PREVENTION AND TREATMENT OF TYPE 2 DIABETES IN CHILDREN AND ADOLESCENTS-–COORDINATING CENTER Release Date: October 5, 2000 RFA: DK-01-011 - (Reissued as RFA-DK-08-502) National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: March 20, 2001 Application Receipt Date: April 17, 2001 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites cooperative agreement applications for a Coordinating Center to support clinical trials for the primary prevention and treatment of type 2 diabetes in children in the U.S. and Canada. Type 2 diabetes has been traditionally viewed as a disease of adults. Recent epidemiological data reveals an increasing number of cases of type 2 diabetes in the pediatric population, especially among adolescents and in certain minority populations. The rise in type 2 diabetes in children and adolescents is presumed to be a consequence of widespread obesity and decreased physical activity. Clinical trials to develop effective primary prevention strategies for this age group are needed. In addition, the drugs currently available for the treatment of type 2 diabetes in adults have not been used widely in children and need to be studied in this population. A complementary RFA (DK-01-010) is being issued to solicit applications for clinical trials for the prevention and treatment of type 2 diabetes in the pediatric population. The intent of this RFA is to create a Coordinating Center (CC) to provide clinical center coordination and analytical and statistical support for the clinical trials. In addition, the CC will work with the NIDDK and the clinical centers as part of a Steering Committee to design the actual trial protocols. An institution or organization can apply to be the CC, as well as submit a proposal for a clinical trial. Separate applications are required for these components, which must be administratively and fiscally distinct. 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, Prevention and Treatment of Type 2 Diabetes in Children and Adolescents, is related to the priority area of diabetes and chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit 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 and frequent meetings among members of the Steering Committee, and possible site visits to ensure adequate recruitment, retention, and the use of standardized procedures across the studies. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. Awards for the clinical centers and for the Coordinating Center will not be made to the same Principal Investigator, to ensure that data analysis is done independently of data acquisition. An institution or organization can apply to be the CC, as well as submit a proposal for a clinical trial, however, separate applications are required for these components, which must be administratively and fiscally distinct. 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 “Objectives and Scope,” “Special Requirements,” and "Terms and Conditions of Award." The total project period for applications submitted in response to the present RFA should be seven years. The anticipated award date is September 30, 2001. This RFA is a one-time solicitation. At this time, the NIDDK has not determined whether or how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE This collaborative effort will be divided into three phases 1) planning, 2) recruitment and study, and 3) analysis. It is anticipated that the planning phase will take 12 months, and $1.25 million is available to support the Coordinating Center during the first year. Substantially greater funds will be available in subsequent years to support the conduct of the trials. The exact dollar amount will depend, in part, on the final design of the trials. Costs are expected to decrease in the final year of each trial, which will be devoted to data analysis and reporting of results. It is anticipated that one award for the Coordinating Center will be made and that 6-10 awards for clinical trial sites will be made. The CC budget for personnel, supplies, equipment, communications, and travel should not exceed $1.25 million in total costs during the first year. After the planning phase, awards in subsequent years will depend on the requirements of the specific studies designed by the Steering Committee. The CC will receive funds to support its personnel, supplies, equipment, communication, and travel. In addition, it will receive money to pay for centralized laboratories and reading centers, as needed by the trials. 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. Awards and level of support depend on receipt of a sufficient number of applications of high scientific merit. RESEARCH OBJECTIVES Background Type 2 diabetes is characterized by insulin resistance and impaired insulin secretion, although its precise etiology and pathogenesis are only incompletely understood. The public health impact of type 2 diabetes is enormous. Clearly associated with aging and obesity, type 2 diabetes has traditionally been considered a disease of adults. Children presenting with diabetes are usually assumed to have type 1 diabetes, an autoimmune disease. In recent years, however, it has become apparent that an increasing number of children who present with hyperglycemia actually have type 2 diabetes. In general, population-based screening data are not available. However, data culled from diabetes clinics in several locations suggest that the percentage of children diagnosed with diabetes who are classified as having type 2 diabetes has risen from less than 5% (prior