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TYPE 1 DIABETES TRIALNET: CORE SUPPORT FACILITIES Release Date: October 5, 2000 RFA: DK-01-004 National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov) National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov) National Institute of Child Health and Human Development (http://www.nichd.nih.gov) Letter of Intent Receipt Date: February 28, 2001 Application Receipt Date: March 29, 2001 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), and the National Institute of Child Health and Human Development (NICHD) are seeking applications for an operations coordinating center which will provide for a data monitoring unit, central distribution pharmacy, and clinical cost reimbursement system to support intervention studies to preserve pancreatic beta cell function and prevent type 1 diabetes. The core facilities will support completion of the ongoing Diabetes Prevention Trial for Type 1 Diabetes (DPT-1), and support and participate in the design and execution of pilot and expanded studies of new agents to prevent or ameliorate type 1 diabetes, and in natural history and genetics studies in populations screened for or enrolled in these studies. Additional core support facilities that are currently participating in the DPT-1, specifically the core laboratories, the compounding pharmacy, and the consultant firm for the central telephone line and publicity/recruitment support, will continue to operate during completion of the DPT-1 in order to ensure the integrity and continuity of the trial. These facilities may change for the conduct of new pilot and expanded intervention studies, however, they are not being solicited in this Request for Application (RFA). The core support facilities selected to complete the ongoing DPT-1 and to participate in new studies, as well as a consortia of clinical centers, will constitute a national diabetes trial network (Type 1 Diabetes TrialNet or TrialNet) of clinical research groups whose aim is to recruit patients and to support studies that may eventually result in an improved understanding of type 1 diabetes and the prevention of the disease. A complementary RFA (DK-01-003) is being published to establish the Type 1 Diabetes TrialNet Clinical Centers and for proposals for intervention studies of new agents to prevent and ameliorate type 1 diabetes. The Operations Coordinating Center (OCC) will coordinate interactions between core support facilities, Clinical Centers and associated networks of recruitment/retention sites, sponsoring agencies, committees, and consultants, and will develop and/or maintain financial management plans and all study protocols, manuals, agendas, and newsletters. The OCC will provide for the Data Monitoring Unit, existing and future Core Laboratories and compounding pharmacies, the Central Distribution Pharmacy, a clinical cost reimbursement system, and the consultant firm providing the central telephone line and publicity/recruitment expertise. If necessary, the OCC will provide for these core support facilities through subcontracts to one or more institutions. The Data Monitoring Unit will be responsible for all study data management and statistical considerations and will coordinate with the Central Distribution Pharmacy and clinical cost reimbursement system. This RFA responds to recommendations of the Congressionally-established Diabetes Research Working Group which developed a strategic plan for research in diabetes (http://www.niddk.nih.gov/federal/dwg/dwgsummary.htm). Among the extraordinary research opportunities mentioned in the plan were: the conduct of additional clinical trials of immunoprevention of type 1 diabetes using antigen-specific, cytokine- or antibody-based immunotherapy and the establishment of a national diabetes trial network of cooperative clinical research groups and core support facilities to create the stable, high-quality infrastructure necessary for the conduct of effective and efficient clinical trials in diabetes. The actual studies to be performed, in addition to completion of DPT-1, will be determined by a steering committee (see Special Requirements, Study Organization, below) composed of Principal Investigators of the Clinical Centers, Operations Coordinating Center, Data Monitoring Unit, Core Laboratories, and NIH Program Officers. The Immune Tolerance Network (ITN), a program of the NIAID, NIDDK, and Juvenile Diabetes Foundation International, also supports clinical trials to evaluate the safety and efficacy of tolerance induction strategies to prevent and ameliorate type 1 diabetes and other autoimmune diseases. Information on this program can be found at http://www.immunetolerance.org. The Type 1 Diabetes TrialNet and the ITN will provide an integrated approach to immunoprevention and amelioration of type 1 diabetes. Promising pilot studies initiated in the ITN may lead to larger clinical trials that could be conducted using TrialNet. In addition, TrialNet may use assays provided through the ITN to generate information on mechanisms by which interventions exert their effect. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA, Type 1 Diabetes TrialNet, is related to the priority area of Diabetes. Potential applicants may view 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 organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. This geographic constraint is necessary because of the need for close communication among members of the Study Group, the requirement for frequent Steering Committee meetings, and the anticipated need for site visits to ensure adequate recruitment, retention, and the use of standardized procedures across the studies. Applicants from racial/ethnic minority groups, women, and persons with disabilities are encouraged to apply as Principal Investigators. 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 agreement(s) are discussed later in this document under the sections titled “Objectives and Scope”, “Special Requirements”, and "Terms and Conditions of Award." It is anticipated that one award will be made to the Operations Coordinating Center which, if necessary, will support subcontracts to the other core support facilities. The total project period for applications submitted in response to the present RFA should be 7 years. The anticipated award date is September 2001. At initiation of the Type 1 Diabetes TrialNet, support for the OCC and its subcontracts will be provided for completion of DPT-1 and planning of new studies to be conducted under TrialNet. Level of support in subsequent years will be determined by the requirements of the specific studies designed and executed by the Steering Committee and by the availability of funds. Awards and level of support depend on receipt of a sufficient number of applications of high scientific merit for the entire Type 1 Diabetes TrialNet. Although this program is provided for in the financial plans of the NIDDK/NIAID/NICHD, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. This RFA is a one-time solicitation. At this time, the NIDDK/NIAID/NICHD have not determined whether or how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE Approximately $4.7 million in total costs per year will be committed for the Operations Coordinating Center and all associated core support facilities for completion of the DPT-1 and for planning new studies in the Type 1 Diabetes TrialNet. It is anticipated that one award will be made to the Operations Coordinating Center which, if necessary, will support subcontracts to one or more institutions to provide for the Data Monitoring Unit, the Core Laboratories, the compounding pharmacy(ies), the Central Distribution Pharmacy, clinical cost reimbursement system, and the consultant firm for the central telephone line and for media/recruitment support. The budget cannot exceed $2,060,000 in total costs annually for the Operations Coordinating Center (personnel, supplies, equipment and communications), Data Monitoring Unit (personnel, supplies, equipment, and communications), clinical cost reimbursement system, and Central Distribution Pharmacy Unit. Additional details are provided below under BUDGET INFORMATION. As indicated below under BUDGET INFORMATION, approximately $2.7 million in total costs annually will be provided for the Core Laboratories, the compounding pharmacy, the consultant firm for the central telephone line and publicity/recruitment support, patient care costs which will be reimbursed to recruitment/retention sites on a per subject basis, travel, and other expenses. Awards and level of support depend on receipt of a sufficient number of applications of high scientific merit for the entire Type 1 Diabetes TrialNet. Funding after completion of DPT-1 will depend on the existence and status of studies of promising new agents, as well as the successful operation of the core support facilities and recruitment and retention sites of the TrialNet. RESEARCH OBJECTIVES Background 1) Diabetes Prevention Trial for Type 1 Diabetes (DPT-1) 1.1) DPT-1 Objectives and Design Type 1 diabetes arises in genetically predisposed individuals as a consequence of immune-mediated destruction of the pancreatic islet insulin secreting beta cells. The onset of clinical symptoms of diabetes represents the endpoint of a chronic progressive decline in beta cell function, and occurs when the majority of beta cells have been lost. First-degree relatives of probands with type 1 diabetes have more than a tenfold risk of type 1 diabetes compared with the general population. Type 1 diabetes can be predicted with a high degree of accuracy in relatives of patients with type 1 diabetes by the presence of autoantibodies and evidence of pancreatic beta-cell dysfunction. The major objective of the ongoing DPT-1 is to determine whether early intervention using antigen-based therapies (parenteral or oral insulin) in nondiabetic relatives of persons with type 1 diabetes can delay the development of type 1 diabetes as a clinical disease. The rationale for