NONHUMAN PRIMATE TRANSPLANT TOLERANCE COOPERATIVE STUDY GROUP Release Date: January 29, 1999 RFA: AI-99-003 P.T. National Institute of Allergy and Infectious Diseases National Center for Research Resources National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: March 15, 1999 Application Receipt Date: May 6, 1999 PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID, the National Center for Research Resources (NCRR), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invite applications from single institutions or consortia of institutions to participate in a multi-center, cooperative research program to evaluate existing and new tolerance induction treatment regimens and to elucidate the underlying mechanisms of the induction, maintenance and/or loss of tolerance in nonhuman primate models of kidney and islet transplantation. The goals of this research program are to: (1) evaluate further the safety, toxicity and efficacy of existing tolerance induction regimens; (2) evaluate the safety, toxicity and efficacy of new tolerance induction regimens; (3) define the underlying mechanisms of action of the therapeutic approaches under investigation; and (4) develop and validate immune and/or surrogate markers of the induction, maintenance and loss of tolerance, graft function, graft acceptance and graft survival. All applicants must comply with the requirements outlined in the section below titled "SPECIAL REQUIREMENTS." HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), NONHUMAN PRIMATE TRANSPLANT TOLERANCE COOPERATIVE STUDY GROUP, is related to the priority area of diabetes and chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402- 9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations; public and private institutions, such as universities, colleges, hospitals, laboratories, units of State and local governments; and eligible agencies of the Federal government. Foreign institutions are not eligible to apply. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The administrative and funding mechanism to be used to undertake this program will be the Multi-project Cooperative Agreement (U19), an "assistance" mechanism, 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. Essential elements of the Multi-project Cooperative Agreement mechanism also include: (1) a minimum of three inter- related individual research projects organized around a central theme; (2) collaborative efforts and interaction among independent projects and their investigators to achieve a common goal; (3) a single Principal Investigator who will be scientifically and administratively responsible for the group effort; (4) a single applicant institution that will be legally and financially responsible for the use and disposition of funds awarded; and (5) support provided, as necessary, for "core" resources or facilities, each of which is expected to be utilized by at least two research projects in order to facilitate the research efforts. Details of the responsibilities, relationships, and governance of a study funded under cooperative agreement(s) are discussed later in this document under the section Terms and Conditions of Award. The total project period for applications submitted in response to this RFA may not exceed five years. At present, the NIAID is administratively limiting the duration of Multi-project Cooperative Agreements to four years; this administrative limitation may change in the future. At this time, the NIAID has not determined whether and how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE The estimated total funds (direct and indirect costs) available for the first year of support for all awards made under this RFA will be $2,000,000. In Fiscal Year 1999, the NIH plans to fund at least two awards. The usual PHS policies governing grants administration and management will apply. Although this program is provided for in the financial plans of the participating institutes, awards pursuant to this RFA are contingent upon the availability of funds for this purpose and the receipt of a sufficient number of applications of high scientific merit. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and availability of funds. RESEARCH OBJECTIVES Background Transplantation is now routine therapy for end-stage renal disease, with one- year graft survival approaching 90% using standard immunosuppressive therapy. However, long-term graft survival has not improved appreciably since the early 1980s and only about 45% of cadaveric kidneys survive ten years post- transplant. For other organs (e.g., liver, lung and pancreas), graft survival does not approach this level. While new immunosuppressive drugs have reduced acute rejection in the first year post-transplant, it is clear that these therapeutic improvements will not significantly alter long-term clinical outcomes. Therefore, much recent attention has focused on the potential for the induction of donor-specific immune tolerance to achieve long-term graft survival without the need for non-specific, life-long immunosuppressive therapy that has deleterious and often life-threatening side effects. Although certain promising tolerogenic molecules have been shown to induce donor- specific tolerance in animal models, and are being tested in humans for the treatment of selected autoimmune diseases, these approaches have not been rigorously evaluated for transplantation. The cosponsors of this RFA are the lead NIH components supporting research focused on immunology, diabetes, kidney and liver diseases, including the development of improved therapies to prevent these diseases and treat their complications as well as the development of nonhuman primate resources for studies leading to further understanding of human health problems and disease processes. The NIAID has made immune tolerance a high