach in the protocol or substantial changes in the agreed-upon protocol with which the Institute does not agree or (b) human subject ethical issues that may dictate a premature termination or (c) failure to achieve and sustain a clinically meaningful differences in any of the trials, or (d) substantial shortfall in recruitment and/or retention of subjects. 4) Governance The Steering Committee, comprised of each of the Principal Investigators of the Clinical Centers the Principal Investigator of the Data Coordinating Center, the NIDDK Project Scientist, and the Study Chairperson, will have primary responsibility for developing common clinical protocols. They will also facilitate the conduct and monitoring of the trials, and reporting the study results. Each member of the Steering Committee will have one vote, and all major scientific decisions will be determined by majority vote of the Steering Committee. A Consortium Chairperson will be chosen from among the Steering Committee members (but not the NIDDK Project Scientist or Data Coordinating Center Director), or alternatively, from among experts in the field of nephrology who are not participating directly in the study. Subcommittees appointed by the Steering Committee and comprised of Principal Investigators and appropriate staff from the Clinical Centers and the Data Coordinating Center will be involved in the design of the protocols and the manual of operations, and in ongoing functions of the trials, such as review of ancillary studies and preparation of publications. Not all Clinical Centers will necessarily be represented on all subcommittees. An Executive Committee comprised of the Consortium Chairperson, the Principal Investigator of the Data Coordinating Center and the NIDDK Project Scientist also will be convened to effect management decisions required between Steering Committee meetings, as needed for efficient progress of the trials. The Executive Committee will report its actions to the Steering Committee on a regular basis. Meetings of the Executive Committee will generally be held by conference call. The Director, NIDDK will appoint an independent Data and Safety Monitoring Board, to review periodically the progress of the trials. It will be comprised of experts in relevant medical, statistical, operational, and bioethical fields who are not otherwise involved in the study. The Data and Safety Monitoring Board will oversee participant safety, evaluate results, monitor data quality, and provide operational and policy advice to the Steering Committee and to the NIDDK regarding the status of the study. The Principal Investigator of the Data Coordinating Center, the NIDDK Project Scientist, and the Director, Division of Kidney, Urologic, and Hematologic Disease (or representative) may participate as ex- officio, non-voting members of the Data and Safety Monitoring Board. The Data and Safety Monitoring Board will review progress and report to the NIDDK at least once per year. 5) Arbitration. Any disagreement that may arise in scientific- programmatic matters between award recipients and NIDDK may be brought to arbitration. An arbitration panel will be composed of three members - one selected by the Steering Committee (with the NIDDK not voting) or by the individual awardees in the event of an individual disagreement, a second member selected by NIDDK, and a third member selected by the preceding two members. These special arbitration procedures in no way affect the award’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 regulations at 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 is provided 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 "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59, 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at http://grants.nih.gov/grants/guide/notice-files/not94-100.html. 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 may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by February 29, 2000, a letter of intent that includes a descriptive title of the proposed research; name, address, and telephone number of the Principal Investigator; identities of other key personnel and participating institutions; and 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 subsequent applications, the information allows NIDDK staff to estimate the potential review workload and to avoid conflict of interest in the review. The Letter of Intent is to be sent to: Ann A. Hagan, Ph.D. Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-37F, MSC 6600 Bethesda, Maryland 20892-6600 Telephone (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these awards. These forms are available at most institutional offices of sponsored research; from the GrantsInfo, Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, Suite 6095, Bethesda, MD 20892-7910, telephone 301-710-0267, email: [email protected]. 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. 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 2a of the face page of the application form and the YES box must be marked. The RFA number must be typed on the label as well. The sample RFA label is 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 Applicants who wish to use express mail or courier service should change the zip code to 20817. At the time of submission, two additional copies of the application must also be sent to: Ann A. Hagan, Ph.D. Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-37F, MSC 6600 Bethesda, Maryland 20892-6600 Applications must be received by March 28, 2000. 