CLINICAL ISLET TRANSPLANTATION: DATA COORDINATING CENTER RELEASE DATE: December 5, 2003 RFA NUMBER: RFA-DK-04-004 (Reissued as RFA-DK-09-501) Department of Health and Human Services (DHHS) (http://www.hhs.gov/) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENTS OF PARTICIPATING ORGANIZATION: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov) National Institute of Allergy and Infectious Diseases (NIAID/NIH) (http://www.niaid.nih.gov) CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: 93.847, 93.855, 93.856 LETTER OF INTENT RECEIPT DATE: March 16, 2004 APPLICATION RECEIPT DATE: April 13, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Cooperative Agreement Terms and Conditions of Award o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of Allergy and Infectious Diseases (NIAID) invite applications for a Data Coordinating Center (DCC) to participate in a consortium of investigators and institutions that will perform clinical studies of islet transplantation in patients with type 1 diabetes mellitus (T1D). This consortium will develop and implement a program of single- and/or multi-center clinical trials, accompanied by mechanistic studies, in islet transplantation with or without accompanying kidney transplantation, for the treatment of T1D. Successful applicants for the DCC, together with Clinical Centers (see below), will constitute a Clinical Islet Transplantation (CIT) consortium whose aim is to design and implement human islet transplantation studies that will result in an improved treatment of T1D. The CIT Data Coordinating Center (CIT-DCC) will provide a broad range of support services for the CIT, including statistical, monitoring, and operational support. It will also assist with the preparation of DSMB reports, scientific manuscripts, and other reports and documents as needed to support the work and goals of the clinical centers in the consortium and/or as required by the NIH. The goals of the consortium, which are elaborated in a complementary solicitation (RFA DK-04-005), include the following: (1) Develop a scientific agenda for clinical and mechanistic studies in islet transplantation that is consistent with the research objectives described in this RFA. (2) Design and implement studies consistent with the scientific agenda. These studies may be performed by single centers within the consortium or by multiple centers implementing a single protocol, as required by the study design. (3) Share information and resources that will advance the field of islet transplantation. Institutions applying to become Clinical Centers under RFA DK-04-005) may also apply for the CIT-DCC solicited under this RFA (DK-04-004). In order to ensure that data analysis is done independently of data acquisition, the CIT-DCC cannot have overlap in personnel with a CIT-CC. An institution may apply for both a CIT-CC and the CIT-DCC, but each application must have separate principal investigators and include a specific plan documenting how the independent operation (i.e., confidentiality of the study-wide data) of each unit will be maintained. RESEARCH OBJECTIVES Background T1D is an autoimmune disease characterized by the destruction of the insulin- secreting beta cells of the pancreas by cytotoxic T cells. T1D is difficult to control with the current therapies available, and as a result patients may suffer devastating consequences including accelerated cardiovascular and peripheral vascular diseases, nephropathy, retinopathy, neuropathy, oral diseases and premature death. The incidence of T1D appears to be increasing worldwide. Although the disease may occur at any age, onset peaks prior to twenty years of age. In some populations, approximately one percent of all newborns will develop T1D during their lifetime. Islet transplantation as a therapy for T1D has been an important focus of NIH support, and significant progress has occurred in recent years. In particular, the success of the "Edmonton Protocol" for islet transplantation in freeing individuals with T1D from the need for insulin therapy has established islet transplantation as a viable therapy for those T1D patients whose disease cannot be effectively managed with current methods of exogenous insulin administration. However, serious obstacles remain for development of islet transplantation as a cure for T1D in the general population, most notably the toxicity associated with current regimens of immunosuppression and islet administration and the limited supply of human cadaveric islets, which is sufficient for only a small fraction of the people who could potentially benefit from this therapy. The recent successes in islet transplantation provide additional impetus for research to develop methods to attain an unlimited supply of islets for transplantation; to improve methods for harvesting pancreata and isolating islets; to improve techniques for the administration of transplanted islets; and to develop approaches to minimize the toxicity of immunotherapy required for transplantation. The NIH has a comprehensive and multifaceted approach to address these challenges and foster development of islet transplantation as a cure for T1D. The National Center for Research Resources (NCRR) and the NIDDK, along with the Juvenile Diabetes Research Foundation (JDRF), have funded the Islet Cell Resource Centers (ICRR), a consortium of ten centers whose mission is to provide clinical-grade islets for islet transplantation; to optimize harvest, purification, and shipment of islets while developing tests that characterize the quality and predict the effectiveness of transplanted islets; and to provide islets for basic research (http://www.infosci.coh.org/icr). The NIDDK also supports the Collaborative Islet Transplant Registry (CITR), which collects, analyzes, and disseminates comprehensive and current data on all islet/beta cell transplants performed in the United States and Canada (http://spitfire.emmes.com/study/isl/index.html). The Immune Tolerance Network, funded by NIAID, NIDDK and JDRF, supports multi-center and single center clinical trials of islet cell transplantation (http://www.immunetolerance.org/research/islet/trials.html). Other components of this effort include the Non-Human Primate Islet Transplantation Consortium (http://www.niddk.nih.gov/fund/diabetesspecialfunds/consortia/NHP.pdf), the Beta Cell Biology Consortium (http://www.betacell.org), and the Type 1 Diabetes Rapid Access to Interventional Development (T1D-RAID) (http://www.niddk.nih.gov/fund/diabetesspecialfunds/T1D-RAID/). Objectives and Scope The purpose of this RFA is to support a Data Coordinating Center for a program of cooperative clinical trials in islet transplantation with associated mechanistic studies. Applicants to the companion RFA, which solicits applications from clinical centers, may propose clinical studies (single-center pilot studies investigating an innovative approach, or multi- center validation of single-center experiences) to evaluate: 1. Increasing the efficiency of islet transplantation, with the goal of achieving successful single-donor islet transplantation. Approaches could include, but are not limited to, the following: innovation or refinement of procedures for islet isolation; improvement in donor selection criteria; optimization/minimization of immunosuppression to reduce islet toxicity and non-adherence to medications; pre-transplant interventions in the donor or recipient that enhance islet engraftment and survival; and innovative approaches to islet implantation. 