to 1994) to 20-30% (after 1994). Not surprisingly, the available published data reveal that one of the major risk factors for type 2 diabetes in children is obesity. Indeed, the increase in reports of type 2 diabetes among children parallels a similar rise in the adult population as obesity has become a major public health concern. In children, the rise in the incidence in type 2 diabetes appears to be concentrated largely in minority populations-– African Americans, Hispanic Americans, and Native Americans. Indeed, type 2 diabetes (in all age groups) is one of the major chronic diseases where significant racial/ethnic health disparities exist. Data from NHANES III suggests that up to 1/3 of adults who have type 2 diabetes may go undiagnosed. A similar situation may exist with children. In fact, the diagnosis of type 2 diabetes in children is often made because of routine laboratory screening being conducted as part of a school physical and not because the child presents to a health care provider with specific complaints. Thus, many children who do not receive such screening may go undiagnosed until they become symptomatic, at which time they may have been hyperglycemic for many years and are at high risk for developing diabetic micro- and macrovascular complications. In addition, significant numbers of children may not have frank diabetes, but may be at high risk of developing diabetes based on the presence of impaired fasting glucose or impaired glucose tolerance. Furthermore, the combination of insulin resistance, hypertension and dyslipidemia (syndrome X), which is being documented with increasing frequency among obese adolescents, is associated in adults with the development of accelerated cardiovascular disease. It is, therefore, imperative to establish appropriate screening criteria and effective primary prevention programs to avoid a potential major public health burden. The NIDDK is currently funding a large, randomized, multicenter trial (The Diabetes Prevention Program, DPP) to study the efficacy of interventions designed to delay or prevent the onset of diabetes in high risk adults. These interventions may not be directly applicable to the pediatric population. The majority of children with type 2 diabetes are in the pre-adolescent or adolescent age range. The adolescent period presents special challenges to health care providers and families when attempting to promote behavior and life style changes. Prevention and treatment programs must also consider cultural differences among racial and ethnic groups that may influence acceptance of medical regimens. This is especially important for type 2 diabetes in children, which currently disproportionately affects minority groups. In addition, children represent a unique “target” population that may be amenable to population-based, public health interventions through schools or other community organizations. When children develop diabetes, efficacious therapy is needed to maintain euglycemia in order to prevent the development of complications. Diabetes is currently estimated to cost the U.S. health care system approximately $98 billion annually. Much of the cost is related to the micro- and macrovascular complications of diabetes. Since the development of complications is related, in part, to the duration of diabetes, children represent a population at high risk. Indeed, studies have documented that from 30-50 percent of children with type 2 diabetes already have adverse cardiovascular risk profiles at the time of diagnosis. Unfortunately, the drugs currently approved for use in adults with type 2 diabetes have not been systematically studied in children. Thus, treatment options for those children diagnosed with type 2 diabetes are restricted by the lack of data on the use of such pharmacological agents. Optimal treatment of type 2 diabetes in children, as well as in adults, should go beyond merely achieving euglycemia. Ideally, therapy would reverse insulin resistance and preserve or improve beta cell function. Lifestyle modifications may be helpful in increasing insulin sensitivity, and recent advances in the drug treatment of type 2 diabetes have focused on insulin sensitizing agents. However, little is known about whether one particular class of agents used to treat type 2 diabetes might be advantageous in helping to maintain insulin secretion, and prevent the inexorable slide to insulin treatment which ultimately characterizes type 2 diabetes. Preserving beta cell function in children with impaired glucose tolerance or type 2 diabetes is of critical importance. Thus, clinical trials are needed to establish appropriate and effective treatment regimens for children with type 2 diabetes. It would be desirable in conducting clinical trials for the prevention and treatment of type 2 diabetes in children to create an infrastructure to standardize clinical and outcome measures which will be used in these clinical trials, so that these studies can be compared and utilized to impact on health care, both for the individual patient and physician, as well as at the public health level. A separate RFA (DK-01-010) will solicit applications for clinical trials for the prevention and treatment of type 2 diabetes in children (ages 6- 18 years). Based on peer review, those proposals judged to be of high scientific merit will be chosen for funding. A Steering Committee will then be created, comprised of the Principal Investigator of each study site, the head of the Coordinating Center, as well as an NIDDK