initiating the DPT-1 was based on several lines of evidence. Parenteral insulin had been successfully used to prevent diabetes in animal models of spontaneous diabetes (e.g., BB rat, NOD mouse). In humans, intensive insulin therapy in newly-diagnosed diabetic patients had preserved beta- cell function, and small pilot studies of prediabetic patients suggested that insulin treatment might delay development of type 1 diabetes. In these studies, it was thought that exogenous insulin may be serving as an immune modulator or may be decreasing the expression of secretory granule-associated antigens from the beta-cells, making them less susceptible to immune attack. Oral insulin had been studied in the NOD mouse model of type 1 diabetes; these studies demonstrated that oral administration of islet cell autoantigens was effective in delaying the onset of type 1 diabetes. In addition, ingestion of glutamic acid decarboxylase (GAD), a beta-cell antigen, by NOD mice also inhibited the development of diabetes. These results suggested that tolerance provoked by presentation of oral insulin or GAD to the immune system via the intestinal mucosa could attenuate pancreatic islet autoimmunity, leading to a delay in the onset of type 1 diabetes. Initial screening for DPT-1 is being conducted by determining the presence of islet cell autoantibodies (ICA) in nondiabetic relatives of individuals with type 1 diabetes. Those individuals found to have ICA are then staged into different categories of risk for type 1 diabetes, depending on their point in the progression to clinical disease. This further assessment of risk of type 1 diabetes in nondiabetic relatives is based on a number of factors, including: genetic susceptibility, the presence of insulin autoantibodies (IAA), and the degree of loss of first phase plasma insulin response (FPIR) during an intravenous glucose tolerance test. Individuals with a protective HLA haplotype are excluded from study. “High risk” relatives are those who have been predicted to have a greater than 50% probability of developing type 1 diabetes within the next five years based on being positive for ICA and having a low FPIR. “Intermediate Risk” relatives are those who have been predicted to have a 25-50% risk of type 1 diabetes during the next 5 years based on being positive for ICA and also for IAA, but not having a low FPIR. Relatives at lower risk lack IAA and do not have a low FPIR. Subjects were divided into predictive risk groups to permit different intervention strategies to be applied based on their stage in the progression of the disease. The more invasive therapeutic approach with parenteral insulin was tested in the group with the higher estimated risk of type 1 diabetes. In the “High Risk” group, the protocol is designed to determine whether parenteral insulin therapy, consisting of daily subcutaneous insulin injections with an accompanying annual course of continuous intravenous insulin, will delay the expected development of clinical type 1 diabetes. Subjects are being randomized to either the experimental treatment group or closely monitored (control) group who will be carefully assessed and offered treatment at the earliest sign of clinical diabetes. The intervention protocol for the “Intermediate Risk” group is designed to determine whether orally ingested insulin can induce immunological tolerance, thereby delaying the development of type 1 diabetes. Subjects are being randomized to either the experimental treatment group or placebo-controlled group. Randomized participants are followed at six- month intervals. Subjects who are ICA positive but who are at lower risk of type 1 diabetes are not being enrolled in the study but are being followed for progression to intermediate or high risk with the opportunity for enrollment at that stage. The design of DPT-1 requires the enrollment of 340 “High Risk” and 490 “Intermediate Risk” subjects. Screening for the trial began in September 1993. Subjects were first randomized to the “High Risk” protocol in December 1994 and to the “Intermediate Risk” protocol in September 1996. Participants are to be followed for at least two years and up to approximately 6 years. As of July 2000, the recruitment for the “High Risk” protocol is approximately 95% complete and for the “Intermediate Risk” protocol is approximately 55% complete. Recruitment is expected to be completed by the end of 2002. 1.2) DPT-1 Clinical Centers and Networks, Core Support Facilities Nine parent Clinical Centers are participating in the DPT-1. Parent Clinical Centers are involved in screening, staging, enrolling, and following study participants. Each Clinical Center provides administrative support for its own network of Affiliates and Satellites. In total, there are approximately 350 Affiliates and Satellites participating in DPT-1 across the United States, Canada, and Puerto Rico. Affiliates screen, stage and follow participants, while Satellites are involved only in screening. In addition, there are designated regional recruitment coordinating centers which provide local outreach to underserved geographic areas of the country to enhance recruitment, as well as minority recruitment centers which focus on increased recruitment of these population subgroups. Current core support facilities of the DPT-1 include the Operations Coordinating Center (OCC), the Data Monitoring Unit (DMU), Core Laboratories, Compounding Pharmacy, Central Distribution Pharmacy, the clinical cost reimbursement system, and the consultant firm managing the central telephone line and providing publicity/recruitment support. The OCC coordinates all interactions between the core support facilities, Clinical Centers and associated networks of Affiliates and Satellites, sponsoring agencies, study committees, and consultants. The OCC also develops and/or maintains financial management plans and all study protocols, manuals, agendas, and newsletters. The DMU is responsible for all study data management and statistical considerations. In addition, the DMU tracks clinical tests performed within the DPT-1 and this information is provided to two fiscal cluster facilities that distribute payments to the appropriate Clinical Centers/Affiliates/Satellites. The Core Laboratories include the Islet Cell Antibody Laboratory, the Insulin Autoantibody Laboratory, the Class II Major Histocompatibility and DNA Extraction Laboratory, and the Beta Cell Function Laboratory. The Central Distribution Pharmacy dispenses all therapeutic agents and placebos in DPT-1 studies. It receives crystallized insulin and placebo in capsules from the Compounding Pharmacy. Currently, the OCC has subcontracts to the DMU, Central Distribution Pharmacy, the consultant firm providing the central telephone line and publicity/recruitment support, and two of the Core Laboratories. The other two Core Laboratories are supported through subcontracts to other U01s currently being funded in DPT-1. DPT-1 is presently funded through August 2001. The trial is jointly supported by the National Institute of Diabetes and Digestive and Kidney Disease, the National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, the National Center for Research Resources through funding of General Clinical Research Centers, the American Diabetes Association, the Juvenile Diabetes Foundation International, and industry. 2.) Studies of New Immunologic Agents and Other Preventive and Treatment Strategies In recognition of the seriousness of diabetes in terms of both human toll and economic costs, Congress directed the establishment of the Diabetes Research Working Group (DRWG) and charged it with developing a comprehensive plan for diabetes research (http://www.niddk.nih.gov/federal/dwg/dwgsummary.htm). During 1998, the DRWG and its subcommittees held a series of meetings, consulted with a wide range of experts in the field, and heard public commentary. A comprehensive strategic research plan was submitted to Congress in 1999. As part of the plan, the DRWG identified areas of extraordinary opportunity for making genuine and significant progress toward understanding, more effectively treating, and ultimately preventing and curing diabetes. Among these opportunities was the recommendation to “define the immunological basis of type 1 diabetes and develop methods for prevention of the disease.” Specific recommendations included: to intensify research to understand the immunological basis of type 1 diabetes; to complete mapping of T cell specificity of autoimmune responses to major pancreatic islet cell proteins and identify optimal strategies for immunotherapy; to expand the scope of efforts to identify immune response markers that reliably detect individuals predisposed to type 1 diabetes in the population at large; and to conduct additional clinical trials of immunoprevention of type 1 diabetes using antigen-specific, cytokine- or antibody-based immunotherapy. In response to these recommendations, the NIDDK and DPT-1 investigators have convened meetings to consider future natural history, pilot and intervention studies. A number of ideas were generated. Potential cohorts for study include: patients with type 1 diabetes who have evidence of residual pancreatic beta-cell function; individuals found to have biochemical antibodies in an ancillary study of the DPT-1 cohort, who do not meet eligibility criteria for the DPT-1; individuals found to be ICA positive in the DPT-1, who lack other beta-cell antibodies and have an intact first phase insulin response; individuals found during staging for the DPT-1 to be positive for protective HLA-haplotypes; individuals found to have diabetes during staging; and randomized DPT-1 subjects who develop diabetes on follow-up. Examples of potential agents to prevent or ameliorate type 1 diabetes include antigen-based therapies such as recombinant human GAD65 and the heat shock protein hsp60 p277 peptide, monoclonal antibodies such as anti-CD3 and anti-CD25, and certain cytokine-based therapies. Multiple pilot, feasibility, and efficacy studies could be done simultaneously to test promising agents in patients with type 1 diabetes who have evidence of residual beta cell function (including DPT-1 subjects who develop diabetes during follow- up), or in patients identified in the screening process for DPT-1 who are not eligible for the trial. Loss of C-peptide secretion would be a suitable design endpoint for such studies. On the basis of these pilot studies, expanded intervention studies might be launched in new-onset type 1 diabetic individuals to assess beta-cell function over time and ultimately in at-risk pre-diabetic individuals to prevent development of diabetes. 