2. Improvements in immunotherapy to reduce toxicity, recurrent autoimmunity and allograft rejection. Approaches could include, but are not limited to, the following: less toxic immunosuppressive agents; regimens reducing the number, dose or duration of immunosuppressive agents; and new and innovative therapeutic approaches to induce donor-specific tolerance with or without standard immunosuppression, including immunosuppression withdrawal. 3. Interventions to reduce the local complications of the islet administration procedure, such as bleeding, thrombosis, and steatohepatitis. Approaches could include, but are not limited to, alternate sites of administration, improved techniques for islet delivery, and use of medications to avert complications. In association with clinical trials the CIT will conduct mechanistic studies to enhance understanding of rejection, engraftment and/or survival of islets in the setting of islet transplantation and their assessment in the clinical protocols. These mechanistic studies are described in detail in RFA DK-04- 005. The Data Coordinating Center for the consortium will provide support in the following areas: 1) Study Design, Conduct, Analyses, and Publications - The DCC will be responsible for statistical leadership and for developing innovative clinical trial design and analysis methodologies consistent with the consortium research agenda; assistance with protocol and manual of operations development; developing a data safety and monitoring plan for each protocol implemented by the CIT; developing and implementing a plan for adverse event reporting, and coordinating this with the activities of the NIAID Regulatory Affairs Staff and/or Support Contractor; performing interim analyses of safety and efficacy for protocol teams, NIH, and the Data Safety and Monitoring Board (DSMB); generating executive summaries of near-final study results for use by the protocol team, NIH, and collaborators; conducting final analyses and participating on publication writing teams; performing cross-protocol or cross study analyses utilizing data from multiple sources within and external to the consortium; producing study monitoring reports for the consortium and NIH; and conducting analyses and summaries for annual and interim reports for NIH-sponsored Investigational New Drug Applications, in cooperation with the NIAID Regulatory Support Contractor (see below). 2) Data Management – Provide central registration and randomization (as required by study protocols) for all study subjects; develop case report forms and standardized criteria for clinical endpoint verification; design and implement systems for the efficient tracking and transfer of clinical and laboratory data (including quality assurance and specimen tracking) to the central database; provide data management training to the clinical sites and laboratories; provide CRF notebooks to collaborators; provide for central storage, security, processing and retrieval of study results; and prepare selected public access databases. 3) Site Monitoring – Initiate, monitor, and close out clinical sites, pharmacies, and laboratories to assure Good Clinical/Laboratory Practice (GCP/GLP); monitor islet facilities for Good Tissue Practice (GTP) compliance; train site personnel on GCP/GLP/GTP compliance and on the policies and procedures established by the NIH, the Food and Drug Administration (FDA), and the Office of Human Research Protections (OHRP); audit clinical, pharmacy, and laboratory sites, as well as islet facilities, as necessary; and provide reports to the NIH and the Steering Committee on monitoring and audit findings and training activities. 4) Administrative Support – organize meetings and teleconferences; provide core laboratory support and coordination, including specimen handling; distribute study drugs. 5) Regulatory Requirements – The DCC will work in concert with the NIAID Regulatory Affairs Staff and/or Support Contractor and NIH staff by providing them with clinical study data, reports, and other support as required for Adverse Event Reporting and IND submissions It is expected that the successful applicant will bring a range of experiences and perspectives to this consortium that will inform group decisions and accelerate the pace of progress toward general clinical applicability of islet transplantation for the treatment of T1D. Specifically, applicants must have demonstrated capability in providing the types of support detailed in 1-5, above, for complex, multi-center trials. CIT-DCC applicants should also demonstrate biomedical knowledge relevant to cell therapies and T1D, and an understanding of FDA requirements. These skills and expertise should contribute to achieving the following CIT objectives. Study Organization The CIT will be a consortium of clinical investigators and core support facilities. In addition, it will include a Data Coordinating Center (CIT-DCC), for which applications are solicited under a separate solicitation (RFA DK-04- 004). A steering committee, (see "Cooperative Agreement Terms and Conditions of Award - Collaborative Responsibilities", below), will have responsibility for establishing the scientific agenda for the consortium, and for the choice, design, planning, execution, and publication of the research studies performed by the CIT. The Steering Committee will review all concepts for scientific merit and feasibility; review all protocols prior to implementation; review all public presentations of CIT results and manuscripts, posters, and abstracts prior to publication; review compliance with protocol requirements; define subcommittees; develop study policies; receive and act upon reports of subcommittees; and review matters relevant to administrative, financial, medical, legal, and ethical considerations of studies. The Steering Committee will maintain surveillance of the CIT performance and, together with the NIH, is responsible for the addition or deletion of Clinical Centers. The Chairperson of the Steering Committee is responsible for the overall administration and science of the CIT activities by providing