PREVENTION AND TREATMENT OF TYPE 2 DIABETES IN CHILDREN AND ADOLESCENTS—CLINICAL CENTERS Release Date: October 5, 2000 RFA: DK-01-010 - (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 to develop 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, however, recent epidemiological data reveal an increasing number of cases of type 2 diabetes in the pediatric population, especially among adolescents and in certain minority populations. The increase of type 2 diabetes in children and adolescents is presumed to be a consequence of widespread obesity and decreased physical activity. Clinical trials to develop both effective primary prevention strategies and treatment regimens for this age group are needed. The intent of this RFA is to focus on community or school-based primary prevention programs that can be applied in a cost-effective manner to decrease risk factors for type 2 diabetes and lower the incidence of the disorder. In addition, the drugs currently available for the treatment of type 2 diabetes in adults have not been used widely in children. Treatment options need to be studied in this population to determine the most efficacious, safe, and cost-effective strategies to achieve euglycemia in the pediatric age group. The purpose of this RFA is to 1) solicit proposals for clinical trials for the prevention and treatment of type 2 diabetes in the pediatric population, and 2) create an infrastructure for the conduct and analysis of such clinical trials. Applicants may submit a proposal for a primary prevention trial or a treatment trial. An institution wishing to propose both a prevention trial and a treatment trial may do so, but must submit two separate applications. It is anticipated that the final cooperative agreement award will fund 1) one multi-center, multi-arm treatment trial and 2) at least one, but possibly more, primary prevention trials, to be conducted at multiple sites. Applicants selected on the basis of a proposal for either a treatment or prevention trial may have the opportunity to participate in both types of trials. A complementary RFA (DK-01-011) will be issued to create a Coordinating Center (CC) to provide administrative, analytical and statistical support for the studies conducted. An institution or organization can apply to be the CC, as well as submit an application 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 institutions in the United States, Puerto Rico and Canada. This geographic constraint is necessary because of the need for close communication and meetings among members of the Steering Committee (see Objectives and Scope). Applicants may be for- profit or 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. Applicants may submit a proposal for a primary prevention trial or a treatment trial. An institution wishing to propose both a prevention trial and a treatment trial may do so, but must submit two separate applications. Awards for the clinical trial centers and for the Coordinating Center will not be made to the same Principal Investigator to insure that data analysis is performed independently of data acquisition. An institution or organization can apply to be the CC as well as submit an application for a clinical trial. 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,” and "Terms and Conditions of Award." The total project period for applications submitted in response to the present RFA should be 7 years. The anticipated award date is September 30, 2001. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or Principal Investigator should be included with the application. 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 The collaborative effort which the NIDDK will support 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. Approximately $1.75 million are available to support the clinical trial sites during the planning year of this cooperative agreement. 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 6-10 awards for clinical trial sites will be made. The exact number of sites for each of the trials will depend on the sample size needed and the potential for recruitment at individual sites. The budget for the planning year is expected to support the salary and travel of the principal investigator and other appropriate key personnel at each study site. Once the trials begin, the NIDDK will provide funds directly to each center to support personnel, supplies, equipment, communication, travel and patient care costs associated with the study. Additional funds will be provided to the Coordinating Center to support subcontracts to centralized laboratories and/or reading centers, as required by the trials. After the planning phase, awards in subsequent years will depend on the requirements of the protocols ultimately designed under this cooperative agreement. Because the nature and scope of each clinical trial will vary, it is anticipated that the size of each award will also vary. 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. In fact, 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 suggest 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 of 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 insulin resistance, 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 disproportionately affects minority groups. In addition, children represent a unique “target” population, which 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 preventing 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. Objectives and Scope This RFA is designed to 1) solicit applications for clinical trials for the prevention and treatment of type 2 diabetes in children, and 2) 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 population level. To accomplish its objectives, this RFA solicits investigator-initiated clinical trial proposals for the primary prevention and treatment of children (6-18 years of age) with type 2 diabetes. Investigators are invited to submit a detailed proposal containing the study design he/she believes best addresses the needs of his/her patient population. The trial proposed should involve either primary prevention or treatment, and the application must contain a rationale for the intervention chosen. An institution may propose both a prevention trial and a treatment trial, however, separate applications must