3.) Type 1 Diabetes TrialNet The Diabetes Research Working Group also noted that clinical research and clinical trials in diabetes have been hampered by the lack of infrastructure to organize and support them (http://www.niddk.nih.gov/federal/dwg/dwgsummary.htm). The long-term natural history of the disease and its complications add to the complexity of clinical trials. Needed are efficient systems for clinical research to provide the necessary numbers of patients and the stability of operations for long-term studies, and opportunities to include sufficient numbers of appropriate minority groups. To that end it was recommended that there be established a national diabetes trial network of cooperative clinical research groups to create the stable, high-quality infrastructure necessary for the conduct of effective and efficient clinical trials in diabetes. The existing structure in the DPT-1 of Clinical Centers and associated networks, as well as its core support facilities, is an excellent platform on which to build an enhanced infrastructure that could comprise the Type 1 Diabetes TrialNet. Currently there are nine parent Clinical Centers participating in screening, staging, randomization, and follow-up of volunteers in the DPT-1. Each Clinical Center provides administrative management and training for an extended network of institutions and physicians, including Affiliates that also screen, stage, randomize, and follow volunteers, as well as Satellites that screen potential participants. Expansion of the number of Clinical Centers and associated Affiliates and Satellites would enhance recruitment of subjects for the DPT-1 and future Type 1 Diabetes TrialNet studies. A complementary RFA (DK-01-003) is requesting applications to expand the number of Clinical Centers. As described above under Section 1.2, “DPT-1 Clinical Centers and Networks, Core Support Facilities,” core support facilities that currently exist in the DPT-1 are the Operations Coordinating Center (OCC), the Data Monitoring Unit (DMU), Core Laboratories, the Compounding Pharmacy, the Central Distribution Pharmacy, and a consultant firm managing the central telephone line and providing publicity and recruitment support. Reimbursement for clinical tests performed within the DPT-1 is tracked by the DMU and this information is provided to two fiscal cluster facilities that distribute payments to the appropriate Clinical Centers/Affiliates/Satellites. Modification of these facilities and of the structure will be necessary resulting from expansion of the number of Clinical Centers and performance of new studies. New studies performed within the Type 1 Diabetes TrialNet may require additional core laboratory measurements. Core Laboratory support may be consolidated under fewer laboratories if deemed possible and advantageous. Assay cores of the Immune Tolerance Network (http://www.immunetolerance.org) may also be used for assessments in the TrialNet. Currently, the OCC has subcontracts or purchase orders with the DMU, Compounding Pharmacy, Central Distribution Pharmacy, two of the Core Laboratories, and a consultant firm managing the central phone line and providing publicity/recruitment support. The other two laboratories are supported through subcontracts to other U01s currently funded in DPT-1. The NIDDK/NIAID/NICHD are creating a new structure funded through one U01 to the OCC which will provide support for all DPT-1 and TrialNet Core Laboratories. Letters of Agreement with the OCC will be obtained from all Clinical Centers/Affiliates/Satellites to allow for the flow of reimbursement dollars for clinical care costs. 4.) Potential Genetics Studies using Type 1 Diabetes TrialNet An additional extraordinary opportunity identified by the Diabetes Research Working Group was the study of the genetics of diabetes and its complications. While it was recognized that most of the basic tools for genetic studies were in place and that much progress had been made, it was noted that current approaches were inadequate to tackle vital genetics questions in a reasonable time frame. Impediments cited were inadequate resources, the lack of an appropriate mechanism to bring together groups of researchers and patient samples to conduct studies, and fragmented genetic repositories. The DPT-1 study population and populations identified by the Type 1 Diabetes TrialNet may be fruitful groups to study predisposing genes to type 1 diabetes and diabetic complications. While it has not been determined whether or how such studies might be implemented, samples and associated data from participants of the DPT-1 and TrialNet may be entered into genetic repositories for use by investigators inside or outside the TrialNet. Objectives and Scope The first objective of the Type 1 Diabetes TrialNet core facilities is to support completion of the DPT-1. The second objective of the core facilities is to support expanded intervention studies of new agents to prevent or ameliorate type 1 diabetes. In addition, the Type 1 Diabetes TrialNet may support natural history and genetics studies in populations screened for or enrolled in these studies. The Operations Coordinating Center (OCC) and associated Core Laboratories, consultant firm for the central telephone line and publicity/recruitment support, Data Monitoring Unit (DMU), Compounding Pharmacy, Central Distribution Pharmacy, and clinical cost reimbursement system will support the recruitment, randomization, and follow-up of participants in the DPT-1. The core facilities will also provide this support for future natural history, genetics, pilot, feasibility, and efficacy studies, and for expanded intervention studies of the TrialNet. Interested applicants should review the complementary RFA for the Type 1 Diabetes TrialNet: Clinical Centers (DK-01-003) in order to appreciate the anticipated duties of the Clinical Centers and associated networks of recruitment and follow-up sites. If necessary, the OCC will provide subcontracts or purchase orders for the Data Monitoring Unit, existing and future Core Laboratories and compounding pharmacies, the Central Distribution Pharmacy, the clinical cost reimbursement system, and the consultant firm providing the central telephone line and publicity/recruitment expertise. The OCC will coordinate interactions between the Clinical Centers and their associated networks of Affiliates and Satellites, the DMU (if separate from the OCC), Core Laboratories, study monitoring groups (e.g., laboratory, clinical centers/networks, safety), study committees and consultants, and sponsoring agencies. In addition, the OCC will: facilitate the execution of study activities in the DPT-1 and Type 1 Diabetes TrialNet as directed by the Steering Committee and Chairperson; develop and prepare study protocols and manuals of operations; provide financial management; communicate with DPT-1 and TrialNet membership, including circulation of newsletters, operations manuals, protocols, minutes of meetings, correspondence, publications, manuscripts, contracts, orders, materials necessary for progress reports and institutional reviews; prepare annual reports and subcontracts; develop publicity and other subject recruitment tools; interact with the media to facilitate recruitment and publicize the study; develop meeting agendas; convene, arrange, and conduct Steering Committee and subcommittee meetings; arrange and prepare materials for Data Safety and Quality Monitoring Group meetings; provide for shipment of samples between clinical sites and laboratories; oversee the performance of quality control audits; maintain membership rosters, study directories, and committee lists; provide updated slide sets for professional meetings on a semi-annual basis; maintain a reference reprint file of DPT-1 and Type 1 Diabetes TrialNet publications; maintain files of conflict of interest forms and Institional Review Board (IRB) approval forms for all Clinical Centers/Affiliates/Satellites; obtain Letters of Agreement with all Affiliates and Satellites to provide for the flow of reimbursement dollars for patient care costs and to document a willingness to abide by study procedures; provide a central file for all ancillary studies and related documents; and oversee certification of personnel at sites for shipping of specimens and performing study tests. A representative from the OCC will attend all study committee meetings, Steering Committee meetings, and Data Safety and Quality Monitoring Group meetings. The OCC will be responsible for the coordination of the Core Laboratories participating in the DPT-1 and Type 1 Diabetes TrialNet. Subcontracts will be provided to the laboratories from the OCC. To ensure the integrity and continuity of the DPT-1, the current Core Laboratories will continue to be responsible for measurement of critical variables in the DPT-1 protocol. The University of Florida will continue to measure cytoplasmic islet cell antibodies (ICA) as needed. The measurement of insulin autoantibodies will be performed by the current laboratory at the Joslin Diabetes Center. The University of Colorado will extract and preserve DNA from all participants staged in the DPT-1 for eligibility for enrollment in the intervention protocols; specifically HLA-DQA1*0102, DQB1*0602 will be determined. In addition, the University of Washington VA Medical Center will continue to assess beta-cell function by