leadership for the steering committee activities described above. He/she will, together with the leadership of the DCC and the NIH Program Directors, schedule steering committee and investigator meetings; establish the agenda for those meetings; and monitor the work of the subcommittees. MECHANISM OF SUPPORT This RFA will use the NIH Cooperative Agreement (U01). This RFA is a one-time solicitation. Future unsolicited, competing- continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2004. The total project period for applications submitted in response to this RFA may not exceed five years. At this time, the NIDDK and NIAID have not determined whether or how this solicitation will be continued beyond the present RFA. This RFA uses just-in-time concepts. It also uses the modular budgeting as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if the investigator is submitting an application with direct costs in each year of $250,000 or less, use the modular budget format. Otherwise follow the instructions for non-modular budget research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm. The NIH (U01) is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award". FUNDS AVAILABLE The NIH intends to commit up to $3 million in total costs in FY 2004 to fund one new grant in response to this RFA. Applicants should request 5 years of support. Because the nature and scope of the research supported by the CIT may vary over time and by site, it is anticipated that the sizes of awards may also vary. After initiation of the CIT, awards in subsequent years will be determined by the requirements of the specific studies designed by the Steering Committee, the level of participation of individual sites, and the availability of funds. Although the financial plans of the NIDDK and NIAID 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 applications of high scientific merit. At this time, it is not known if this RFA will be reissued. ELIGIBILE INSTITUTIONS You may submit an application if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic (U.S.A) institutions only o Foreign institutions are not eligible to apply INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with his/her institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. In order to ensure that data analysis is done independently of data acquisition, the CIT-DCC cannot have the same Principal Investigator as a CIT- CC. Within the Consortium an institution may apply for both a CC and the DCC, but each must have separate principal investigators and submit a separate application with a specific plan of how the independent operation (i.e., confidentiality of the study-wide data) of each unit of the CC and DCC will be maintained. In addition, there should be no overlap in personnel between the CC and DCC. COOPERATIVE AGREEMENT TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator (PI) 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 part 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is the cooperative agreement (U01), an "assistance", rather than an "acquisition", mechanism, in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the 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 awardees for the project as a whole, although specific tasks and activities in carrying out the research will be shared among the awardees and the NIH Scientific Coordinators. Cooperative agreements are subject to the administrative requirements outlined in OMB circulars A-102 and A-110. All pertinent HHS, PHS, and NIH grant regulations, policies and procedures, with particular emphasis on PHS regulations at 42 CFR Part 52 and HHS regulations at 45 CFR Part 74, are applicable. These special terms and conditions pertaining to the scope and nature of the interaction between the NIH and the investigators will be incorporated in the Notice of Grant Award. However, these terms will be in addition to, not in lieu of, the customary programmatic and financial negotiations that occur in the administration of cooperative agreements. Recipient institutions must agree as a term of award to accept per-patient funding for clinical activities. "Start up" costs for clinical research resources that must be in place prior to enrollment of subjects may be exempt from this requirement, subject to approval by the Steering Committee and the NIH Program Directors. 1. Monitoring Clinical Studies When clinical studies or trials are a component of the research proposed, NIH policy requires that studies be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study. The NIAID policy was published in the NIH Guide on July 8, 2002 and will be used for this award. It is available at: http://grants.nih.gov/grants/guide/notice-files/NOT-AI-02-032.html. The full policy, including terms and conditions of award, is available at: http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf. This award provides support for one or more NIH-defined Phase III clinical trials. The NIH Policy for research supported as an NIH Phase III Clinical Trial has been updated in Section III.B. of the "NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research – Amended, October 2001" http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm A description of plans to conduct analyses, as appropriate, by sex/gender and/or racial/ethnic groups must be included in clinical trial protocols and the results of the subset analyses must be reported to NIH in Progress Reports, Competitive Renewal Applications, and in the required Final Progress Report, as stated in Section III.B. of the Guidelines. 2. Awardee Rights and Responsibilities Awardees will have primary responsibility for defining the research objectives, approaches and details of the projects within the guidelines of the RFA and for performing the scientific activity. Specifically, awardees have primary responsibility as described below. Each PI will be a voting member of the Steering Committee and will be required to participate in all Steering Committee activities and to follow the policies and procedures that are developed by the Steering Committee. The Clinical Site PIs will be required to provide primary study data to the Coordinating Center for management, quality control, and analysis. Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The collaborative protocol and governance policies will call for the continued submission of data centrally to the CIT-DCC for a collaborative database; the submission of copies of the collaborative data sets to each principal investigator upon completion of the study; procedures for data analysis, reporting and publication; and procedures to protect and ensure the privacy of medical and genetic data (if any) and records of individuals. The NIH Program Directors, on behalf of the NIH, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the Steering Committee. The Data Coordinating Center will be involved in collaborations with the NIH and the Clinical Centers during all phases of the trial and will maintain or contract with the central laboratory used. The DCC will also coordinate with the NIDDK Biosample Repository, if it is available and chosen as the study repository for this consortium. If the NIDDK Biosample Repository is not available or is not chosen as the sample repository by the NIH at the time the study is in the protocol development phase, the DCC will be required to maintain or contract with a repository for central storage and distribution of serum, tissue, and other samples. Applications must include documentation of the ability to acquire human samples and clinical data for the proposed studies. The NIH brochure entitled "Research on Human Specimens: Are You Conducting Research Using Human Subjects?" (http://www-cdp.ims.nci.nih.gov/policy.html) and OHRP guidance on Repositories, Tissue Storage Activities and Data Banks http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm are available as resources for investigators. In addition, the DCC will coordinate with the NIDDK Data Repository, if it is available, to prepare the data for eventual archiving and distribution. Thus, the awardee is expected to work cooperatively with Clinical Centers and sponsoring organizations and oversee the implementation of and adherence to a common protocol, as well as assure quality control of the data collected and storage of collected biologic specimens. In addition to organizing and attending regular meetings (including conference calls), the CIT-DCC will be expected to maintain close communications with the NIH Scientific Coordinators, and the Principal Investigators of the Clinical Centers. Awardees are expected to publish and to publicly release and disseminate results, data and other products of the study, concordant with the study protocol and governance and the approved plan for making data and materials available to the scientific community and the NIH. Support or other involvement of industry or any other third party in any study performed by the Consortium -- e.g., participation by the third party; involvement of project resources or citing the name of the project or the NIH support; or special access to project results, data, findings or resources -- may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only in the context of a Clinical Trials Agreement with the NIH. Upon completion of the project, the DCC is expected to put all study intervention materials and procedure manuals into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community and the NIDDK/NIAID, for the conduct of research at no charge other than the costs of reproduction and distribution. Indeed, NIH policy requires that investigators make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication [NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/nihgps ; Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: Final Notice, December 1999 (http://www.ott.nih.gov/policy/rt_guide_final.html)]. It is expected that the specimens and data collected in projects funded by this RFA will eventually be made available to the broader scientific community, after the proprietary period. Awardees acknowledge in their approved "Sharing Plan" that they will share the specimens and data collected with the wider scientific community, through eventual transfer of these materials to the NIDDK Central Biosample and Data Repositories or through another mechanism determined by NIH. Evaluation of the Non-competing Grant Progress Report (PHS 2590) will include assessment of the effectiveness of research resource release. The PIs' responsibilities regarding Steering Committee membership, protocol development and conduct, and data coordination and management are described under Collaborative Responsibilities. 3. NIH Staff Responsibilities NIH Program Directors will be assigned to perform normal program stewardship responsibilities for this award. The Government, via the NIH Program Directors, will have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. NIH Staff may use information obtained from the data for the preparation of internal reports on the activities of the study. However, awardees will retain custody of and have primary rights to all data developed under these awards. Program Review: The NIH Program Directors, together with the CIT-DCC and the Steering Committee, will review the progress of each participating institution through consideration of the annual reports, site visits, patient logs, etc. This review may include, but is not limited to, compliance with the study protocol, meeting patient enrollment targets, adherence to uniform data collection procedures, and the timeliness and quality of data reporting. Monitoring Study Performance: The NIH Program Directors and the CIT-DCC will assist the Steering Committee in the development of mechanisms and procedures for monitoring study performance. This includes participation in periodic on-site monitoring of compliance with protocol specifications, quality control and accuracy of data recording, and patient accrual. The monitoring plan will incorporate any relevant regulatory requirements. The NIH reserves the right to terminate or curtail any study or any individual award in the event of (a) substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of the protocol, (b) substantive changes in the consensus protocol to which the NIH does not agree, (c) reaching a major study endpoint substantially before schedule with persuasive statistical significance, or (d) human subject ethical issues that may dictate a premature termination. Organizational Changes: Certain organizational changes require the prior written approval of the NIH Program Directors. These changes include the addition or replacement of a physician, scientific investigator, affiliate, component, or research base that is associated with this study. A change in the PI, or in any key personnel identified on the Notice of Award, must have the prior written approval of the NIH Grants Management Specialist in consultation with the NIH Program Director. The NIH Program Director may also serve as the NIH Scientific Coordinator. NIH Scientific Coordinator. NIH staff assistance as NIH Scientific Coordinators will be provided by the Islet Transplantation Program Director, DDEM, NIDDK, and the Chief of the Clinical Transplantation Section, DAIT, NIAID or designate. These NIH Scientific Coordinators and/or their designees will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below. During performance of the award, the NIH Scientific Coordinators, with assistance from other scientific program staff who are designated based on the research topic and their relevant