representative. The Steering Committee will meet during the planning phase of the cooperative agreement to design the intervention protocols, and develop standardized tools, assays, tests and analysis techniques that will be utilized in all the funded trials. This RFA solicits applications for a Coordinating Center to participate in the collaborative planning process and to provide administrative, analytical and statistical support for the clinical trials. Objectives and Scope Applicants should read the companion RFA (DK-01-010) for the clinical centers to fully understand the objectives and scope of the clinical trials to be conducted. The Steering Committee, which will include the Principal Investigator of the CC, will meet during the planning phase of the cooperative agreement to design the actual study protocols. It is anticipated that the Steering Committee will develop one, multi-arm trial for the treatment of type 2 diabetes in children to be carried out in multiple sites, to ensure geographic and racial/ethnic diversity. Treatment trials may include lifestyle interventions and/or pharmacological therapy. At least one but possibly more primary prevention protocols will be developed. The prevention trials may involve a standard protocol with variations based on the need for cultural sensitivity at different sites, or the Steering Committee may opt for several distinct prevention trials. Prevention trials will focus on cost-effective, school- or community- based interventions with the potential for broad, public health application. In addition to establishing the intervention protocols, the Steering Committee will also develop standardized tools, assays, tests and analysis techniques that will be utilized in all the funded trials. The CC will have both scientific and administrative functions. The first objective of the CC is to participate in the design of the intervention protocols and the development of standardized measures to be used in the clinical trials for the prevention and treatment of type 2 diabetes in the pediatric population. The Principal Investigator of the CC will serve on the Steering Committee, which will meet during the planning phase to design and approve protocols and establish standardized tests, analytical methods and outcome measures to be used in all trials (see below, Special Requirements). During the planning phase, the CC, in particular, will provide input to determinations of sample size and statistical analysis. The CC will also be responsible for arranging meetings and conference calls, generating meeting agendas and minutes of meetings, developing manuals of operation, questionnaires and data collection forms, and facilitating communication among Steering Committee members. The CC will also generate materials to be used in recruiting study participants. The second objective of the CC is to be a data management center. The CC will receive data from all study sites. The application should provide details for the establishment of a data transmission system and database, it should detail the procedures for data transmission and record keeping, including methods to validate data and check for discrepancies and missing data/forms. Trial sites must be informed of incomplete or missing information. It is expected that CC staff will travel to clinical trial sites to monitor data collection and quality control procedures. The CC will provide for central registration of all study participants, maintain records on all enrolled participants and track participant status. The CC will randomize patients, when required by a particular study. The application should describe the system for patient registration, tracking and randomization, and should detail methods to protect patient confidentiality. For multi-center trials, the CC will coordinate interactions between study centers. The CC will process, review and analyze all data transmitted from the clinical trials and will provide statistical reports at all Steering Committee meetings on progress of the trials. In addition, the CC will provide reports and analyses for review by an independent Data Safety and Quality Monitoring Board (DSQ, see “Study Organization,” below). The third objective of the CC is to provide analytical and statistical support for the trials. The CC will be responsible for all data management and statistical analysis for the various clinical trials. The CC will review all proposed protocols and develop statistical designs for studies, analyze study results, and review all manuscripts for statistical design considerations. The fourth objective of the CC is to assist in the performance of all standardized measures. The CC will establish centralized laboratories and reading centers, possibly through subcontracts, and provide for shipment of samples between study sites and these centralized facilities, as dictated by the needs of the various clinical trials. These standardized tests (see below, “Special Requirements”) will be determined by the Steering Committee during the planning phase. The CC staff will, as necessary, train clinical and/or laboratory staff, and certify the qualifications of personnel or laboratories to perform assays and tests. The CC will monitor quality control of all centralized laboratory tests and clinical measures. Examples of the types of centralized laboratory functions that may be required include assays of blood glucose, insulin, glycosylated hemoglobin, lipid and lipoproteins, islet cell antibodies and various hormone measurements (e.g., IGF-1, IGFBPs, leptin, sex steroids). Other tests might include anthropomorphic measures (e.g., height, weight, BMI, skin fold thickness), determination of insulin sensitivity and insulin secretion, and assessment of body composition. Reimbursement for laboratory tests will be done by the CC, via subcontracts to centralized laboratories and/or reading centers. This will require tracking all clinical tests performed and maintaining necessary files, and generating reimbursement reports. The CC will be responsible for soliciting proposals from, and helping to select, such central laboratories and reading centers. The CC must conform to the guidelines of the Office of Human Research Protection (OHRP) by obtaining an assurance, having an institutional review board (IRB) and obtaining IRB approval annually. In addition, the CC will maintain a centralized file of all IRB approval forms for the various trials. The CC, in conjunction with the Principal Investigator of each study site, must establish and implement a plan for monitoring and reporting all adverse events to the NIDDK and the DSQ. Because of its role in generating materials to be used in recruiting patients, the CC should demonstrate evidence of cultural sensitivity and the ability to develop culturally competent protocols and train appropriate staff. SPECIAL REQUIREMENTS A goal of this RFA is to develop an infrastructure for conducting studies related to the prevention and treatment of type 2 diabetes in the pediatric population. In particular, it is intended to create a series of standardized measurement tools and analytical procedures that will be used in all the clinical trials funded under the companion RFA, DK-01- 010, and that may serve as a framework for future studies. For example, all the trials should utilize the same test to assess such parameters as glucose homeostasis, insulin sensitivity, insulin secretion, or body composition. Laboratory tests (e.g., insulin, glycosylated hemoglobin, lipids) should be performed by a single laboratory. Uniform surveys or questionnaires (e.g., for family history, dietary history, or physical activity assessment) should be developed. Surrogate markers and outcome measures should be standardized across the trials. To promote the development of a collaborative program among the award recipients, a Steering Committee will be formed, composed of the Principal Investigator of each study site and of the Data Coordinating Center, as well as the NIDDK program official. It is expected that the Steering Committee will meet a minimum of six times at the NIH and have frequent contact by telephone during the planning phase, which is expected to take one year. Once the trials are initiated, the Steering Committee will continue to meet at least twice each year and have frequent conference calls. It is anticipated that, during these meetings and calls, issues related to study protocol will be discussed and ideas will be exchanged to enhance study progress. The Steering Committee may create subcommittees to accomplish its goals. Each application must designate a Director and Deputy Director. The CC Director should be an experienced biostatistician, epidemiologist, physician or other professional with experience in directing a coordinating center for a large collaborative clinical trial or other large-scale epidemiological research project. Staff needs may be modified based on the final protocols established by the Steering Committee, however, statisticians, systems analysts, programmers, statistical assistants, clerks and administrative assistants must be available. It is expected that senior statistical staff will devote time to developing data analysis methods for use in the trials. Since the treatment trials may involve the use of drugs not currently approved for use in children, the CC must have the capability to obtain and maintain an Investigational New Drug application. Study Organization The cooperative agreement will have three phases: 1) planning (12 months), 2) recruitment and study (5 years), and 3) analysis (final year of each trial). Each clinical trial center will receive funding through a separate U01 award mechanism. When the individual U01s are awarded, each center will receive direct funds to cover the cost of personnel, equipment, supplies, communication, travel and patient care costs associated with the study. Reimbursement of laboratory tests will be done through the Coordinating Center via subcontracts to centralized laboratories and/or reading centers. The Principal Investigator of each center will, in collaboration with other Steering Committee members, develop the study protocol and uniform data collection forms. Each center will have direct responsibility for identifying eligible study participants, assessing eligibility, promoting adherence to study design, conducting baseline and follow-up visits, obtaining blood, urine and other physical measurements, and sending samples and data to the Coordinating Center, reading centers and laboratories, as appropriate, according to time frames set by the Steering Committee. The Coordinating Center will have primary responsibility for the biostatistical analyses and data management aspects of the clinical trials. The CC will have both scientific and administrative functions. The CC will review all proposed protocols and help develop the statistical design for each study, analyze study results and review all manuscripts for statistical considerations. The CC will prepare and update protocols, manuals of