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 announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such an application must follow the guidance in the PHS Form 398 application instructions for the preparation of revised applications, including an introduction addressing the previous critique. Special Instructions for Preparing Applications Within the narrative portions of the applications for the Clinical Center, the following issues should be covered: o Applicants should propose primary and secondary outcomes for randomized clinical trials of drug therapy to improve vascular access survival and reduce complications. It is anticipated that clinical trials will be conducted among patients with both AV fistulas and AV grafts with individual trials focused on one or other type. Applicants should propose a single study design although a series of trials will be conducted over the course of this program. Solutions should be suggested for potential problems related to the design of conduct of such trials. The applicant’s study design should propose the type of vascular access to be investigated, eligibility requirements for study participation, including patient age, gender, racial/ethnic background, duration of hemodialysis treatment, the use of placebo, and cause of ESRD. In addition, exclusion criteria should be specified, along with a rationale for the major criteria proposed. Applicants should provide a justification for the subject selection criteria, including discussion of statistical considerations, an estimate of the number of subjects (and power calculations) required for the proposed trial, and the projected time necessary for recruitment. Applicants must propose primary and secondary outcomes. A rationale for selection of a specific drug for the proposed trial must also be provided. Because of the substantial burden of complications among hemodialysis patients with diabetes as a cause of their renal failure, Clinical Centers must be able to recruit at least 50% diabetic patients for each of the trials. According to the National Kidney Foundation’s Dialysis Outcomes Quality Initiative, several different techniques are useful in monitoring hemodialysis AV grafts and fistulas for stenosis, including dynamic venous pressures, static venous pressures, intra- access flow, among others. A uniform method to monitor hemodialysis AV grafts and AV fistulas for stenosis will be adopted by all of the participating Clinical Centers. The rationale for selecting one technique over another for adoption trial-wide should also be described. However, there may be the opportunity to prospectively evaluate different methods of monitoring in order to compare their ability to predict access failure and complications. o Clinical Center applicants should describe their experience in recruiting and studying hemodialysis patients, and in minimizing losses of patients to follow-up during clinical trials. Particular emphasis will be placed on documenting the ability to recruit women and racial/ethnic minorities for the trials to be conducted by the consortium. The capability to randomize at least 125 individual participants for each of the clinical trials is required. Clinical Centers also should document prior involvement in multi-center clinical trials, success in recruiting minority and women participants, and the ability to recruit a high proportion (at least 50%) of patients whose cause of ESRD is attributed to diabetes mellitus. It is planned that both AV grafts and fistulas will be studied in separate clinical trials over the five-year period of this research program. However, it is not known at this time in what order the trials for these types of vascular accesses will be performed. Thus applicants for Clinical Centers must document a sufficient number of hemodialysis patients having AV fistulas and AV grafts that could be readily recruited and are likely to be eligible to participate in a clinical trial of drug therapy. An organizational structure for the Clinical Center should be provided in the application, delineating lines of authority and responsibility for dealing with problems in all general areas. There should be evidence of strong institutional support for the Clinical Center, including documentation of adequate space in which to conduct clinic activities and office space for staff. Applicants should submit adequately justified budgets for each 12- month period of the trials. These budgets must reflect the major changes in proposed activities that occur as the first protocol is developed, patients recruited and followed-up, development and implementation of subsequent protocols, and final data analyses for each of the trials. See the timetable above for a detailed listing of the proposed activities over the five-year period of this program. Applicants are to assume that all meetings of the Steering Committee (budget for three meetings per year for each year of the program) will be held in the Washington, D.C. area. Within the narrative portions of the applications for the Data Coordinating Center, the following issues should be covered: o Applicants must propose a single design for a clinical trial of drug therapy for vascular access addressing the essential study elements as described above for a Clinical Center, including a plan for methods to monitor the functioning of the access. Applicants must also address the potential requirements of the trial by providing a description of projected tasks likely to be performed by the Data Coordinating Center. The application should be structured around the requirements of a projected study design that addresses the proposed primary and secondary outcomes. Detailed information on the sample size and power calculations must also be provided. A rationale for proposed primary and secondary outcomes must be included in the application. A discussion about promoting adherence to the recommended