scientific priority and in the fall of 1997, NIAID initiated a scientific planning process designed to accelerate research in this area. A broad-based, long-range NIAID Plan for Research on Immune Tolerance is available at: http://www.niaid.nih.gov/publications/immune/bookcover.htm The NIAID Expert Panel for Research on Immune Tolerance enthusiastically endorsed the conceptual framework, scope and timeliness of the plan and encouraged the NIAID to take a leadership role in designing and directing major research programs in tolerance, particularly with respect to the application of tolerance induction strategies for the treatment of human disease. NIAID convened a second expert panel, The NIAID Expert Panel on Ethical Issues in Clinical Trials of Transplant Tolerance, which concluded that ethically acceptable human tolerance induction protocols can be developed and recommended that the NIAID pursue clinical research in kidney and islet transplantation. In addition, both Expert Panels and the Expert Review Panel for NIAID's Extramural Transplantation Research Program identified nonhuman primate tolerance research as an essential step to provide "...critical data on safety, toxicity and potential efficacy that can not be obtained ethically in human clinical trials." In response to these recommendations and current scientific opportunities, the NIAID will support multiple programs to accelerate the clinical application of tolerance induction strategies to prevent and treat immune-mediated diseases. One effort is the establishment of the Collaborative Network for Clinical Research on Immune Tolerance, a collaborative consortium of institutions that will conduct clinical trials and integrated studies of underlying mechanisms focused on the induction and maintenance of immune tolerance to treat multiple immune system diseases, including: autoimmune diseases; asthma and allergic diseases; and graft rejection in kidney and islet transplantation. This RFA is the second endeavor in this area and establishes the Nonhuman Primate Transplant Tolerance Cooperative Study Group to obtain proof of concept, safety and toxicity data as well as pursue studies of underlying mechanisms of, and appropriate immune/surrogate markers for the induction, maintenance and loss of tolerance. Studies of existing and new tolerogenic treatment regimens in nonhuman primate models of kidney and islet transplantation are critical to the design of scientifically sound and ethically acceptable clinical trials. In addition, nonhuman primate studies are especially useful as they closely approximate the human immune system and physiology and these studies allow collection of important samples necessary to provide information necessary for validation of new noninvasive or minimally invasive diagnostic tests for tolerance, graft function, graft survival and graft rejection. Research Objectives and Scope The purpose of this RFA is to support a multi-site cooperative research program to investigate existing and new tolerance induction protocols in nonhuman primate models of kidney and islet transplantation. For purposes of this RFA, immune tolerance is defined as a selective lack of an immune response to targeted antigens that is accomplished by any of a variety of approaches, including: deletion, induction of anergy, immune deviation, sequestration, or suppression. Targets may include antigen-specific receptors, molecules of the co-stimulation pathways, homing molecules, or other relevant molecules; and may use a variety of agents, including: antigens, peptides, altered peptides, monoclonal antibodies, cytokines, molecularly engineered cells or tissues, DNA vectors, or other relevant approaches. All participating sites will utilize uniform controlled study designs and standardized data collection procedures. Specifically, each member of the cooperative research program will design and conduct: o Studies of the safety, toxicity and efficacy of existing and new tolerance induction regimens to improve graft survival and/or prevent graft rejection, including pre-, peri-, and post-transplant tolerogenic therapies to induce donor-specific tolerance: (1) alone; (2) in combination with standard immunosuppressive therapy; (3) in combination with new immunosuppressive therapies; and (4) in combination with immunosuppressive therapy withdrawal. Major scientific approaches to immune tolerance include, but are not limited to, the following: --Co-stimulatory blockade (e.g., anti-CD40 ligand antibody, anti-B7 antibody, CTLA4-Ig) --Cytokine modulation (e.g., IL-4, IL-12, TNF, TGF() --Clonal deletion (e.g., Fas-ligand) --Other approaches such as leukocyte migration blockade, peptide-based therapies targeted at specific antigens, and the use of molecularly engineered cells and tissues for deletion or inactivation of pathogenic lymphocytes. o Studies of the underlying mechanisms of action of the therapeutic approaches being evaluated, including changes in immune response and function, measures of the induction, maintenance and loss of donor-specific tolerance. Possible approaches to the study of underlying mechanisms include, but are not limited to, the following: --Quantitation of disease-related, alloreactive T lymphocytes using methods such as MHC/peptide tetramers, chimeric antibodies, or very early activation antigens; --Analysis of alloreactive T cells for expression of genes implicated in immunity or inflammation, or by FACS for cell surface markers that identify functions (e.g., cytokine receptors that distinguish Th1 from Th2 or chemokine receptors or integrins that indicate preferential patterns of homing); --Use of new technologies, (e.g., Magnetic Resonance Imaging and other non- invasive diagnostic and monitoring techniques; high throughput technologies such as gene chips using expressed sequence tags