operation and all forms to be used in data collection, and will provide materials to aid in patient recruitment. The CC will be responsible for establishing a database to accommodate data generated by each trial, developing a data transmission system, and assessing data quality and completeness throughout each study. The CC will provide for central registration and randomization, when necessary, of all individuals enrolled in trials. The CC will establish, via subcontracts, central laboratories and reading centers, as determined by the Steering Committee. The CC will provide statistical reports on the progress of trials at Steering Committee meetings, oversee the patient care cost reimbursement system, and facilitate communication among investigators, including scheduling meetings and conference calls, developing agendas and documenting minutes, and maintaining membership rosters and committee lists. The director of the CC will be a member of the Steering Committee and cannot have any responsibility for recruitment or follow-up of study participants. The Steering Committee will have overall responsibility for the design of the studies performed. The Steering Committee will design the prevention and treatment interventions, and develop standardized testing methods and outcome measures, as described above, to be utilized in the various clinical trials. The Steering Committee will approve all protocols, changes to protocols, and manuals of operation. Responsibility for the execution of each trial will rest with the Principal Investigator of each study site, who will provide progress reports to the Steering Committee. The Steering Committee will also develop policies relating to access to patient data and specimens, and ancillary studies. The Steering Committee will establish guidelines for presentations at scientific meetings and for writing and publishing manuscripts on the findings of the study. The Steering Committee will meet initially to develop the protocols and subsequently to discuss the progress of the study. The NIDDK will select a chairperson from among the non-federal Steering Committee members or other experts in diabetes clinical trials. The chairperson of the Steering Committee must not have responsibility for recruitment or follow-up of study participants. If a study investigator is chosen as chairperson, he/she must designate a replacement investigator at his/her institution. The chairperson must have proven evidence of leadership ability and be able to make an adequate time commitment to the cooperative agreement. The Data Safety and Quality Monitoring Group (DSQ) is an external oversight committee that will be appointed by the NIDDK. It will be composed of diabetes and clinical trial experts not directly involved in any of the clinical trials. Prior to the initiation of a trial, the DSQ will review the protocols to ensure proper scientific design and protection of human subjects. The studies will move forward into the recruitment phase only with the concurrence of the awardees, the DSQ and the NIDDK. The DSQ will monitor each trial for safety and efficacy, with authority to recommend protocol or procedural changes or early termination of any trial. The DSQ is advisory to both the NIDDK and the Steering Committee. The Chairperson of the Steering Committee and the Principal Investigator of the CC will attend DSQ meetings, which will take place at least twice a year. 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 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 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 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. 1. Awardee Rights and Responsibilities Awardees will have primary and lead responsibilities for the project as a whole, including research design and protocol development, participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and preparation of publications, with assistance from the NIDDK Project Scientist. Awardees will collaborate with other investigators participating in this project and agree to follow common protocols developed by the Steering Committee. The awardees also agree to provide progress reports to the Steering Committee. The inability to meet performance requirements may result in an adjustment of funding, withholding of support, restriction of funds already awarded, or termination of the award. All awardees (including the CC) must be able to demonstrate that there is a current, approved Assurance on file with the NIH 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. The Principal Investigator must agree and assure that adequate records will be available, to enable outside monitors to assess compliance with applicable federal laws and regulations. The Coordinating Center will have primary responsibility for clinical center coordination, and the biostatistical analyses and data management aspects of the clinical trials. The CC will have both scientific and administrative functions. The CC will review all proposed protocols and help develop the statistical design for each study, analyze study results and review all manuscripts for statistical considerations. Based on input from the Steering Committee, the CC will prepare and update protocols and manuals of operation, and will provide materials to aid in patient recruitment. The CC will be responsible for establishing a database to accommodate data generated by each trial, developing a data transmission system, and assessing data quality and completeness throughout each study. The CC will provide