COOPERATIVE MULTICENTER RESEARCH NETWORK TO TEST GLUCOSE SENSORS IN CHILDREN WITH TYPE 1 DIABETES MELLITUS Release Date: February 22, 2001 RFA: RFA-HD-01-009 National Institute of Child Health and Human Development (http://www.nichd.nih.gov) National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov) Letter of Intent Receipt Date: March 27, 2001 Application Receipt Date: May 11, 2001 PURPOSE The National Institute of Child Health and Human Development (NICHD) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invite cooperative agreement applications for participation in a collaborative research consortium that will utilize new continuous glucose monitoring devices to: (1) evaluate glycemic control and the incidence, magnitude, and duration of hypoglycemia in a contemporaneous population of children with type 1 diabetes mellitus, and (2) to evaluate glucose homeostasis in children without diabetes. This research consortium may also evaluate the value of providing data from these devices to health care professionals with regard to achieving glycemic control and minimizing hypoglycemia in children with type 1 diabetes mellitus. In addition to applications for Clinical Centers (CC), which will recruit subjects, and develop and implement a common protocol, separate applications are invited for support of a Data Coordinating Center (DCC). The DCC will have primary responsibility for Clinical Center coordination, and the biostatistical analyses and data management aspects of the clinical trials. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of Healthy People 2010, a PHS- led national activity for setting priority areas. This Request for Applications (RFA) is related to one or more of the priority areas. Potential applicants may obtain Healthy People 2010 at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and North American, 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. The need for continuous and active communication among sites dictates that only institutions in the United States and North America are eligible to apply. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) cooperative clinical research (U10) award mechanism, 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 stimulate the recipients activity by involvement in the activity and otherwise working jointly with the award recipients in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreements are discussed below under Terms and Conditions of Award. FUNDS AVAILABLE The NICHD and NIDDK intend to commit approximately $2 million in total costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2001 to fund four Clinical Center applications and one Data Coordinating Center application in response to this RFA. Applicants for the Clinical Centers and for the Data Coordinating Center may request a project period of up to five years and a budget for total costs of up to $400,000 per year. Although the financial plans of NICHD and NIDDK provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. RESEARCH OBJECTIVES Background Hypoglycemia is the major limitation to implementation of intensive glycemic control, which has been shown to substantially prevent or delay microvascular complications in adolescents and adults with type 1 diabetes. Intensive therapy has not been systematically evaluated in children under 13 years with type 1 diabetes. Younger children may be at increased risk for hypoglycemia in the setting of intensive therapy and the risk/benefit ratio of intensive glycemic control achieved with current therapeutic tools may be less favorable in this population. This RFA will address that concern through creation of a Type 1 Diabetes in Children Research Consortium. The Consortium will develop and implement a protocol using continuous monitoring devices in children with type 1 diabetes, in order to evaluate the utility of continuous monitoring devices and to determine if these devices are useful in improving glycemic control and preventing hypoglycemia in children with type 1 diabetes. This protocol might also evaluate and develop distinct, age- appropriate treatment approaches to type 1 diabetes in children. The solicitation is part of a multi-faceted research program at the NICHD and the NIDDK intended to reduce morbidity and mortality from type 1 diabetes in the U.S. population. Results of the Diabetes Control and Complications Trial (DCCT) demonstrated that near-normalization of blood glucose levels can be achieved through intensive therapy, and slows the progression and significantly reduces the risk of developing the microvascular complications of diabetes. Although the same regimen and glycemic goals were imposed on both adults and adolescents, the latter group was distinctive in their response to the treatment regimen. Intensive treatment in adolescents caused a three-fold greater risk for severe hypoglycemia and a two-fold risk for obesity compared to similarly treated adults with diabetes. Additionally, the hemoglobin A1c levels remained significantly higher in the adolescent group compared to the adult subjects despite generally higher insulin dosages. Notwithstanding the striking differences in the adolescents and adults, the conclusion of the DCCT was that intensive therapy was recommended for children over the age of 13, since the benefits appeared to outweigh the risks. Insulin pumps and multiple daily injections, now the mainstays of strict glycemic control, are being prescribed more frequently in young children. This treatment approach may be associated with high rates of severe hypoglycemia, possibly leading to various adverse outcomes in some children. One problem inherent in the current system of blood glucose monitoring is that we do not know the true incidence, magnitude or duration of these hypoglycemic episodes. New continuous monitoring systems for measuring interstitial glucose concentrations have the potential to revolutionize diabetes treatment. These systems have been tested in adults but still require testing in children with type 1 diabetes to determine their value in improving metabolic control and reducing the risk of hypoglycemia. This multi-center observational study, using the new continuous