expertise, may provide appropriate assistance, advice, and guidance by: participating in the design of the activities; advising in the selection of sources or resources (e.g., determining where a particular reagent can be found, or assay performed); coordinating or participating in the collection and/or analysis of data; advising in management and technical performance; or participating in the preparation of publications. The Scientific Coordinators and NIH Regulatory Staff will serve as a liaison/facilitator between the awardee, pharmaceutical and biotech industries, and other government agencies (e.g., FDA, USDA, CDC) and will serve as a resource of scientific and policy information related to the goals of the awardee's research. However, the role of the NIH will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus, and that the NIH Program Directors will participate in this process. Regulatory Affairs: The NIH Regulatory Affairs staff, assisted by the staff of the CIT-DCC and the NIAID Regulatory Contractor, will be responsible for preparing all regulatory documents required by the Food and Drug Administration, and will provide to the PI the guidance and assistance necessary to ensure that compliance with FDA regulations is maintained. The NIH regulatory affairs staff will initiate and participate in all communication with FDA representatives. Site Support: NIH Scientific Coordinators or their designates and/or CIT-DCC staff (or contractors) will visit all sites prior to patient enrollment, to carry out site education with regard to protocol requirements and data submission procedures. NIH Scientific Coordinators and DCC staff will meet monthly, by teleconference, with the site coordinators for each study, to discuss recruitment issues and study operations. The NIH Scientific Coordinators will serve as voting members of the Steering Committee and will participate in all Committee activities. Protocol Development: As members of the Steering Committee, the NIH Scientific Coordinators will serve as a resource with respect to the design of the protocol and will, along with the CIT-DCC, assist the Steering Committee in protocol development. Data Coordination and Management: The NIH Scientific Coordinators and the CIT-DCC will provide technical assistance and data management services to the participating institutions with respect to quality control, uniformity of data collection, management of the collective database, and data analysis. Publication and Presentation of Study Findings: The NIH Scientific Coordinators may contribute, through review, comment, analysis, and/or co-authorship, to reporting results of the study to the investigator community and other interested scientific and lay organizations. Co-authorship by the NIH Program Directors will be subject to approval in accordance with NIH policies regarding staff authorship of publications resulting from extramural awards. 4. Collaborative Responsibilities Steering Committee: A Steering Committee will be established to serve as the main governing body of the cooperative research program. The Steering Committee will review all concepts for scientific merit and feasibility; review all protocols prior to implementation; review all public presentations of CIT results and manuscripts, posters, and abstracts prior to publication; review compliance with protocol requirements; define subcommittees; develop study policies; receive and act upon reports of subcommittees; and review matters relevant to administrative, financial, medical, legal, and ethical considerations of studies. The Steering Committee will maintain surveillance of the CIT performance and, together with the NIH, is responsible for the addition or deletion of Clinical Centers. The Chairperson of the Steering Committee is responsible for the overall administration and science of the CIT activities by providing leadership for the steering committee activities described above. He/she will, together with the leadership of the DCC and the NIH Scientific Coordinators, schedule steering committee and investigator meetings; establish the agenda for those meetings; and monitor the work of the subcommittees. At a minimum, the Steering Committee will be composed of the following individuals: the Principal Investigators (PI) of the Clinical Centers; the PI of the CIT-DCC; the chair of the Mechanistic Studies Subcommittee (see below); and the NIH Scientific Coordinators (the Islet Transplantation Program Director, DDEM, NIDDK; and the Chief of the Clinical Transplantation Section, DAIT, NIAID or designate). Additional members, voting or non-voting, may be added to the steering committee by majority vote of the Steering Committee; non-voting members may be added at the discretion of the NIH Scientific Coordinators. All major scientific decisions will be determined by the Steering Committee, with each Clinical Center PI, the NIH Scientific Coordinators, and the PI of the CIT-DCC having one vote. The first meeting of the Steering Committee will be convened by the NIH Scientific Coordinators. At this meeting, the group will elect a Chairperson from among the Steering Committee members; the NIH Scientific Coordinators and the PI of the CIT-DCC are not eligible to be the Steering Committee Chair. The Committee will meet in person or by teleconference at least four times during the first 12 months of the study and at least twice annually thereafter. Additional meetings by teleconference will be scheduled as needed, with need determined by the Steering Committee Chair and the NIH Scientific Coordinators. This Committee will have primary responsibility for developing the common clinical protocols, approving the design and implementation of all mechanistic studies (via the Mechanistic Studies Subcommittee), facilitating the conduct and monitoring of all clinical trials and mechanistic studies, analyzing and interpreting study data, and reporting study results. Studies will not be approved if the NIH or the Steering Committee determines that it will not be feasible to accrue patients within the specified time frame. The Steering Committee or a subcommittee will review the budget and expenditures at least once each year at a face-to-face meeting. Clinical trials and mechanistic studies will proceed into the implementation stage only with the concurrence of both the Steering Committee and the NIH Program Directors. Each Steering Committee member will be expected to participate in all Steering Committee activities, e.g., meetings, conference calls, special subcommittee activities, etc. as may be necessary. Executive Committee: An Executive Committee comprised of the Steering Committee Chair, the Principal Investigator of the CIT-DCC, and the NIH Scientific Coordinators will be convened to effect management decisions required between