for central registration and randomization, when necessary, of all individuals enrolled in trials. The CC will establish, via subcontracts, central laboratories and reading centers, as determined by the Steering Committee. The CC will provide statistical reports on the progress of trials at Steering Committee meetings, oversee the patient care cost reimbursement system, and facilitate communication among investigators, including scheduling meetings and conference calls, developing agendas and documenting minutes, and maintaining membership rosters and committee lists. The director of the CC will be a member of the Steering Committee and cannot have any responsibility for recruitment or follow-up of study participants. The CC and study investigators must agree to implement an adverse event tracking system, as designed by the 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 below under “Inclusion of Women and Minorities in Research Involving Human Subjects.” 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. The CC, together with the study Principal Investigators, must achieve and maintain quality data in accordance with the common protocols and manuals of operation specified by the Steering Committee. Prompt presentation and publication in the scientific literature of study findings is required. Awardees must agree to acknowledge NIDDK support in the publications and oral presentations resulting from research conducted under this cooperative agreement. Manuscripts and presentations will be written and reviewed according to policies established by the Steering Committee. Awardees will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS and NIH policies. The CC will be expected to put all study intervention materials and procedure manuals in the public domain and/or make them available to other investigators. The NIDDK also expects that biologic samples and associated clinical data will be made available to the scientific community at an appropriate juncture, for further studies related to understanding, preventing and/or treating type 2 diabetes in children and adolescents. 2. NIDDK Staff Responsibilities The NIDDK Project Scientist will provide scientific support to the awardees’ activities, including protocol development and modification, quality control and performance monitoring, interim data monitoring, final analysis, and preparation of publications. Consistent with the cooperative agreement nature of this study, the NIDDK Project Scientist will be substantially involved as an active partner in all aspects of the scientific and technical management of the trials. This level of involvement will be above and beyond the level required for administration of traditional research grants. The NIDDK Project Scientist will have voting membership on the Steering Committee and, will participate, as appropriate, on its subcommittees. The NIDDK 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 can also terminate or curtail a study if a major study endpoint is reached substantially before schedule with persuasive statistical significance, if futility in reaching a significant difference between the treatment groups is realized, if there is emergence of new information that diminishes the scientific importance of the study, or if human subject safety or ethical issues dictate a premature termination. The NIDDK may also terminate the project if there is failure to develop or implement a mutually agreeable collaborative protocol. 3. Collaborative Responsibilities The Steering Committee, which will be the main governing board of the study, will be composed of the Principal Investigator of each study site, the Principal Investigator of the CC, and a representative of the NIDDK, with each member having one vote. The Steering Committee will have primary responsibility for developing common research designs, protocols and manuals, facilitating the conduct and monitoring of studies, and reporting study results. The Steering Committee will design the prevention and treatment interventions, and develop standardized testing methods and outcome measures, as described above, to be utilized in the various clinical trials. The Steering Committee will approve all protocols, changes to protocols, and manuals of operation. Responsibility for the execution of each trial will rest with the Principal Investigator of each study site, who will provide progress reports to the Steering Committee. The Steering Committee will also develop policies relating to access to patient data and specimens, and ancillary studies. The Steering Committee will establish guidelines for presentations at scientific meetings and for writing and publishing manuscripts on the findings of the study. The Steering Committee will meet initially to develop the protocols and subsequently to discuss the progress of the study. The NIDDK will select a chairperson from among the non-federal Steering Committee members or other experts in diabetes clinical trials. The chairperson of the Steering Committee must not have responsibility for recruitment or follow-up of study participants. If a study investigator is chosen as chairperson, he/she must designate a replacement investigator at his/her institution. The chairperson must have proven evidence of leadership ability and be able to make an adequate time commitment to the cooperative agreement. To promote the development of a collaborative program among awardees, Principal Investigators are expected to attend Steering Committee meetings and participate in