be submitted for each trial. This Objectives and Scope section outlines the scientific goals of the RFA. Additional details regarding the content of the application are outlined under “Application Procedures.” While the study population at any one site may vary based on local demography, an overall goal of this RFA is to address the prevention and treatment of type 2 diabetes in children and adolescents from minority groups, including African Americans, Hispanic Americans, and Native Americans. The final demographic composition of the trial will reflect the high rates of type 2 diabetes among minority children. To accomplish this goal, investigators are encouraged to develop collaborations with care providers who have access to underserved minority populations. It is highly desirable for investigators to establish meaningful mentorships with such caregivers, who may not be trained as scientific investigators. This collaboration might involve a university appointment for a collaborator located outside the institution and opportunities for this individual to obtain experience as a clinician-scientist. Also encouraged is participation of newly trained physicians. It is desirable to provide opportunities and experiences that may lead such individuals to develop as clinical investigators. In addition, all applicants must address the issue of the cultural sensitivity of the intervention proposed. Based on peer review, awards will be made to those centers whose proposals are judged to be of high scientific merit (see Review Criteria and Award Criteria, below). A Steering Committee will then be created, comprised of the Principal Investigator of each study site, the head of the Coordinating Center (to be recruited through a companion RFA, DK 01- 011), as well as an NIDDK representative. The Steering Committee will meet during the planning phase of the cooperative agreement to design the actual study protocols. The Steering Committee will be the main governing board of the studies and will have primary responsibility for developing common research designs, protocols and manuals, facilitating the conduct and monitoring of studies, and reporting study results. 1. Treatment Trial 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 at multiple sites, to insure an adequate sample size, as well as geographic and racial/ethnic diversity. Investigators who proposed a primary intervention trial will also be eligible to participate in the treatment trial. However, any one funded clinical site may not necessarily participate in all conducted protocols, depending on the need for patient numbers and diversity. The treatment trial may involve lifestyle intervention and/or drug therapy. It is desirable for the designed trial to assess pathophysiological issues, such as preservation of beta cell function, in addition to simply measuring glucose control. The inclusion of a board- certified pediatric endocrinologist among the trial personnel or as a consultant is encouraged. 2. Prevention Trial At least one, but possibly more, primary prevention protocols will be developed. The prevention trial ultimately designed by the Steering Committee 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. If multiple prevention trials at different sites are carried out, the Steering Committee will establish standardized entry criteria, clinical assessments and outcome measures so that all the trials can be compared. Thus, 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 (see below). Primary prevention trials should focus on cost-effective, school- or community-based interventions with the potential for broad, population- wide application. Other (i.e., non school-based) community-based interventions are also acceptable. However, the intervention cannot consist of a one-on-one intervention between a health care provider (or other adult) and a child. Physician- or clinic-based primary prevention trials will not be accepted. Applicants may propose an intervention designed to alter risk factors for type 2 diabetes, improve insulin sensitivity, decrease development of impaired glucose tolerance, or prevent conversion to frank diabetes. While it is expected that interventions will focus on lifestyle modifications and may, therefore, include assessment of weight, BMI or physical fitness, the protocol must include measures of insulin sensitivity and glucose homeostasis. The final design of the prevention trial will rest with the Steering Committee. The prevention trial must represent a collaborative, multidisciplinary effort between a physician (who need not be the Principal Investigator) and appropriate qualified personnel, as required by the needs of the study designed (e.g., epidemiologist, psychologist, nurse, nutritionist, exercise specialist, etc.). The inclusion of a board-certified pediatric endocrinologist among the trial personnel or as a consultant is encouraged. It is anticipated that the design of the prevention trial may be labor intensive because of the need to assess insulin sensitivity or glucose homeostasis to establish that the intervention is efficacious. However, the actual intervention must be one that ultimately could be widely applied to a large population of children. 3. Steering Committee In addition to designing the clinical trial protocols, the Steering Committee is also expected 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 this RFA, 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, and 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. 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 will establish subcommittees, as necessary, to accomplish its goals. 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. 4. Study Organization The cooperative agreement will have three phases: 1) planning (12 months), 2) recruitment and study (five years), and 3) analysis (final year of each trial). Each clinical trial center will receive funding through a separate U01 award. When the individual U01s are awarded, each center will receive direct funds to cover the cost of personnel, equipment, supplies, travel, communication, and patient care costs associated with the study. Reimbursement for laboratory tests will likely be done by the Coordinating Center, via subcontracts to centralized laboratories and/or reading centers. If additional sites are needed to recruit adequate numbers of patients, subcontracts may be added to individual study sites. The Principal Investigator of each center will, in collaboration with other Steering Committee members, develop the study protocols 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 (recruited through a separate RFA DK-01-011) 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 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 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. 