measurement of immunoreactive insulin and C-peptide, plasma glucose, and glycosylated hemoglobin HbA1c. New studies performed within the Type 1 Diabetes TrialNet may require additional core laboratory measurements. Core Laboratory support may be consolidated under fewer laboratories if deemed possible and advantageous. Assay cores of the Immune Tolerance Network (http://www.immunetolerance.org) may also be used for assessments in the TrialNet. The OCC will be responsible for soliciting and reviewing submissions for additional Core Laboratories, and selecting optimal applications, as dictated by the TrialNet Steering Committee. The current DPT-1 Core Laboratories and future Core Laboratories will communicate on a regular basis with Clinical Centers/Affiliates/Satellites regarding receipt of samples, sample integrity, and results of measurements as directed by DPT-1 and TrialNet protocols. Future Core Laboratories will have had demonstrated expertise in performing the assays for research purposes, ideally in a clinical trial setting. Laboratories will have on-line communication with the DMU and have equipment to read bar-coded samples; transmission of data must occur on a regular basis as dictated by the DPT-1 and Type 1 Diabetes TrialNet. The laboratories will have appropriate quality control procedures that are documented and will participate in external quality assurance programs. Laboratory directors should participate in all study Steering Committee meetings, and directors and other laboratory personnel are expected to participate in other committee meetings as needed. The laboratories must abide by DPT-1 and Type 1 Diabetes TrialNet protocols and manuals of operations. The OCC will also provide for a Compounding Pharmacy. The current Compounding Pharmacy will continue to provide crystallized insulin and placebo in capsule for the DPT-1 oral insulin trial, to ensure the integrity and continuity of the trial. Compounding Pharmacy requirements may change as new trials are designed using new agents. The OCC will be responsible for soliciting and reviewing submissions for new compounding pharmacies, and selecting optimal applications, as dictated by the TrialNet Steering Committee. Some drugs may be donated by pharmaceutical companies. The consultant firm that currently manages the central telephone line for the DPT-1 (1-800-HALT-DM1) will continue in this capacity during completion of the DPT-1. The consultant firm will respond to callers by describing the study and mailing brochures and study materials according to current protocol. The firm will track telephone activity, and ascertain the source of hearing about the DPT-1 and other characteristics of the callers. In addition, the firm will continue to produce the patient newsletter and provide necessary recruitment materials and publicity and outreach support. Representatives from the consultant firm will attend Steering Committee and other Study Group meetings as needed. If necessary, the OCC will provide support for the DMU through a subcontract. The DMU will be responsible for all data management and statistical considerations for the DPT-1 and Type 1 Diabetes TrialNet. The DMU will receive data electronically from remote sites (i.e., Core Laboratories and Clinical Centers/Affiliates/Satellites) when appropriate. When this is not appropriate, the DMU will receive data via hardcopy forms. Data on hardcopy forms should be scannable for data entry when appropriate or double-entered to check for discrepancies. Data should be checked for logic and consistency. Changes in participant status will be updated and reported to Clinical Centers/Affiliates/Satellites indicating the need for further tests and visits, or the need for randomization. When appropriate and applicable, the DMU will generate letters describing test results to subjects. Errors on study forms and requests for correct information will be communicated back to Clinical Centers/Affiliates/Satellites. A system of barcodes for use by the Core Laboratories will be generated by the DMU. The DMU will provide for central registration and random assignment of all subjects enrolled in trials. Computer files will be maintained and backed up and hardcopy forms will be copied as necessary and filed. The DMU will generate data quality reports such as for inconsistent/missing information, missing/damaged laboratory samples, subject status reports, center status reports, tests and forms past due, and reimbursement reports. It is highly desirable that aggregate data be available online to individuals conducting DPT-1 and TrialNet studies at a website maintained by the DMU. Information provided at the website might include, for example, recruitment data, recruitment data specific to individual Clinical Centers, monitoring group data (e.g., laboratory, clinical, and safety monitoring), up-to-date study forms, publications, DPT-1 and Type 1 Diabetes TrialNet site contact information, and information on ancillary studies. These data should be accessible only by unique passwords. The DMU will provide statistical reports at all meetings on progress of the trials. The DMU director or representative will serve on all DPT-1 and Type 1 Diabetes TrialNet administrative committees, will attend all Steering Committee meetings and Data Safety and Quality Monitoring Group meetings, and will be asked to serve on other committees as needed. The DMU will help develop and implement and will abide by DPT-1 and TrialNet protocols and manuals of operations. The DMU will review all proposed protocols and develop statistical designs for studies, analyze study results, review all manuscripts for statistical considerations, develop and test predictive models for disease progression, and perform all other statistical needs for the DPT-1 and TrialNet. There must be assurance that all study data transmitted electronically and stored data are secure and cannot be obtained by anyone other than those for whom it was intended. For example, electronic data should be encrypted, methods should be in place to ensure that no modifications can be made during data transmission, and it should be possible to authenticate who sent and received the data and when the data were sent and received. The DMU will coordinate with the clinical cost reimbursement system by tracking all clinical tests performed in the DPT-1 and the TrialNet and maintaining necessary files. Reimbursement reports will be generated for checking and approval by Clinical Centers. The clinical cost reimbursement system will provide for the distribution of payments to appropriate Clinical Centers/Affiliates/Satellites as directed by the DMU. The DMU will also coordinate with the Central Distribution Pharmacy. For the DPT-1, the current Compounding Pharmacy will supply the Central Distribution Pharmacy with oral insulin and placebo. The Central Distribution Pharmacy will dispense all therapeutic agents and placebos used in DPT-1 and Type 1 Diabetes TrialNet studies. The Central Distribution Pharmacy will distribute these agents to Clinical Centers in a masked manner as directed by the DMU. The OCC, DMU, Core Laboratories, Compounding Pharmacy, Central Distribution Pharmacy, and clinical cost reimbursement system must conform to the guidelines of the Office of Human Research Protections (OHRP) by obtaining an assurance, having an IRB of record, and obtaining IRB approval annually. The NIDDK expects that biologic samples and associated clinical data will be made available to the broader scientific community at an appropriate juncture to support further studies related to the prevention and etiology of type 1 diabetes, and in studies to identify genes predisposing to diabetes and its complications. SPECIAL REQUIREMENTS Collaboration of Investigators of DPT-1 and Type 1 Diabetes TrialNet To promote the development of a collaborative program among the award recipients, principal investigators, trial coordinators, recruitment coordinators and representatives of the Operations Coordinating Center, Core Laboratories, and Data Monitoring Unit are expected to attend DPT-1 and TrialNet Steering Committee meetings. These are anticipated to meet twice a year for established trials but may meet more frequently for development of new protocols. At these meetings, new studies will be designed, study progress will be monitored, issues related to study protocol operations will be discussed, and ideas will be exchanged to enhance study progress. Representatives of the core support facilities will also be expected to serve on other study committees as needed. Applicants must document their experience and capability to participate in a complex multicenter trial of this nature using a standard protocol. Evidence of institutional support for participating in a multicenter clinical trial to prevent type 1 diabetes should be provided. Site visits by members of the DPT-1 and Type 1 Diabetes TrialNet Study Groups or the external Data Safety and Quality Monitoring Group may be required. Study Organization The Type 1 Diabetes TrialNet, or TrialNet, will be a national network of cooperative clinical research groups, consisting of a consortia of clinical centers and core support facilities, whose aim is to recruit patients and to support studies that may eventually result in an improved understanding of type 1 diabetes and the prevention of the disease. Up to 20 parent Clinical Centers are expected to complete the DPT-1 and participate in new studies within the TrialNet. For the DPT-1, parent Clinical Centers are involved in screening, staging, and following study participants. Each Clinical Center provides administrative support for its own network of Affiliates and Satellites. In total, there are approximately 350 Affiliates and Satellites participating in DPT-1 across the United States, Canada, and Puerto Rico. Affiliates screen, stage and follow participants, while Satellites are involved only in screening. Current core support facilities of the DPT-1 include the Operations Coordinating Center (OCC), the