conference calls on a regular basis. In the first, planning year, it is anticipated that at least six meetings will be required, to establish common measurements and outcomes. Once patient recruitment has started, at least two Steering Committee meetings will occur annually, with communication by conference call continuing on a regular basis to discuss emerging issues. The Data Safety and Quality Monitoring Group (DSQ) is an external oversight committee which will be appointed by the NIDDK. It will be composed of diabetes and clinical trial experts not directly involved in any of the clinical trials. Prior to the initiation of a trial, the DSQ will review the protocol to ensure proper scientific design and protection of human subjects. The studies will move forward into the recruitment phase only with the concurrence of the awardees, the DSQ and the NIDDK. The DSQ will monitor each trial for safety and scientific validity, with authority to recommend protocol or procedural changes or early termination of any trial. The DSQ is advisory to both the NIDDK and the Steering Committee. The chairperson of the Steering Committee and the Principal Investigator of the CC will attend DSQ meetings, which will take place at least twice a year. 4. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIDDK may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the Steering Committee (with the NIDDK member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by the NIDDK, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee"s right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. 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. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. Under the statute, when an NIH defined Phase III clinical trial is proposed, evidence must be reviewed to show whether or not clinically important 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. 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 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. The Research Plan in the application or proposal must include a description of plans to conduct the 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. LETTER OF INTENT Prospective applicants are asked to submit, by March 20,2001, 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. Applicants must document their willingness to participate on the Steering Committee and appropriate subcommittees, work cooperatively with other members of the Steering Committee and follow the common protocols established cooperatively by the Steering Committee. Applicants must address the following responsibilities of the CC: 1) participation in the design of the final protocols and development of the manuals of operation, data collection forms, and questionnaires, 2) development and implementation of systems for communication among Steering Committee members, and among study sites, 3) data collection, editing, processing, analysis and reporting, 4) monitoring of adherence to protocols and of data quality, and 5) establishment of procedures that insure the safety and confidentiality of all records. Applicants must describe plans for maintaining effective collaboration and communication among investigators. They should provide information on prior experience participating in diabetes research and clinical trials. Applicants must describe their ability to 1) provide fiscal management and administrative support for the clinical trials established by the Steering Committee, and 2) design, support, conduct and provide statistical expertise for clinical trials. The CC must have the ability to handle an IND application. A description of appropriate facilities, personnel, equipment and institutional support must be provided. Experience handling numerous subcontracts should be documented. Examples of forms and correspondence useful for coordinating tasks should be included. A thorough description of experience and methods for tracking patient care costs and reimbursing multiple study sites must be given. The applicant should describe the approach that would be used for soliciting and evaluating proposals for centralized laboratories and/or reading centers. Applicants should describe their physical facilities, data management and computer resources, and facilities for data retrieval and storage. Examples of data forms, questionnaires and software/computer programs should be included and described. Methods for sending and receiving data, and maintaining data should be described. Data management and quality control procedures must be detailed. Applicants must include a plan for randomization of patients into protocols. Methods for assuring privacy and maintaining confidentiality should be included. There must be a data and safety management plan. Applicants must state their plans for reporting accrual by gender, race and ethnicity and for the reporting of results that examine differences in treatment effects across these subgroups (see above, “Inclusion of Women and Minorities in Research Involving Human Subjects”). Applicants must document their willingness to participate in Steering Committee and DSQ activities, including meetings at the NIH and regular conference calls, and should state their willingness to follow the common protocol agreed to during the planning phase. Evidence of strong institutional support must be provided. Applications should not exceed 35 pages, excluding appendices, which may contain copies of pertinent forms or examples of correspondence useful for coordinating tasks. Budget