Steering Committee meetings, as needed for efficient progress of the studies. Investigational Protocols: One PI or subcommittee will take the lead responsibility for drafting each individual protocol, with the assistance of the CIT-DCC and NIH Scientific Coordinators. The Steering Committee will provide input and will be responsible for oversight of protocol development. The decision to implement the protocol will be determined by a vote of the entire steering committee, and will be subject to additional review by the DSMB and NIH. Monitoring Study Progress: The steering committee, via a Performance Subcommittee, will develop a set of criteria for assessing the performance of the participating institutions, including institutions participating in consortia arrangements, with particular attention to accrual of adequate numbers of eligible patients, timely submission and quality of required data and conscientious observance of protocol requirements. These criteria will be the basis for determining continued participation. The steering committee or a designated sub-committee will prepare an annual report containing the following information: progress in ongoing and newly- initiated clinical trials and mechanistic studies; subject accrual and protocol compliance at all participating clinical sites; manuscripts published, in press, and in preparation; presentations at regional, national, and international meetings; and budget review. The first such report will be presented at a joint meeting of the Steering Committee and Mechanistic Studies Subcommittee not later than 13 months after the initial notice of award, and yearly thereafter. The CIT-DCC will take the lead in writing this report; the NIH Scientific Coordinators will not participate substantively in the development or submission of the annual report, and will serve as the primary NIH staff members responsible for review of the report by the sponsoring agency. Mechanistic Studies Subcommittee: The Steering Committee shall appoint a Mechanistic Studies Subcommittee to review and approve or modify proposed mechanistic studies. Each PI shall select one representative from his/her consortium as voting members of the Mechanistic Studies Subcommittee. In addition, the NIH Scientific Coordinators shall serve as voting members. The Mechanistic Studies Subcommittee may ask the Steering Committee to appoint additional Mechanistic Studies Subcommittee members if additional expertise in a specific area is needed. The Mechanistic Studies Subcommittee shall elect a Chair from among its non-Federal members. The Chair shall serve as a voting member of the Steering Committee. The Subcommittee will meet at least twice yearly and its members will be expected to participate in all meetings, conference calls, and other Subcommittee activities. Performance Subcommittee: The performance subcommittee will develop a set of performance criteria to evaluate accrual, data submission, and compliance at each participating institution in the consortium, including institutions participating in consortium arrangements. These criteria, after approval by the Steering Committee, will form the basis for determining continued participation of each site in the consortium, on a yearly basis. Data and Safety Monitoring Board (DSMB): An independent DSMB, appointed by the NIH, will review CIT studies at least annually and report their findings to the NIH Program Directors. Clinical protocols and mechanistic studies will be subject to review by the DSMB, in an advisory capacity, prior to implementation. The DSMB review will focus on the safety, ethics, and scientific and statistical integrity. Data Coordination and Management: Data Coordination and Management will be carried out by the CIT-DCC. Each participating institution will be responsible for providing primary study data to NIH via the CIT-DCC for management, quality control, and analysis, using procedures and standards determined by the Steering Committee and the CIT-DCC. The NIH will provide, via its program staff and the CIT-DCC, the following: technical assistance and data management services to the participating clinical institutions with respect to quality control, uniformity of data collection, management of the collective database, and data analysis; centralized data collection and management; and quality assurance. Specific analyses to be performed will be directed by the Steering Committee or the NIH Scientific Coordinators. The results of those analyses will be delivered to the Steering Committee. The Steering Committee is responsible for determining how the results are interpreted, whether the results should influence ongoing data collection, and how the findings should be disseminated. All participating sites will have access to all data originating from their sites. The awardees will retain custody of and have primary rights to all data developed under these awards, subject to Government rights of access consistent with HHS, PHS, and NIH policies. Publication and Presentation of Study Findings: Timely publication of major findings is encouraged. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of the participating institutions and NIH support. Policies for directing analyses of aggregate and site-specific data will be developed by the Steering Committee. Review and approval by the Steering Committee will be required for all analyses prior to publication or presentation according to criteria that will be developed by the Steering Committee. The Steering Committee may establish a Publications and Presentations Subcommittee to carry out this function. 5. Arbitration Any disagreement that may arise on scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An arbitration panel will be composed of three members -- one selected by the Steering Committee or by the individual awardee in the event of an individual disagreement, a second member selected by the NIH, and the third member with expertise in the relevant area and selected by the two prior members will be formed to review any scientific or programmatic issue that is significantly restricting progress. While the decisions of the Arbitration Panel are binding, these special arbitration procedures will in no way affect the awardee's right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, subpart D, and HHS regulations at 45 CFR Part 16. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct questions about scientific/research issues to: Thomas L. Eggerman, M.D., PhD Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Room 697 Bethesda, MD 20892-5460 Telephone: (301) 594-8813 FAX: (301) 480-3503 Email: firstname.lastname@example.org Nancy D. Bridges, M.D. Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Disease 6610 Rockledge Drive, Room 3039 Bethesda, MD 20892-6603 Telephone: (301) 451-4406 FAX: (301) 480-3503 Email: email@example.com Questions may also be submitted to the email address firstname.lastname@example.org where they will be answered by email. In addition, these questions and answers will be posted at the NIDDK website http://www.niddk.nih.gov/fund/diabetesspecialfunds/CIT/ which links to frequently asked questions that prospective applicants have submitted. Applicants are strongly encouraged to visit this website on a regular basis in the course of preparing their applications. o Direct questions about peer review issues to: Francisco O. Calvo, PhD Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 653 Bethesda, MD 20892-5452 Telephone: (301) 594-8885 FAX: (301) 480-3505 Email: email@example.com o Direct questions about financial or grants management matters to: Mary K. Rosenberg Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 708 Bethesda, MD 20892-5452 Telephone: (301) 594-8891 FAX: (301) 594-9532 Email: firstname.lastname@example.org Ann White-Devine Division of Extramural Activities National Institute of Allergy and Infectious Disease 6700B Rockledge Drive, Room 2118 Bethesda, MD 20892-7614 Telephone: (301) 402-5601 FAX: (301) 480-3780 Email: email@example.com LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o 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 IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 653 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8885 FAX: (301) 480-3505 SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS 1. Applications may be submitted by a single center or by a consortium of centers. 2. The applicant for a CIT-DCC must demonstrate experience and ability in coordinating multi-center clinical trials in all phases, consistent with the objectives and scope described above, including: protocol and manual of operations development, staff training in study procedures, research instrument development, data collection and management, quality assurance, data analysis, distributed data entry, electronic communications, administrative management and coordination. Specific experience in coordinating or monitoring studies of diabetes and/or surgical procedures is not required, but the applicant may wish to include an investigator with this expertise in the application as a collaborator or advisor. 3. The CIT-DCC application must propose a research plan that includes the structure of a database and an information core that they believe should be collected on all participants that are prospectively enrolled. 4. CIT-DCC Applications must provide evidence the applicant's expertise and experience in biostatistics, clinical study design and protocol development. Specific examples of prior or ongoing successful collaborations with clinical investigators in the design and implementation of multicenter studies should be included, with reference to the applicant's role in establishing eligibility criteria, baseline and outcome measures, methods of randomization, sample size and power calculations, and methods and frequency of data collection and entry. In addition, experience with monitoring accuracy of data collection, quality control procedures including training and certification for multiple protocols, some of which may occur simultaneously, and managing labeling and handling of serum and tissue samples (see below) should be described. The CIT-DCC application must also describe the applicant's expertise and experience in the development of Data Safety and Monitoring Plans (DSMP) and administrative support of Data and Safety Monitoring Boards (DSMB). The CIT-DCC application should also document expertise and experience with Institutional Review Board (IRB) and the United States Food and Drug Administration (FDA) approval processes. 5. The applicant for the DCC must provide a plan for handling of laboratory specimens. NIDDK and NIAID anticipate that some clinical outcome measures may be centrally assessed. Laboratories responsible to the CIT-DCC will manage specimens and laboratory studies as required by the Steering Committee. Applications must include documentation of the ability to acquire human samples and clinical data for the proposed studies. The NIH brochure entitled "Research on Human Specimens: Are You Conducting Research Using Human Subjects?" (http://www-cdp.ims.nci.nih.gov/policy.html) and OHRP guidance on Repositories, Tissue Storage Activities and Data Banks http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm are available as resources for investigators. 6. The application must reflect adequate time commitment of personnel. Levels of effort that are awarded will vary depending on the requirements of the studies to be performed and anticipated contributions to the CIT. 7. The CIT will be a collaborative effort that will require frequent interactions of awardees among themselves and with the NIH. Applicants must explicitly indicate their willingness to: participate in Steering Committee meetings (expected to occur approximately 4 times during the first year and 2 times per year in subsequent years, in or near Bethesda, MD), site visits required by the NIH, and regular telephone conference calls; cooperate with other awardees in the development and design of research protocols; abide by common definitions, common methods for patient selection and enrollment, and common protocols, procedures, tests, as chosen by majority vote of the Steering Committee; comply with data reporting procedures and timelines as established by the Steering committee and the DCC; comply with study policies and quality assurance measures approved by the Steering Committee; agree to oversight of the study by a Data and Safety Monitoring Board (DSMB); report all adverse events in accordance with procedures established by the Steering Committee and NIH policies; cooperate with other awardees in the publication of study results and the eventual release to the scientific community of study procedures and other resources, and accept the Cooperative Agreement Terms and Conditions of Award given below. 8. Applicants should state in their application their willingness to participate in collection of biologic samples as well as clinical data that may be used for future studies related to the treatment of T1D by investigators both inside and outside of the CIT. This RFA has a special requirement that applicants acknowledge in a "Sharing Plan" in the proposal that they will share the specimens and data collected with the wider scientific community, through eventual transfer of these materials to the NIDDK Central Biosample and Data Repositories or through another mechanism determined by NIH. A data sharing plan as approved, after negotiation with the applicant when necessary, will be a condition of the award. Evaluation of the Non-competing Grant Progress Report (PHS 2590) will include assessment of the effectiveness of research resource release. 