Data Monitoring Unit (DMU), Core Laboratories, the Compounding Pharmacy, the Central Distribution Pharmacy, the clinical cost reimbursement system, and the consultant firm providing the central telephone line and publicity/recruitment support. Type 1 Diabetes TrialNet study structure is anticipated to be similar. The OCC will coordinate all interactions between the core support facilities, Clinical Centers and associated networks of Affiliates/Satellites, sponsoring agencies, study committees, and consultants. The OCC will assist in financial management of the study, will develop and/or maintain all study protocols, manuals, agendas, and newsletters, and will provide subcontracts as needed to other core support facilities. The functions of the DMU may be performed at the OCC or through a subcontract. The DMU will be responsible for all study data management and statistical considerations. In addition, the DMU will track clinical tests performed within the DPT-1 and Type 1 Diabetes TrialNet and will provide this information to the clinical cost reimbursement system for the distribution of payments to appropriate Clinical Centers/Affiliates/Satellites. In the DPT-1, the core laboratories include the Islet Cell Antibody Laboratory, the Insulin Autoantibody Laboratory, the Class II Major Histocompatibility and DNA Extraction Laboratory, and the Beta Cell Function Laboratory. New studies performed within the TrialNet may require additional core laboratory measurements. Core laboratory support may be consolidated under fewer laboratories if deemed possible and advantageous. Assay cores of the Immune Tolerance Network (http://www.immunetolerance.org) may also be used for assessments in the Type 1 Diabetes TrialNet. The Central Distribution Pharmacy will dispense all therapeutic agents and placebos in DPT-1 and TrialNet studies as directed by the DMU. The Central Distribution Pharmacy may receive agents from drug companies or other pharmacies, similar to the compounding pharmacy currently being used in DPT-1. The Steering Committee has overall responsibility for the design, planning, execution, and publication of the research performed by the DPT-1 Study Group and Diabetes TrialNet. The Steering Committee will approve all protocols, changes to protocols, and manuals of operations. It will define subcommittees, develop study policies, receive and act upon reports of subcommittees and review matters relevant to administrative, financial, medical, legal, and ethical considerations of studies. The Steering Committee will maintain surveillance of DPT-1 and Type 1 Diabetes TrialNet performance and, together with the NIDDK/NIAID/NICHD, is responsible for the addition or deletion of core support facilities as well as Clinical Centers. At the present time, voting members of the DPT-1 Steering Committee include each of the directors of the Clinical Centers, the director of the Operations Coordinating Center, the director of the Data Management Unit, each of the directors of the Core Laboratories, and the three representatives from the NIDDK, NIAID, and NICHD. The chair of the Planning Committee is also a voting member; the Planning Committee is responsible for coordinating other Working Committees and integrating the Working Committees’ input into the DPT-1 Steering Committee agenda. (Examples of current Working Committees are the Eligibility and Events Committee, Treatment Committee, Ancillary Studies Committee, Clinical Center Directors Committee, and Trial Coordinators Committee. Members of the Planning Committee consist of the Chair of the Steering Committee, Chairs of each Working Committee, and Operations Committee members. The Operations Committee consists of the Chair of the Steering Committee, and a representative from the OCC, the DMU, and the NIDDK. The Chair of the Planning Committee is selected by the Operations Committee.) The NIDDK will select a Chairperson for the DPT-1 and Type 1 Diabetes TrialNet Steering Committee from among the Study Group members or other experts in clinical trials in type 1 diabetes. The NIDDK may appoint a new Chairperson of the Type 1 Diabetes TrialNet once the DPT-1 is completed. The Chairperson of the Steering Committee is responsible for the overall administration and science of the DPT-1 and Type 1 Diabetes TrialNet activities by: reviewing all concepts for science and feasibility; reviewing all protocols prior to implementation; reviewing all manuscripts, posters, and abstracts prior to publication; monitoring committee activities; assuring compliance with protocol requirements; observing and enforcing all DPT-1 and TrialNet policies and guidelines; and facilitating performance of institutions and centers participating in the DPT-1 and TrialNet. Research proposals for pilot and expanded intervention studies are being proposed in response to the DPT-1 and Type 1 Diabetes TrialNet Clinical Center RFA (DK-01-003). It is anticipated that the majority of pilot and expanded intervention studies performed in the TrialNet will be proposed through this RFA. The TrialNet Steering Committee will refine the design and implement the studies. After awards are made in response to this RFA, research proposals for pilot, feasibility, and efficacy studies, and expanded clinical trials requiring TrialNet resources may be submitted by non-members of the TrialNet (see Eligibility Requirements in RFA DK-01- 003). The mechanism for receiving and evaluating future proposals, and prioritizing studies, will be determined by the Type 1 Diabetes TrialNet Steering Committee. These competitions will be fair and open and may involve external reviewers. The Data Safety and Quality Monitoring Group (DSQ) is an external oversight committee of the DPT-1 appointed by the NIDDK and is composed of members not directly involved in the study. The DSQ monitors the conduct and results of the DPT-1 study for safety and efficacy, with authority to recommend protocol or procedural changes or early termination of the study. The DSQ is advisory both to the NIDDK and to the DPT-1 Steering Committee. The NIDDK may also appoint members to an external oversight committee for natural history, genetics, and intervention studies conducted in the Type 1 Diabetes TrialNet. In addition to DSQ review, NIDDK may obtain review by external advisory groups to provide additional expertise regarding the design and implementation of clinical trials, natural history, and genetics studies to be conducted under TrialNet. The NIDDK expects that biologic samples and associated clinical data will be made available to the broader scientific community at an appropriate juncture to support further studies related to the prevention and etiology of type 1 diabetes, and in studies to identify genes predisposing to diabetes and its complications. 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. TERMS AND CONDITIONS OF AWARD The Type 1 Diabetes TrialNet, or TrialNet, will be a national network of cooperative clinical research groups, consisting of a consortia of clinical centers and core support facilities, whose aim is to recruit patients and to support studies that may eventually result in an improved understanding of type 1 diabetes and the prevention of the disease. These 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 policy statements. 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(s) 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/NIAID/NICHD Program Officers. 1. Awardee Rights and Responsibilities Awardees will have primary and lead responsibilities for the DPT-1 and future studies performed in the Type 1 Diabetes TrialNet, including research design and protocol development and modification, participant recruitment and follow-up, data collection and adherence to protocol, quality control, interim data and safety monitoring, final data analysis and interpretation, and preparation of publications, with assistance from the NIDDK/NIAID/NICHD Program Officers. Awardees will collaborate with all individuals involved in conducting the DPT-1 and TrialNet studies, with investigators conducting ancillary studies, and with the NIDDK/NIAID/NICHD Program Officers. Modifications to the protocols will be approved by the Steering Committee. Clinical Centers and their networks of Affiliates and Satellites are expected to meet patient recruitment goals as specified by the DPT-1 and TrialNet Steering Committee. Performance measures, such as patient recruitment, data acquisition and transmission, use of budget, and timeliness of progress reports are expected to be assessed by the DPT-1 and Type 1 Diabetes TrialNet Steering Committee and subcommittees, and NIDDK/NIAID/NICHD, and may provide information needed to support future funding decisions. The inability to meet performance requirements and responsibilities may result in an adjustment of funding, withholding of support, restriction of funds already awarded, or suspension or termination of the award. The Operations Coordinating Center, Data Monitoring Unit, and Core Laboratories, together with the Clinical Centers and associated networks, must achieve and maintain quality data in accordance with the common protocols and manuals of operations specified by the DPT-1 and Type 1 Diabetes TrialNet Steering Committee. Core support facilities must provide periodic financial and administrative reports required by NIH for administration of cooperative agreements. The Operations Coordinating Center must provide an overall summary of study progress on an annual basis. Clinical Centers will work with their Affiliates and Satellites, the Operations Coordinating Center, the Data Monitoring Unit, and Core Laboratories to achieve and maintain quality data in accordance with the common protocols and manuals of operations specified by the DPT-1 and Type 1 Diabetes TrialNet Steering Committee. The data must be obtained within expected timeframes as set by the DPT-1 and TrialNet Steering Committee. In addition, all study data must be transmitted continuously to the Data Monitoring Unit according to