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. Clinical Center awardees will collaborate with other investigators participating in this cooperative agreement and agree to follow common protocols developed by the Steering Committee. The awardees also agree to meet patient recruitment goals, to transmit data in a timely manner to the CC, as determined by the Steering Committee, and 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. The Steering Committee will develop and maintain specific measures to ensure the safety and protection of the rights of study patients. The Principal Investigator of each study site 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 awardees 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 (recruited through a separate RFA DK-01-011) 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. 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. 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, PHS, 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. A study site and its institution may not be involved simultaneously in other studies involving the treatment or prevention of type 2 diabetes in the pediatric population if enrollment criteria overlap between the studies and if the studies are actively recruiting participants. Applicants will forego participation in studies that would compete for recruitment of the same study population. 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, as appropriate, will participate in 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 mutually agreeable collaborative protocols. 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 year, it is anticipated that at least six meetings will be required, to design the protocols and establish common measurements and outcomes. Once patient recruitment has started, at least two Steering Committee meetings will occur annually, with additional communication by conference call 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 (1) both males and females and (2) members of minority groups and their subpopulations 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 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 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 GrantsInfo, Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, Suite 6095, Bethesda, MD 20892-7910, telephone 301-710-0267, email: GrantsInfo@nih.gov. Instructions for Applicants Applications responding to this RFA should not use the modular grant format. All applicants should provide a detailed description of the design of the study, including what eligibility, baseline, and follow-up tests are to be done, what surrogate markers and endpoints will be examined, and the duration of follow-up. Examples of data forms and questionnaires proposed should be given. The process for biologic sample collection, storage and handling needs should be included. A description of the laboratory tests that are needed with appropriate methods for performing them should be provided. If multiple tests are available to assess a parameter (e.g., assessment of insulin sensitivity), a justification for the chosen method should be included. Also included should be the methods that would be used to ensure privacy and maintain confidentiality of data. There must be a data and safety monitoring plan. 1. Treatment Trial Applicants should provide a detailed description of the target population to be studied with justification including a definition of the cohort by age, sex and race. The ability to recruit this target population and the methods to be used should be described, with an estimation of the potential number of patients who fit the eligibility criteria and expected accrual rates. Sample size needs and the assumptions and calculations used to estimate sample size should be detailed. Because the ultimate trial carried out under this RFA will be a collaborative effort, an investigator may propose an intervention that requires more patients than can be recruited from within his/her institution. In this case, the investigator should provide a detailed description of the total sample size needed as well as the number of patients that could be recruited from his/her own site. 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”). The application must provide a detailed account of the local population pool from which patients will be recruited, including the gender and racial/ethnic make-up of the population and the expected numbers of patients from each group that could be recruited. While the study population for any individual trial may vary based on local demography, an overall goal of this RFA is to address the prevention and treatment of type 2 diabetes in children and adolescents from minority groups, including African Americans, Hispanic Americans, and Native Americans. A plan for recruitment and retention of participants must be provided. Subcontracts may be used to recruit patients from additional local sites not a part of the parent institution. In this case, the Principal Investigator must include a detailed description of the patient pool at these additional sites, as well as letters of cooperation from potential subcontractors. It must be made clear that, depending on the final design of the clinical trial, not all potential subcontractors will be needed. Applicants must demonstrate evidence of cultural competency. (2) Prevention Trial The prevention intervention must be carried out at a school or other community-based setting. The application must provide a detailed account of the local population pool from which patients will be recruited, including the gender and racial/ethnic make-up of the population and the expected numbers of patients from each group that could be recruited. While the study