Information Applicants should submit an adequately justified budget for the entire anticipated project period. The budget should be divided into three phases: 1) planning (12 months), 2) recruitment and study (five years), and 3) analysis (final year of each trial). The application should contain a detailed budget for each phase. The planning phase will be for the development of the protocols and the manuals of operation by the Steering Committee. The budget should contain costs for personnel, supplies, equipment, communication and travel. In addition, the NIDDK will supply funds for the reimbursement of laboratory tests, which will be distributed by the CC to centralized laboratories and reading centers through appropriate subcontracts. The actual budget awarded will be determined following the design of the various clinical trials. 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 April 17, 2001. If an application is received after that date, it will be returned to the applicant without review. Supplemental materials for the application must be received by May 21, 2001. Material received after that date will not be accepted. All supplemental material should be sent to: Scientific Review Administrator Division of Extramural Activities, NIDDK 6707 Democracy Boulevard Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) The name of the SRA will be provided to the applicant in the letter acknowledging receipt of the application. 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 All 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 expected scientific and intellectual contributions to the collaborative effort, will be part of the evaluation criteria. Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDDK in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the 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. Applications will be reviewed for scientific and technical merit using the following criteria: o Approach: Is there an adequate understanding of the scientific agenda of the cooperative agreement? Can the CC contribute to the goals and enhance the study group as a whole? Does the applicant have a thorough understanding of the complexities of administering and monitoring a large-scale clinical trial and of maintaining effective communication and collaboration among study group members? Does the applicant illustrate the ability to design, support, conduct and provide statistical expertise in clinical trials? Does the application contain an appropriate plan to capture. monitor, transmit, store, ensure security and otherwise manage clinical data on large-scale clinical trials? Does the applicant describe a reasonable plan for distributing drug in large-scale, multi- centered clinical trials in a masked manner, and des rive appropriate procedures for unmasking drug, if necessary? Is there an efficient and reliable plan for tracking patient tests that are performed at the clinical sites? Are there appropriate plans to protect confidentiality of data? Is there an appropriate data and safety monitoring plan? Does the applicant’s approach conform to NIH guidelines for inclusion of women and minorities as human subjects in clinical research? Is there evidence that the CC staff can develop culturally sensitive study materials? o Investigator: Are the investigators appropriately trained and well suited to carry out this work? Is the scientific, technical and administrative work proposed appropriate to the experience level of the principal investigator and other staff? Prior experience in the collection of data from multiple sites, as well as experience monitoring the quality of such data must be demonstrated. Is the investigator likely to contribute intellectually to the collaborative effort? Is there evidence of prior experience working collaboratively in carrying out a standard protocol involving multiple study sites? Is there evidence of willingness to work collaboratively on the Steering Committee to develop and follow unified protocols? Is there an appropriate amount of time planned for effective collaboration? 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 multiple clinical trials, for data acquisition, management and analysis, and for fiscal administration of a multi-site study? Is there evidence of institutional support? 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) program balance, including in this instance, sufficient compatibility of features to make a successful collaborative program a reasonable likelihood, and (c) availability of funds. Schedule Letter of Intent Receipt Date: March 20,2001 Application Receipt Date: April 17, 2001 Peer Review Date: June 2001 Council Review: September 2001 Earliest Anticipated Start Date: September 30, 2001 INQUIRIES Written 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: Barbara Linder, M.D., Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases NIDDK 6707 Democracy Boulevard, Rm. 699 Bethesda, MD 20892-5460 Telephone: (301) 594-0021 FAX: (301) 480-3503 E-mail: email@example.com Direct inquiries regarding fiscal matters to: Kim Law Division of Extramural Activities NIDDK 6707 Democracy Boulevard, Rm. 639 MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8869 FAX: (301) 480-3504 E-mail: firstname.lastname@example.org AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847. 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 PHS mission to protect and advance the physical and mental health of the American people.
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