intervention should be included. Plans for collection and handling of data consistent with the projected needs of the trial should be discussed. Approaches to interim and final data analysis must also be proposed. Special emphasis should be given to sub-group and comparative analyses of outcomes in diabetic patients. o Applicants should submit adequately justified budgets for each 12- month period of the trials. These budgets must reflect the major changes in proposed activities that occur as the first protocol is developed, patients recruited and followed-up, development and implementation of subsequent protocols, and final data analyses for each of the trials. See the timetable above for a detailed listing of the proposed activities over the five-year period of this program. Applicants are to assume that all meetings of the Steering Committee (budget for three meetings per year for each year of the program) will be held in the Washington, D.C. area. In addition, meetings of the Data and Safety Monitoring Board (budget for one meeting per year for each year of the program) will be held in the Washington, D.C. area. REVIEW CONSIDERATIONS Applications will be judged on the basis of the scientific merit of the proposed project and the documented ability of the investigators to meet the RESEARCH OBJECTIVES of the RFA. Although the technical merit of the proposed protocol is important, it will not be the sole criterion for evaluation of a study. Other considerations, such as the importance and timeliness of the proposed clinical trial, access to patients, and experience in multi-center collaborative studies, will be part of the evaluation criteria. Review Method 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. 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 will be discussed, assigned a priority score, and receive a second level review by the National Diabetes and Digestive and Kidney Diseases Advisory Council. Review Criteria Applicants are encouraged to submit and describe their own ideas about how best to meet the goals of the cooperative study and their specific protocols, and are expected to address issues identified under SPECIAL REQUIREMENTS of the RFA. Review Criteria for Clinical Centers The review group will assess the scientific merit of the protocols and related factors, including: Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Demonstrable knowledge of the problems associated with the conduct of randomized clinical trials of vascular access and possible solutions is necessary. The final design for the first clinical trial will be developed collaboratively by the Steering Committee. Thus, the peer review group will focus on evidence that the applicant has carefully thought about the issues involved and possesses the knowledge necessary to contribute meaningfully to the final designs, including understanding of the scientific, ethical, and practical issues underlying the proposed clinical trial. Plans for monitoring the performance of AV grafts or AV fistulas will also be evaluated. Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Investigators: Are the investigator appropriately trained and well- suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? Evidence of prior experience in working collaboratively to carry out a developed study protocol is necessary. Willingness to work cooperatively in this study is required. For the vascular access clinical trials consortium described in this RFA, this criterion will focus on the documented evidence of the training, experience, and specific competence of the investigators and staff relevant to the operation of a Clinical Center. Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? Review of applications for Clinical Center awards also will focus on the following specific criteria: Recruitment Capability: Evidence of prior experience in the recruitment of hemodialysis patients to clinical trials is necessary. In addition, realistic plans for the recruitment of patients, including women and minority participants for the vascular access clinical trials consortium must be included in the grant application. Major emphasis will be placed on the ability of a Clinical Center to recruit at least 50% diabetic patients. The recruitment of at least 125 individual hemodialysis patients for each of the trials to be conducted by the consortium must be documented although a clinical trial design requiring fewer patients may be proposed. The recruitment plans must include the number of hemodialysis units proposed for the trials. In addition, the number of patients available, the number and type of grafts, fistulas and other vascular accesses prevalent in the target patient population, and an estimate of the percent of patients willing to participate in the proposed trial must be provided. If the hemodialysis units from which patients are to be recruited are not under the direct medical management of the Principal Investigator, then assurance that patients can be recruited from these sites must be made available. Retention Capabilities: Plans and/or experience in achieving high rates of follow-up of trial participants and promoting high levels of adherence to the protocol are essential. Data Management and Transmission: Adequacy of plans to ensure complete, reliable, and timely transmission of the study data. Collaboration between Centers: For those applications proposing collaborative efforts between two applicants from different institutions to form a single Clinical Center additional factors to be considered would include the advantages of collaboration in terms of cost and recruitment capabilities. The organizational/administrative plan for such arrangements needs to be clearly