population for any individual trial may vary based on local demography, an overall goal of this RFA is to address the prevention and treatment of type 2 diabetes in children and adolescents from minority groups, including African Americans, Hispanic Americans, and Native Americans. A plan for recruitment and retention of participants must be provided, with an estimation of the potential number of patients who fit the eligibility criteria and expected accrual rates. Sample size needs and the assumptions and calculations used to estimate sample size should be detailed. The applicant must provide letter(s) of agreement from the school or community group that will be targeted. The letter(s) must be provided in the application or be sent to the Scientific Review Administrator no later than July 2, 2000. If the applicant is unable to provide letter(s) of agreement by July 2, he/she must contact the Scientific Review Administrator before that date. Applications that do not have appropriate letter(s) of agreement will not be reviewed. There must be a data and safety monitoring plan. The applicant must demonstrate evidence of cultural competency. 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”). (3) Budget Information Detailed budget information should be provided for the proposed trial. The budget should be divided into 3 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. It is anticipated that during the planning phase, the budget will primarily support the salary and travel of the Principal Investigator and other key personnel. Once the award is made, each study site will directly receive costs for personnel, supplies, equipment, communication, travel, and patient care costs associated with the study. The application should detail these costs as dictated by the study that is proposed. The actual budget awarded will be determined once the Steering Committee finalizes the protocols. Each site does not have to participate in every trial actually conducted. Therefore, the final awards may vary among sites. Costs for laboratory tests will be reimbursed using subcontracts through the CC, at rates determined by the NIDDK. (4) Issues To Be Addressed By All Applicants Qualifications and Experience. Applicants must include a description of their experience and expertise to conduct a clinical trial and participate in a multi-center collaborative effort. In addition, the application must provide evidence of the Principal Investigator’s ability to contribute to the scientific effort of this cooperative agreement. Institutional Support. There should be evidence of strong institutional support for the proposed study, including adequate space, resources and facilities for patient care and follow-up. Willingness to Collaborate. Applicants must document their willingness to participate in Steering Committee 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. Applicants must describe plans to accommodate stated program requests, criteria and staff involvement. 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 (not to exceed 3 pages) for the application must be received by May 25, 2001. Material received after that date will not be accepted. Twenty copies of 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 General 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 importance and timeliness of the proposed clinical trial(s), access to patients, and 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. Those applications that are complete and responsive will undergo scientific merit review in accordance with the criteria stated below for scientific/technical merit by an appropriate peer review group convened by the NIDDK. 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 of 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. The review group will assess the scientific merit of the protocols and related factors, including: o Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific and/or medical knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? o Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Is there evidence of the ability to recruit, enroll and maintain subjects in a randomized trial? This includes an adequate description of the racial, ethnic and gender composition of the proposed cohort and documentation of access to an adequate patient population who may be approached in finding potentially eligible study participants. Are there adequate plans to ensure accurate collection and timely transmission of study data to the CC and/or central laboratories and reading centers? 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? o Innovation: Does the project employ novel concepts, approaches or methods? Does the project challenge existing paradigms or develop new methodologies or technologies? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? Is the investigator likely to make a significant intellectual contribution to the collaborative effort? Is there evidence of prior experience in working collaboratively to carry out a clinical trial or standard protocol? Is there evidence of willingness to work cooperatively on the Steering Committee to develop and follow unified protocols? o Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? 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 humans. AWARD CRITERIA Applications recommended by the NDDK Advisory Council will be considered for award based on the scientific merit of the proposed project and the ability of the investigators to meet the research objectives of this RFA. In addition, other considerations, including program balance will be considered. Additional considerations might include the racial and ethnic composition of the populations being studied, the geographical location of the trial, and the type of intervention being proposed. Awards are also contingent upon the 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: firstname.lastname@example.org Direct inquiries regarding fiscal matters to: Kim Law Division of Extramural Activities NIDDK 6707 Democracy Boulevard, Rm. 639 Bethesda, MD 20892-5456 Telephone: (301) 594-8869 FAX: (301) 480-3504 E-mail: email@example.com 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 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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