the timeframes specified by the Steering Committee. Clinical Centers will provide administrative support, supervision, and training for their Affiliates and Satellites. Affiliates must sign a Letter of Agreement that outlines the details of their participation in the study. All study investigators must agree to implement and adhere to an adverse event tracking system as designed by the DPT-1 Study Group and Type 1 Diabetes TrialNet Steering Committee. In addition to periodic financial and administrative reports required by NIH for administration of cooperative agreements, Awardees must agree to furnish reports documenting recruitment and follow-up activity if requested by the Steering Committee and subcommittees. As members of the DPT-1 and Type 1 Diabetes TrialNet Steering Committee, awardees will retain custody of and have primary rights to the data and biologic specimens developed and obtained under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The NIDDK expects that biologic samples and associated clinical data will be made available to the broader scientific community at an appropriate juncture to support further studies related to the prevention and etiology of type 1 diabetes, and in studies to identify genes predisposing to diabetes and its complications. The Operations Coordinating Center and Data Monitoring Unit will be expected to put all study intervention materials and procedures manuals in the public domain and/or make them available to other investigators. Prompt and timely presentation and publication in the scientific literature of findings resulting from research undertaken by the DPT-1 and Type 1 Diabetes TrialNet is required. Awardees must agree to acknowledge NIH support in the publications and oral presentations resulting from research conducted under the cooperative agreements. Manuscripts and presentations will be written and reviewed according to the policies and procedures set forth by the DPT-1 and TrialNet Steering Committee. Awardees must conform to the guidelines pertaining to the accrual of women and minorities as subjects in clinical research, and the reporting of results in these subgroups, as specified in the “NIH Guidelines for Inclusion of Women and Minorities in Clinical Research.” The NIDDK will select the Chairperson of the Steering Committee. This individual must not have responsibility for recruitment or follow-up of study participants. If a study investigator is selected as a Chairperson, he/she must designate a replacement investigator at his/her institution. The Chairperson must have proven evidence of leadership ability and adequate time commitment for DPT-1 and/or Type 1 Diabetes TrialNet activities. Core Laboratory Directors and the Director of the Data Monitoring Unit must not have responsibility for recruitment or follow-up of study participants. A Clinical Center and its institution may not be involved simultaneously in the DPT-1, other TrialNet protocols, and in studies not affiliated with TrialNet if enrollment criteria overlap between studies and if the studies are actively recruiting participants. Applicants should indicate their willingness to forego participating in studies that would compete for recruitment to the same study population. This restriction does not apply to Affiliates and Satellites. NIDDK may consider exemptions from this policy to allow institutions to participate in pilot studies of the ITN. 2. NIDDK and Other NIH Staff Responsibilities The NIDDK Program Officer and NIAID and NICHD Program Officers will provide scientific support to the awardees’ activities including protocol development and modification, quality control, interim data monitoring, final analysis, preparation of publications, and performance monitoring. Consistent with the cooperative agreement nature of this study, the Program Officers will be substantially involved as active partners in those aspects of the scientific and technical management of the trial as described in these Terms and Conditions. This level of involvement will be above and beyond the levels required for administration of traditional research grants. The NIDDK/NIAID/NICHD Program Officers each will have voting membership on the Steering Committee, and as appropriate, its subcommittees. The NIDDK will appoint the Chairperson of the DPT-1 and TrialNet Steering Committee from among investigators of the studies or other experts in clinical trials in type 1 diabetes. The NIDDK may appoint a new Chairperson of the TrialNet once the DPT-1 is completed. The NIDDK will maintain and appoint members of the Data Safety and Quality Monitoring Group and other external advisory groups as necessary for proper oversight of DPT-1 and TrialNet activities. The Data Safety and Quality Monitoring group, appointed by NIDDK, will provide overall monitoring of interim data and safety issues, and can advise the NIDDK/NIAID/NICHD on changes to protocol, elimination of Clinical Centers/Affiliates/Satellites, and study termination, if warranted. These meetings will be held twice per year. The NIDDK/NIAID/NICHD Program Officers, on behalf of their NIH Institutes, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the DPT-1 and Type 1 Diabetes TrialNet Steering Committee. The NIDDK, in consultation with the NIAID and NICHD, reserves the right to terminate or curtail the study (or an individual award) in the event of substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of the protocol. The NIDDK may terminate or curtail the study if a major study endpoint is reached substantially before schedule with persuasive statistical significance, if futility in reaching a significant difference between treatment groups is realized, if there is emergence of new information that diminishes the scientific importance of the study question, or if human subject safety or ethical issues dictate a premature termination. The NIDDK may also terminate the project in the event of a failure to develop or implement mutually agreeable collaborative protocols for the Type 1 Diabetes TrialNet or if there are substantial changes in the agreed-upon protocols with which the NIDDK cannot concur. 3. Collaborative Responsibilities The Steering Committee is composed of the Principal Investigator(s) of each Clinical Center, the director of the Operations Coordinating Center, the director of the Data Management Unit, each of the directors of the Core Laboratories, the Chair of the Planning Committee and the three representatives from the NIDDK, NIAID, and NICHD. (The Planning Committee is responsible for coordinating other Working Committees and integrating the Working Committees’ input into the Steering Committee agenda. Examples of current Working Committees are the Eligibility and Events Committee, Treatment Committee, Ancillary Studies Committee, Clinical Center Directors Committee, and Trial Coordinators Committee. Members of the Planning Committee consist of the Chair of the Steering Committee, chairs of each Working Committee, and Operations Committee members. The Operations Committee consists of the Chair of the Steering Committee, and a representative from the Operations Coordinating Center, the Data Monitoring Unit, and the NIDDK. The Chair of the Planning Committee is selected by the Operations Committee.) The Steering Committee has overall responsibility for the design, planning, execution, and publication of the research performed as part of the DPT-1 and Type 1 Diabetes TrialNet. External reviewers may be included in the review and planning of new trials in the Type 1 Diabetes TrialNet to gain the necessary expertise required for evaluating and implementing new proposals. The Steering Committee will approve all protocols, changes to protocols, and manuals of operations. Each member of the Steering Committee will have one vote. Subcommittees will be established by the Steering Committee, as it deems appropriate; the NIDDK/NIAID/NICHD Program Officers will serve on subcommittees as they deem appropriate. The Steering Committee will develop and maintain specific measures as outlined in the protocols and manuals of operations to assure the safety and protection of the rights of volunteers involved in the DPT-1 and Diabetes TrialNet. The Principal Investigator for each awardee and investigators at Affiliates and Satellites will assume and accept primary responsibility for ensuring that studies are conducted in compliance with all federal regulations. These include but are not limited to Title 21 CFR 50, 56, 312, and Title 45 CFR 46. All Clinical Centers, Affiliates and Satellites must be able to demonstrate that there is a current, approved Assurance on file with the HHS Office of Human Research Protections (OHRP), that each protocol and informed consent is approved and reviewed annually by the Institutional Review Board (IRB) of record, and that each subject has given written informed consent as set forth in the Study protocols and manuals of operations. The Principal Investigator agrees and assures that adequate records will be available, to enable outside monitors to assess compliance with applicable federal laws and regulations. To promote the development of a collaborative program among the award recipients, Principal Investigators, trial coordinators, and recruitment coordinators are expected to attend DPT-1 and TrialNet Steering Committee meetings. These are anticipated to meet twice a year for established trials but may meet more frequently for development of new protocols. Trial coordinators and recruitment coordinators will meet on a regular basis by conference call, perhaps monthly, to discuss recruitment issues and study operations. Clinical Center Principal Investigators will also meet on a regular basis by conference call to discuss emerging issues. Clinical Center Principal Investigators, trial coordinators, and recruitment coordinators will be asked to serve as Chairpersons or as members of Study Committees as needed. Members of Affiliates and Satellites are encouraged to participate in Committee meetings as well. As members of the DPT-1 and Type 1 Diabetes TrialNet Steering Committee, awardees will retain custody of and have primary rights to the data and biologic specimens developed and obtained under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The NIDDK expects that biologic samples and associated clinical data will be made available to the broader scientific community at an appropriate juncture to support further studies related to the prevention and etiology of type 1 diabetes, and in studies to identify genes predisposing to diabetes and its complications. The Operations Coordinating Center and Data Monitoring Unit will be expected to put all study intervention materials and procedures manuals in the public domain and/or make them available to other investigators. 4. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIDDK/NIAID/NICHD may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the Steering Committee (with the NIDDK/NIAID/NICHD members not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NIDDK in consultation with NIAID and NICHD, 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 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 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 or conducting 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. Under this statute, when an NIH defined Phase III clinical trial is proposed, evidence must be reviewed to show whether or not clinically important sex/gender and/or race/ethnicity differences in the intervention effect are to be expected. This evidence may include, but is not limited to, data derived from prior animal studies, clinical observations, metabolic studies, genetic studies, pharmacology studies, and observational, natural history, epidemiology and other relevant studies. Cost is not an acceptable reason for exclusion of women and minorities from clinical trials. When planning, conducting, and reporting an NIH defined Phase III clinical trial, it must be considered whether, based on prior studies, one of the following three situations apply: that prior studies support the existence of significant differences, that prior studies support no significant differences, and that prior studies neither support nor negate significant differences. The NIDDK believes that prior studies neither strongly support nor negate significant differences in expected intervention effects by sex/gender and/or race/ethnicity. In this case, the NIH Phase III clinical trial will be required to include sufficient and appropriate entry of sex/gender and/or racial/ethnic subgroups, so that valid analysis of the intervention effect in subgroups can be performed. However, the trial will not be required to provide high statistical power for each subgroup. Research conducted as a result of this RFA must include valid analyses of the intervention effect in subgroups. The final protocol(s) approved by the IRB(s) must include these plans for analysis. The award will require that the results of subset analyses must be reported to NIH in Progress Reports, Competitive Renewal Applications, and in the required Final Progress Report. Inclusion of the results of subset analyses is strongly encouraged in all publication submissions. If the analysis reveals no subset differences, a brief statement to that effect, indicating the subsets analyzed, will suffice. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research conducted or supported by the NIH unless there are scientific or 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. 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. URL FOR INFORMATION ABOUT RFA FOR PROSPECTIVE APPLICANTS Information about this RFA may be found at NIDDK’s website http://www.niddk.nih.gov/patient/trialnet.htm. The website links to answers to frequently asked questions (FAQs) that prospective applicants have submitted. Prospective applicants are encouraged to submit their questions to the email address: TrialNet@extra.niddk.nih.gov so that their questions and answers can be made available on the website. LETTER OF INTENT Prospective applicants are asked to submit, by February 28, 2001, a letter of intent that includes a descriptive title of the proposed research; name, address, and telephone number of the Principal Investigator; identities of other key personnel and participating institutions; and 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 plan the review. The Letter of Intent is to be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 653, MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) 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 301-435-0714, email: GrantsInfo@nih.gov. Additional Materials to Include in the Application Applicants must describe plans to achieve the stated “Objectives and Scope”, “Special Requirements”, and “Terms and Conditions of Award” stated in this RFA. In addition, applicants should address the following issues that are important to the successful development of a collaborative program to promote the DPT-1 and TrialNet. A description of the activities of the Operations Coordinating Center must detail the plan for recruiting the remaining participants needed to complete the DPT-1, and to retain participants, since this effort will be coordinated and partially directed by the OCC. The activities that would be performed by the consultant firm to aid the study recruitment and retention effort should be described. These activities should be in addition to the consultant firm’s responsibilities of answering the central telephone line and responding to potential participants by mailing brochures and information, and producing the patient newsletter. Potential media strategies, important recruitment and retention materials, and outreach activities should be detailed. Strategies for recruitment of minorities should be described, to enable accrual that would conform to NIH policy (see above under “INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS”). Potential problems likely to occur during recruitment and follow-up of minority or non- minority participants should be described with a discussion of how to handle them. Applicants must adequately describe plans for maintaining effective collaboration and communication between Clinical Center/Affiliate/Satellite Principal Investigators, Core Laboratories, the Data Monitoring Unit, and study participants. They must describe their ability to provide fiscal management for large multicenter clinical trials. A description of appropriate facilities, personnel, equipment, and evidence of institutional support must be provided. Experience handling numerous subcontracts should be detailed. Examples of forms and correspondence useful for coordinating tasks should be included. While the existing Core Laboratories will continue during completion of the DPT-1, the applicant should describe the approach that would be used for soliciting and evaluating proposals from new Core Laboratories that would support the conduct of pilot and expanded intervention studies of new agents. [As mentioned previously, the utilization of laboratories of the Immune Tolerance Network by new trials may be appropriate (http://www.immunetolerance.org).] A solicitation and evaluation plan must also be provided for new compounding pharmacies that would support future intervention studies. Applicants should provide information on prior experience in participating in diabetes research and clinical trials. The Data Monitoring Unit should be described in terms of physical facilities, data management and computer resources, facilities for data retrieval and storage, and equipment for generating bar codes. Applications should describe proposed personnel and investigator/staff experience in large multicenter clinical trials, particularly in diabetes. Specifically, a description of investigator/staff ability to design, support, conduct, and provide statistical expertise for clinical trials should be included. Examples of data forms and questionnaires and software/computer programs appropriate for their use should be included and described. Methods for sending and receiving data, electronically and by hardcopy, and maintaining data, should be provided. Data management and quality control procedures must be detailed. If applicable, a description of experience with voice-activated randomization should be given. A description should be provided of experience and plans for multi-institutional study monitoring of data (e.g., center, laboratory, safety monitoring). A simple description of methods for monitoring accrual by sex/gender and/or race/ethnicity and reporting differences in intervention effects in these subgroups should be provided (see above under “INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS”). Any experience in website communication of specific study-wide data and information should be provided. Methods for assuring privacy and maintaining confidentiality of data, including specific protections for internet-based data systems must be stated. Evidence of institutional support must be provided. If the Data Monitoring Unit will be at a different institution than the Operations Coordinating Center, and if the DMU will be handling subcontracts, the experience of the DMU in providing this function should be detailed. Applicants must indicate their willingness to collaborate in multicenter trials of this nature using a common protocol. Applicants should describe the facilities of the Central Distribution Pharmacy, their experience in and usual procedures for distribution of drugs in multicentered trials in a masked manner, quality control procedures, and procedures for unmasking drug in the case of an adverse event. The clinical cost reimbursement system must be thoroughly described in terms of experience and the methods to be used for tracking patient care costs and reimbursing a large number of Clinical Centers/Affiliates/Satellites. Facilities, computer hardware and computer software/programs, and turnaround time should be adequately detailed. Applicants