delineated. Review of applications for the Data Coordinating Center will be based on the following specific criteria: Significance: Does the proposed clinical trial 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 grant application clearly delineate the proposed design, including sample size and power calculations, for a randomized controlled clinical trial of drug treatment to improve survival of either AV fistulas or grafts? Demonstrable knowledge of the problems associated with the conduct of randomized clinical trials of vascular access and possible solutions is necessary. The final design for the first clinical trial will be developed collaboratively by the Steering Committee. Thus, the peer review group will focus on evidence that the applicant has carefully thought about the issues involved and possesses the knowledge necessary to contribute meaningfully to the final designs, including understanding of the scientific, ethical, and practical issues underlying the proposed study. Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Investigators: Are the investigator appropriately trained and well- suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? Evidence of prior experience in working collaboratively to carry out a developed study protocol is necessary. Willingness to work cooperatively in this study is required. Documented specific competence and relevant experience of professional, technical, and administrative staff pertinent to the operation of a Data Coordinating Center for a series of randomized clinical trials of drug therapy to improve performance of hemodialysis vascular accesses. Prior experience collecting data from multiple clinical sites, monitoring the data quality and developing and utilizing statistical methods to analysis of data should be demonstrated. Experience in developing remote entry, web- based data transmission systems for the Clinical Centers is required. Experience of Data Coordinating Center personnel in utilizing procedures to insure the safety and confidentiality of all records should be documented. Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? Data Management: Adequacy of the proposed plans and experience relating to data collection, management, editing, processing, quality control, analysis, and reporting. Resources: Adequacy of the proposed facility, technical hardware, and space. Appropriateness of the organizational and administrative structure of the proposed Data Coordinating Center is necessary. Evidence of institutional support and commitment for the proposed program should be provided. Knowledge of Problems: Demonstrable knowledge of the potential problems associated with the conduct of clinical trials of drug therapy to improve survival and decrease the complication rate of both AV grafts and fistulas and approaches to their solution. Experience in working with drug packaging and distribution centers: It is anticipated that a central distribution center will be established to furnish both drug and placebo in a timely fashion to the Clinical Centers. The experience in establishing and working cooperatively with a Drug Distribution Center in cooperative studies should be clearly documented. Cooperative Experience and Approach: Adequacy of the approach to developing a cooperative relationship among the participating Clinical Centers and exercising appropriate leadership in matters of study design, data acquisition, data management, data quality, and data analysis. Evidence of experience in and willingness to participate appropriately in a collaborative study as described in this RFA. In addition to the above criteria, in accordance with NIH policy, all applications for Clinical Centers and the Data Coordinating Center will also be reviewed with respect to the following: The reasonableness of the proposed budget. The adequacy of the proposed protection for human subjects and the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA It is anticipated that awards will by made on September 30, 2000. Applications recommended by the National Institute of Diabetes and Digestive and Kidney Diseases Advisory Council will be considered for award based upon (a) scientific and technical merit; (b) program balance, including in this instance, sufficient compatibility of features to make a successful collaborative program a reasonable likelihood; (c) geographic location of the applicant, (d) recruitment of racial and ethnic minorities and diabetic patients, (e) cost, and (f) availability of funds. Schedule Letter of Intent: February 29, 2000 Application Receipt Date: March 28, 2000 Review by NIDDK Advisory Council: September 20-21, 2000 Anticipated Award Date: September 29, 2000 INQUIRIES Written, including electronic mail, and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: John W. Kusek, Ph.D. Division of Kidney, Urologic, and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Building 45, Room Number 6AS13J, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-7735 FAX (301) 480-3510 Electronic mail: [email protected] Direct inquiries regarding fiscal matters to: Helen Ling Grants Management Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, MSC 6600 Room 6AN-44F Bethesda, Maryland 20892-6600 Telephone: (301) 594-8857 FAX: (301) 480-3504 Email: [email protected] AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.849 and 93.864. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under 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 NIH strongly encourages all grant and contract 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 NIH mission to protect and advance the physical and mental health of the American people.

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