monitoring systems, should complement knowledge gained about the risks and benefits of intensive therapy in adolescents and adults during and after the DCCT. While the benefits of intensive glycemic control in reducing complications are likely to accrue in younger children as well as in the DCCT population, the risks may be substantially different. The incidence and severity of hypoglycemia may be increased the younger the age of the child. Also, children with recurrent episodes of hypoglycemia may be at increased risk for learning disabilities and behavior problems. Although these issues cannot be fully addressed in an observational study of this length, they remain the driving force behind this RFA. Data on the incidence, magnitude, and duration of hypoglycemia, as well as its sequelae, are needed to arrive at a clear consensus about the potential risks of contemporaneous treatment regimens of varying intensity in the pediatric population, especially in prepubertal children. Data to inform decisions on treatment and monitoring options for young children and age cutoffs for such options will be developed through this observational study. Objectives and Scope This RFA solicits applications 1) for support of Clinical Centers (CCs) to evaluate glycemic control in children with Type 1 Diabetes by the use of continuous glucose monitoring devices and 2) for support of a Data Coordinating Center (DCC) which will be responsible for providing administrative, analytical, and statistical support for this study. The CCs and the DCC will jointly comprise a Type 1 Diabetes in Children Research Consortium to achieve the following objectives: o To determine the extent of hypoglycemia (frequency, duration and degree) in a contemporaneously treated population of children with type 1 diabetes, o To examine the relationship between intensity of therapy and risk of hypoglycemia, o To identify factors, including method of treatment, exercise, nutrition, other aspects of lifestyle and behavior, age, duration of diabetes, and other patient characteristics, that affect the risk for hypoglycemia, o To examine the value of current monitoring capabilities in management of children with type 1 diabetes, o To measure the blood glucose levels of children without diabetes who are of comparable age and studied in the same manner as the study population using the continuous glucose monitoring devices. Study Protocol This RFA solicits investigator-initiated clinical proposals to recruit, assess, and monitor subjects. Each application for support as a Clinical Center should propose a protocol that can be carried out in a multi-center study of continuous glucose monitoring in children with and without diabetes to accomplish the objectives described above. Investigators are invited to submit a detailed proposal containing the study design he/she believes best addresses these objectives. This longitudinal study should provide information on glucose levels throughout a 24-hour period in normal children and in children with type 1 diabetes treated by either conventional therapy or intensive therapy. It should also address opportunities for ascertainment of the threshold for clinical recognition of hypoglycemia in children with type 1 diabetes using the continuous monitoring device. The application should present a rationale for the number of children of each age to be studied, describe how subjects will be selected to achieve appropriate representation of patient characteristics including methods of treatment, describe and justify the anticipated race, ethnic, and gender composition of the study population, describe and justify the proposed monitoring device to be used, and the setting, duration, and frequency of monitoring. Emphasis should also be placed on inclusion of children across age, gender, socioeconomic, and racial-ethnic groups. Incentives to enhance accrual and retention should be described in the application. A common protocol to be used by all CCs will be established by the Steering Committee during the planning phase (the first six months) of the project. Although the actual protocol to be implemented will ultimately be determined by the Steering Committee, the protocols proposed will provide the major basis for peer review of CC applications. The Steering Committee, composed of the Principal Investigator of each Clinical Center, the Principal Investigator of the Data Coordinating Center, as well as the NICHD and NIDDK Project Scientists, will meet during the planning phase of the cooperative agreement to design the actual study protocol. The Steering Committee will be the main governing board of this study and will have primary responsibility for developing common research designs, protocols, and manuals of operations, facilitating the conduct and monitoring of studies, and reporting study results. Composition of Clinical Center Personnel Applications for Clinical Centers will be strengthened by the participation of individuals with clinical expertise in pediatric endocrinology, behavioral research, nutrition, clinical research, and biostatistics. Approximate Timetable During the first six months, the Steering Committee and other personnel with appropriate expertise from the Clinical Centers and the Data Coordinating Center will work collaboratively to develop the study protocol, manual of operations, and analysis plan. Enrollment and data collection efforts will occur in the latter half of the first year and in Years 02-04.5. Data analysis will occur in the latter part of year five. SPECIAL REQUIREMENTS Attendance at Meetings 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 six months, it is anticipated that at least three meetings will be required, to design the protocol and to 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. Application budget requests should include funds to support travel of the PI and one other investigator to attend scheduled Steering Committee meetings. In addition, the chairperson of the Steering Committee and the Principal Investigator of the DCC will be expected to attend Data Safety and Quality Committee meetings, which will take place at least twice a year. Terms and Conditions of Award The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator(s) as well as the institutional official at the time of award. 