should state in their application their willingness to collect biologic and genetic samples as well as clinical data that may be used for future studies related to the prevention, etiology, and genetics of type 1 diabetes by investigators both inside and outside the Type 1 Diabetes TrialNet. Applications should not exceed 35 pages, excluding appendices. Budget Information Approximately $4.7 million in total costs per year will be committed for core support facilities for completion of the DPT-1 and planning for new studies in TrialNet. It is anticipated that one award will be made to the Operations Coordinating Center which, if necessary, will support subcontracts to one or more institutions to provide for the Data Monitoring Unit, the Core Laboratories, the compounding pharmacy(ies), the Central Distribution Pharmacy, clinical cost reimbursement system, and the consultant firm for the central telephone line and for media/recruitment support. The budget should not exceed $2,060,000 in total costs annually for the OCC (personnel, supplies, equipment and communications), Data Monitoring Unit (personnel, supplies, equipment, and communications), clinical costs reimbursement system, and Central Distribution Pharmacy Unit. Additional funds (in total costs) that are expected to be provided to the OCC annually and which should be included in submitted budgets are: $200,000 for the consultant firm to manage the central telephone line and provide publicity/recruitment support; $400,000 for the clinical centers’ use of laboratory supplies, and shipping tubes, vials, and boxes; $250,000 for overnight mail expenses and shipping of study specimens study-wide; $10,000 for the compounding pharmacy; $725,000 for patient care costs related to study tests that will be distributed to Clinical Centers/Affiliates/Satellites; and $48,000 for travel costs for representatives of the OCC, DMU, and core laboratories to attend necessary Steering Committee and DSQ meetings (estimated at $1500 per person per meeting); $105,000 for the Insulin Autoantibody Laboratory, $420,000 for the Islet Cell Antibody Laboratory, $120,000 for the Class II Major Histocompatibility and DNA Extraction Laboratory, and $405,000 for the Beta Cell Function Laboratory. Additional funds will be added to support the Study Chairperson if the Chairperson is selected from among members of the core support facilities. 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 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 20827 (for express/courier service) At the time of submission, two additional copies of the application must also be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 653 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8885 FAX: (301) 480-3505 Applications must be received by March 29, 2001. 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. REVIEW CONSIDERATIONS 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 in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique. Those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the NDDK Advisory Council. Applications will be reviewed for scientific and technical merit using the following criteria. Applicants should note that the criteria incorporate consideration of the quality and feasibility of the proposed activities as well as consideration of past performance. o Approach. Is there an adequate understanding of the scientific agenda of the DPT-1 and Type 1 Diabetes TrialNet? Can the core support facility and its staff contribute to the goals and enhance the capability of the Study Group as a whole? Pertaining to Operations Coordinating Center activities, does the recruitment and retention plan outlined for the OCC and consultant firm appear reasonable for a large-scale clinical trial in type 1 diabetes and is it likely to succeed? Does the approach conform to NIH guidelines for inclusion of women and minorities as human subjects in clinical research? Does the applicant have a thorough understanding of the complexities of administering and monitoring a large-scale clinical trial and of maintaining effective collaboration and communication with members of the Study Group in large-scale clinical trials; is the plan likely to succeed? Does the applicant show a good understanding of the requirements related to fiscal management and management of subcontracts? Does the applicant provide a fair, open and reasonable plan for soliciting and evaluating future applications for laboratories and compounding pharmacies? Pertaining to Data Monitoring Unit activities, is there a thorough understanding shown of the complexities of large-scale clinical trials, particularly in type 1 diabetes, and does the applicant illustrate the ability to design, support, conduct, and provide statistical expertise in clinical trials? Does the applicant illustrate the ability to capture, monitor, transmit, store, ensure security, and otherwise manage clinical data in large-scale clinical trials? Does the approach conform to NIH guidelines for inclusion of women and minorities as human subjects in clinical research? Does the applicant describe a reasonable plan for a Central Distribution Pharmacy for distributing drug in large-scale multi-centered clinical trials in a masked manner, and describe appropriate procedures for unmasking drug if necessary? Are the quality control procedures of the Central Distribution Pharmacy adequate? Is the plan for tracking patient tests that are performed at Clinical Centers/Affiliates/Satellites efficient and reliable and is there evidence of an efficient and fiscally responsible system to reimburse institutions with quick turnaround? o Investigators. Are the investigators appropriately trained and well- suited to carry out this work? Is the work proposed appropriate to the experience level of the investigators and staff? Is there previous experience and competence with the design and administration of multi- institutional clinical trials with extensive data collection requirements pertaining specifically to experimental design and statistical analysis, quality control and quality assurance, study monitoring, data collection and management, and compliance with regulatory requirements? What are the qualifications and experience of the Project Coordinator(s) and key personnel, statisticians, computer programmers and data managers, pharmacists, and fiscal clerks? Is there an appropriate amount of time planned for effective collaboration with Clinical Centers/Affiliates/Satellites and other core support facilities? Is there evidence of prior experience in working collaboratively in carrying out a standard protocol in multicenter clinical trials or other clinical studies? Is there evidence of willingness to work cooperatively in the DPT-1 and Type 1 Diabetes TrialNet? o Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Are the available facilities adequate for coordination of multicenter clinical trials tasks, data management and statistical support, drug distribution in a masked manner, and fiscal administration for distributing and managing funds involving multi-site studies? Is there evidence of institutional support and commitment for the proposed program? In addition to these criteria, in accordance with NIH policy, all applications will be reviewed with respect to the reasonableness of the proposed budget and the adequacy of the proposed protection for human subjects. AWARD CRITERIA Applications recommended by the NDDK Advisory Council will be considered for award based upon (a) scientific and technical merit; (b) programmatic and administrative considerations; and (c) availability of funds. Letter of Intent Receipt Date: February 28, 2001 Application Receipt Date: March 29, 2001 Peer Review Date: June-August, 2001 NDDK Council Review Date: September, 2001 Earliest Anticipated Start Date: September, 2001 INQUIRIES Written and telephone inquiries concerning this RFA are strongly encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Catherine C. Cowie, PhD Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Rm 691, MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 594-8804 FAX: (301) 480-3503 Email: cowiec@extra.niddk.nih.gov Questions may also be submitted to the email address TrialNet@extra.niddk.nih.gov where they will be answered by email. In addition, these questions and answers will be posted at the NIDDK website http://www.niddk.nih.gov/patient/trialnet.htm which links to frequently asked questions that prospective applicants have submitted. Applicants are strongly encouraged to visit this website on a regular basis in the course of preparing their applications. For FEDEX, UPS, send to: Catherine C. Cowie, PhD Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Rm 691 Bethesda, MD 20817 Inquiries may also be made to representatives of NIAID and NICHD: Elaine Collier, MD Chief, Autoimmunity Section Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases 6700-B Rockledge Drive, Room 5135, MSC 7640 Bethesda, MD 20892-7640 Telephone: (301) 496-7104 FAX: (301) 402-2571 Email: ec5x@nih.gov Gilman D. Grave, MD Chief, Endocrinology, Nutrition, and Growth Branch National Institute of Child Health and Human Development 6100 Executive Blvd, Room 4B-11, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5593 FAX: (301) 480-9791 Email: gg37v@nih.gov Direct inquiries regarding fiscal matters to: Cheryl Chick Grants Management Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Rm 606, MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8825 FAX: (301) 480-3504 Email: chickC@extra.niddk.nih.gov For FEDEX, UPS, send to: Cheryl Chick Grants Management Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Rm 606 Bethesda, MD 20817 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847, No. 93.855, and No. 93.113. 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 PHS 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 PHS mission to protect and advance the physical and mental health of the American people.
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