9. Budget Information: The actual award will vary yearly, depending upon the number and character of studies developed and implemented by the CIT. However, applicants for the CIT-DCC must prepare estimated budgets for five 12-month periods, not to exceed $3 million total cost per year. The budget must address all of the DCC responsibilities outlined in other sections of this RFA. In particular, the budget should reflect the expectation that the clinical trials will require training, monitoring, and auditing for GCP and GTP at three to five sites for each protocol. They should reflect the assumption that the consortium will initiate 2 protocols in the first year, and up to 4 protocols per year in years 2 through 4; each of these protocols is expected to be completed over a course of 2 to 4 years. Thus, several protocols will be running concurrently, in different phases (development, implementation, analysis, or writing). The budget must also include costs of the following: developing, maintaining, and entering data into the database; administrative support of the Data and Safety Monitoring Board (including twice yearly face- to-face meetings and twice yearly telephone calls); face-to-face steering committee meetings (exclusive of travel and per diem for CC investigators) up to four times during the first year and two times/year in subsequent years in or near Bethesda, MD; telephone conference calls of the executive committee and subcommittees, and with NIH program staff; shipping and analysis of serum and tissue specimens sent to Central Laboratory(s), as well as shipment and storage of other samples in a repository, which may be administered through a subcontract from the CIT-DCC or through the NIDDK Biosample Repository. While the actual award may vary, the CIT-DCC may estimate $600,000 total costs/year for consortium/contractual agreements with a central laboratory(s) and/or sample and data repositories, including costs of shipping, and/or for the purchase and distribution of study drugs. 10. The applicant must provide a plan for sharing of research data for use by other researchers (See Terms and Conditions of Award). For guidance, the applicant is referred to The Final NIH Statement on Sharing Research Data, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: 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 and all appendices must be sent to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 752 Bethesda, MD 20892 (Courier use ZIP 20817) APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK and NIAID. Incomplete applications will not be reviewed. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDDK in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score. o Receive a written critique o Receive a second level review by the National Diabetes and Digestive and Kidney Disease Advisory Council. REVIEW 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 evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application's overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment 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. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 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)? 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: Documentation of experience and ability in all aspects of multi-center clinical trials, including protocol and manual of operations development, staff training, research instrument development, data collection and management, quality assurance, biostatistical expertise as applied to study design, randomization, and data analysis, administration and coordination, and human subjects protection. Documentation of experience and expertise in development of safety monitoring plans, including considerations for "stopping rules", administrative support of a DSMB, and interactions with site IRBs. Adequacy of the proposed research database design, data entry methods, and subject information core. Documentation of experience and ability in the handling of laboratory specimens in multi-center clinical studies. Documentation of experience and expertise in FDA regulatory requirements pertaining to IND applications and Good Tissue Practice compliance, and with auditing of production and testing records for manufacture of cellular products. Description of personnel and facilities adequate to implement the proposal, including personnel time commitment. PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below) INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. SHARING RESEARCH DATA: Applicants requesting more than $500,000 in direct costs in any year of the proposed research are expected to include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data-sharing plan into the determination of scientific merit or priority score. (See instructions and URL to policy in the Federal Citations, below.) BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: March 16, 2004 Application Receipt Date: April 13, 2004 Peer Review Date: July, 2004 Council Review: September, 2004 Earliest Anticipated Start Date: September 30, 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose- finding studies (phase I); efficacy studies (phase II), efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMB's) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). SHARING RESEARCH DATA Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking more than $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a clear and compelling justification is 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 clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. This policy announcement is in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. 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. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. 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 is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS This program is described in the Catalogue of Federal Domestic Assistance at http://www.cfda.gov/ in the following citations: No. 93.847, Diabetes Research, No. 93.855, Immunology, Allergy, and Transplantation Research and No. 93.856, Microbiology and Infectious Diseases Research. 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 NIH Grants Policy Statement is available at http://grants.nih.gov/grants/policy/policy.htm. This document includes general information about the grant application and review process; information on the terms and conditions that apply to NIH Grants and cooperative agreements; and a listing of pertinent offices and officials at the NIH. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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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