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, the NIH Grant Policy statement. The administrative and funding instrument used for this program is a cooperative agreement (U10), 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 NICHD and NIDDK Project Scientists. 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 NICHD and NIDDK Project Scientists. 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 (as determined by the Steering Committee), to transmit data in a timely manner to the DCC, 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 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 Data Coordinating Center (DCC) will have primary responsibility for Clinical Center coordination, the biostatistical analyses, and data management aspects of the clinical study. The DCC will have both scientific and administrative functions. The DCC will review all proposed protocols and help develop the statistical design for the study, analyze study results and review all manuscripts for statistical considerations. Based on input from the Steering Committee, the DCC will prepare and update protocols and manuals of operation, and will provide materials to aid in patient recruitment. The DCC will be responsible for establishing a database to accommodate data generated by the study, developing a data transmission system, and assessing data quality and completeness throughout the study. The DCC will provide for central registration of all individuals enrolled in the study. The DCC will establish, via subcontracts, central laboratories and reading centers, if a need for such is determined by the Steering Committee. The DCC will provide statistical reports on the progress of study 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 DCC 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, children and minorities as subjects in clinical research, and the reporting of results in these subgroups. 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 NICHD and 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 DCC will be expected to put all study materials and procedure manuals in the public domain and/or make them available to other investigators. A study site and its institution may not be involved simultaneously in other studies involving the testing of glucose sensors in children with and without diabetes 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. NICHD and NIDDK Staff Responsibilities The NICHD and NIDDK Project Scientists will provide scientific assistance 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 NICHD and NIDDK Project Scientists will be substantially involved as an active partner in those aspects of the scientific and technical management of the study stated in these Terms and Conditions. This level of involvement will be above and beyond the level required for administration of traditional research grants. The NICHD and NIDDK Project Scientists will have voting membership on the Steering Committee and, as appropriate, will participate in its subcommittees. The NICHD and NIDDK reserve 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 NICHD and 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 NICHD and 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 Clinical Center, the Principal Investigator of the DCC, and the NICHD and NIDDK Project Scientists (one vote combined). The Steering Committee will have primary responsibility for developing common research designs, protocols and manuals, facilitating the conduct and monitoring of the study, and reporting study results. The Steering Committee will design the protocol, and develop standardized methods and measurements to be utilized in the study. The Steering Committee will approve the protocol, changes to the protocol, and the manual of operation. Responsibility for the execution of the study 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 protocol and subsequently to discuss the progress of the study. The NICHD and the NIDDK will select a chairperson from among the non-federal Steering Committee members or other experts in diabetes clinical research. 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 which will be appointed by the NICHD and the NIDDK. It will be composed of pediatric and diabetes and clinical research experts not directly involved in the protocol. Prior to the initiation of the study, 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, the NICHD and the NIDDK. The DSQ will monitor the study for safety and scientific validity, with authority to recommend protocol or procedural changes or early termination of the study. The DSQ is advisory to the NICHD, the NIDDK, and the Steering Committee. The chairperson of the Steering Committee and the Principal Investigator of the DCC will attend DSQ meetings, which will take place at least twice a year. 4. Arbitration Process Any disagreement that may arise on scientific/programmatic matters (within the scope of the award) between award recipients and the NICHD and NIDDK may be brought to arbitration. An arbitration panel (with appropriate expertise) will be formed to review the NICHD and NIDDK decision and recommend a course of action to the Directors, NICHD and NIDDK. The arbitration panel will be composed of three members: one selected by the Steering Committee (with the NICHD and the NIDDK not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by the NICHD and the NIDDK, and the third member selected by the two prior selected members. These special arbitration procedures in no way affects the awardee"s right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D, and DHHS regulations 45 CFR Part 16. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The revisions relate to NIH-defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects, published in the NIH Guide for Grants and Contracts, March 6, 1998, and available on the Internet at: 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 a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of this RFA. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NICHD staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Dr. Karen K. Winer at the address listed under INQUIRIES, below, by March 27, 2001. 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. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research, on the Internet at http://grants.nih.gov/grants/funding/phs398/phs398.html, and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892- 7910, telephone 301-710-0267, E-mail: grantsinfo@nih.gov. Application Requirements To promote the development of a collaborative program among the award recipients, a number of issues need to be addressed in the grant applications as discussed below. Applicants should document their ability to recruit a sufficient number of participants, their ability to interact effectively with the coordinating center, and their willingness and capability to participate in monthly meetings during the planning phase (up to six months) and semi- annual meetings over the duration of the five-year award. It is anticipated that two investigators (including the PI), from each clinical site will attend these meetings. Also, applicants should state their willingness to follow the common protocol that will be agreed upon during the planning phase. 1. Clinical Center Applications All applicants should provide a detailed description of the design of the study and should demonstrate how the continuous monitoring will be implemented. Additionally, applicants should justify the proposed monitoring device to be used, along with the setting, duration, and frequency of monitoring. The application should contain a rationale for the number of children in each age to be studied and should describe how subjects will be selected to achieve appropriate representation of patient characteristics, including methods of treatment. A crucial element of the study design is specification of the precise methods and timing for collecting data including the eligibility, baseline, and follow-up testing. Examples of proposed data forms and questionnaires should be given. The process for 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, a justification for the chosen method should be included. Also include the methods that would be used to ensure privacy and maintain confidentiality of data. There must be a data and safety monitoring plan. 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 number of potential subjects 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. Emphasis should also be placed on inclusion of children across age, gender, socioeconomic, and racial-ethnic groups. Incentives to enhance accrual and retention should be described in the applications. Because the ultimate study carried out under this RFA will be a collaborative effort, an investigator may propose a study that requires more subjects than can be recruited from within his/her institution. The investigator should provide a detailed description of the total sample size needed as well as the number of subjects 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 section, Inclusion of Women and Minorities in Research Involving Human Subjects ). The application must provide a detailed account of the local population pool from which subjects will be recruited, including the gender and racial/ethnic make-up of the population and the expected numbers of subjects from each group that could be recruited. A plan for recruitment and retention of participants must be provided. Subcontracts may be used to recruit subjects from additional local sites not a part of the parent institution. In this case, the Principal Investigator must include a detailed description of the subject 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 study, not all potential subcontractors will be needed. 2. Data Coordinating Center (DCC) Applications A separate complete application is required from institutions applying to be the DCC for the Type 1 Diabetes in Children Consortium. Applicants for the DCC component are not required to be a clinical site within the Consortium, though applicants for clinical sites may also submit an application to be the DCC. 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 protocol established cooperatively by the Steering Committee. Applicants must address the following responsibilities of the DCC: 1) participation in the design of the final protocol and development of the manual 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 the protocol and of data quality, and 5) establishment of procedures that insure the safety and confidentiality of all records. Data management and quality control procedures must be detailed. 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 the reporting of results that examine differences in treatment effects across these subgroups (see section, Inclusion of Women and Minorities in Research Involving Human Subjects ). Applications may not exceed 25 pages for sections a - d, excluding appendices, which may contain copies of pertinent forms or examples of correspondence useful for coordinating tasks. 3. Issues To Be Addressed By All Applicants Qualifications and Experience: Applicants must include a description of their experience and expertise to conduct a clinical study 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 subject 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. 4. Budget Information Detailed budget information should be provided for the proposed Clinical Center or Data Coordinating Center. The budget should be divided into three phases: 1) planning (first six months), 2) recruitment and study (three - four years), and 3) analysis (final six months). The application should contain a detailed budget for each phase. The planning phase will be for the development of the protocol and the manual 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 subject care costs associated with the study. The application should detail these costs as dictated by the study that is proposed. The actual budget awarded after the initial project period will be determined once the Steering Committee finalizes the protocol. Therefore, the final awards may vary among sites. If any centralized laboratory assessments are required, costs for laboratory tests will be reimbursed using subcontracts through the DCC, at rates determined by the NICHD and the NIDDK. Submission Instructions The RFA label available in the PHS 398 (rev. 4/98) application form must be stapled to the bottom of the face page of the application and must display the RFA number HD-01-009. A sample RFA label is available at http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note this is in the pdf format. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package, to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application should be sent to: L. R. Stanford, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5E03, MSC 7510 Bethesda, MD 20892-7510 Rockville, MD 20852 (for express/courier service) Applications must be received by May 11, 2001. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and for responsiveness by the NICHD and 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 NICHD in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Child Health and Human Development Advisory Council and the National Diabetes and Digestive and Kidney Diseases Advisory Council. Review Criteria All applications will be reviewed according to the following criteria: The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. o Significance: The application should address the problem outlined in the RFA. The application should demonstrate how the study will advance scientific and/or medical knowledge. o Approach: The adequacy of the proposed conceptual framework, design, methods, and analyses. The acknowledgement of potential problem areas and the consideration of alternative tactics. o Innovation: The applicant should demonstrate how the project challenges existing paradigms or develops new methodologies or technologies. o Investigator: The investigator should be appropriately trained and well suited to carry out this work. The proposed study should be appropriate to the experience level of the principal investigator and other researchers (if any). There should be evidence of prior experience in working collaboratively to carry out a clinical study or standard protocol as well as evidence of willingness to work cooperatively on the Steering Committee to develop and follow a unified protocol. o Environment: The environment in which the work will be done should contribute to the probability of success. The proposed protocol should take advantage of unique features of the scientific environment and employ useful collaborative arrangements. There should be evidence of institutional support. In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. All applications for the Clinical Centers will also be reviewed with respect to the following: o Approach: Plans for the recruitment and retention of subjects will be evaluated. Evidence of the ability to recruit, enroll and maintain subjects. 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. o The adequacy of plans to ensure accurate collection and timely transmission of study data to the DCC. o The appropriateness of plans to protect confidentiality of data. o The adequacy of the data and safety monitoring plan. All applications for the Data Coordinating Center will be reviewed with respect to the following: o Data Management System Demonstrated experience and ability to implement a data management system for collecting, checking, editing, and correcting data from Clinical Centers and entry of corrected data into a computer. The system should include provisions to ensure the accuracy of data entry. o Quality Control System Demonstrated ability to implement a quality control system for monitoring data collection procedures with timely feedback to the individual centers. o Personnel Evidence that the proposed Principal Investigator and other personnel have expertise in all aspects of study coordination including monitoring and computerizing data, design and implementation of multicenter study protocols, and the design and execution of appropriate statistical analysis and reporting of data. o Facilities Adequacy of facilities and software for data management, monitoring and analysis. AWARD CRITERIA Applications recommended by the NICHD and NDDK Advisory Council will be considered for award based on the scientific merit of the proposed project, as determined by peer review, and the ability of the investigators to meet the research objectives of this RFA. In addition, program balance, defined as the scope and variety of research strengths to enable a successful collaborative program, the racial and ethnic composition of the populations being studied, and the geographical location of the trial will be considered. Awards are contingent upon the availability of funds. SCHEDULE Letter of Intent Receipt Date: March 27, 2001 Application Receipt Date: May 11, 2001 Peer Review Date: June 2001 Council Review: September 2001 Earliest Anticipated Award Date: September 2001 INQUIRIES 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: Karen K. Winer, M.D. Endocrinology, Nutrition and Growth Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B11, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6877 FAX: (301) 480-9791 E-mail: WinerK@mail.nih.gov Joan T. Harmon, Ph.D. Division of Diabetes, Endocrinology, and Metabolic Diseases National Institute of Diabetes Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 697, MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 301-594-8813 FAX: (301) 480-3503 E-mail: harmonj@extra.niddk.nih.gov Direct inquiries regarding fiscal matters to: Mary Daley Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17E, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1305 FAX: (301) 402-0915 E-mail: md74u@nih.gov Kim Law Division of Extramural Activities National Institute of Diabetes Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 639, MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8869 FAX: (301) 480-3504 E-mail: lawk@extra.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.865 and 93.847. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant 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 routing 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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