to identify and evaluate the function of genes activated at sites of rejection); and --Comparison of samples from peripheral blood and urine with those from sites of rejection. o Studies to develop, evaluate and validate standardized, reliable and sensitive immune and/or surrogate markers of the induction, maintenance and/or loss of tolerance, short- and long-term graft function, graft survival and graft rejection, with particular emphasis on defining clinically relevant predictors of acute and chronic rejection. This includes establishing appropriate measures (e.g., lymphokines or cytokines and/or their receptors, lymphocyte subsets, etc.), selecting appropriate samples (e.g., blood, urine, biopsies, etc.), and selecting appropriate techniques (e.g., quantitative PCR, gene chip technology, imaging, cellular immune assays, etc.) for routine use. Possible markers include: changes in gene or protein expression in blood, urine or biopsy materials; antibody or cytokine levels in blood, urine or biopsies; or in vitro lymphocyte responsiveness to donor antigens as determined by proliferation, cytotoxic activity, or antibody or cytokine secretion. Under this RFA, support will not be provided for research focused on improving the quality and/or supply of islets for transplantation. This includes developmental work to produce improved islets and technologies for immune isolation through approaches such as encapsulation. In addition, cross-species transplantation is not within the scope of this RFA. Costs associated with the procurement of nonhuman islets, however, will be supported under this RFA. SPECIAL REQUIREMENTS A. Study Organization 1. Steering Committee A Steering Committee will be established to serve as the main governing body of the Nonhuman Primate Transplant Tolerance Cooperative Study Group (hereafter referred to as the Cooperative Study Group). At a minimum, the Steering Committee will be composed of the NIAID Coordinator, the Principal Investigators, the Chair of the Adjunct Studies Subcommittee (see below), and a Statistical Coordinator for each Cooperative Study Group. If the awardee is a consortium of institutions, one additional investigator from the consortium will serve on the Steering Committee as a permanent member, or on a rotating basis, if appropriate, as determined by the protocols under development or implemented. A broad range of scientific and technical expertise is required to carry out the objectives of this RFA, including extensive experience in: the study of immune-mediated diseases, transplantation immunobiology and genetics, nonhuman primate models of immune system disorders, solid organ, cell and tissue transplantation, molecular and cellular biology, particularly as applied to the identification and evaluation of biomarkers and assay development and validation, and research design and statistics. The Cooperative Study Group must include scientific expertise in these areas under the direction of a senior scientist, serving as the Principal Investigator, with responsibility for the scientific, technical and administrative coordination and management of the Cooperative Study Group. All major scientific decisions will be determined by the Steering Committee, with each Principal Investigator, additional investigators, Chair of the Adjunct Studies Subcommittee, and the NIAID Coordinator. A Chairperson will be selected by the Steering Committee from among the non-federal members during the first meeting of the Committee, to be convened by the NIAID Coordinator. The Committee will meet at least twice during the first 12 months of the project and annually thereafter. The Steering Committee will have primary responsibility for developing the common treatment protocols, approving the design and implementation of all adjunct studies, facilitating the conduct and monitoring of all studies, analyzing and interpreting study data, and reporting study results. Studies will proceed to the implementation stage only with the concurrence of the Steering Committee. Each Steering Committee member will be expected to participate in all other Steering Committee activities, e.g., conference calls, special subcommittees as may be necessary, etc. The Steering Committee shall appoint an Adjunct Studies Subcommittee to design, implement and evaluate (1) studies of underlying mechanisms of action of the therapeutic approaches under investigation, and (2) studies to develop, evaluate and validate immune and/or surrogate markers of the induction, maintenance and/or loss of tolerance, graft survival, graft function and graft rejection. The members of the Adjunct Studies Subcommittee shall be selected by the Principal Investigators, with each Principal Investigator appointing two Subcommittee members, and shall include the NIAID Coordinator as a voting member. The Chair of the Adjunct Studies Subcommittee shall be elected from among the non-federal members and shall serve as a voting member of the Steering Committee. The Subcommittee will meet in conjunction with Steering Committee meetings twice during the first 12 months of the project and annually thereafter. Subcommittee members will be expected to participate in all meetings and in other Subcommittee activities, e.g., conference calls. Other subcommittees of the Steering Committee may be established as necessary. NIAID will facilitate collaboration and coordination between the Nonhuman Primate Transplant Tolerance Cooperative Study Group and the Collaborative Network for Clinical Research on Immune Tolerance, to be established in the fall of 1999 under the cosponsorship of NIAID, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the Juvenile Diabetes Foundation International (JDFI). This Collaborative Network will be composed of a consortium of institutions focused on the study of immune tolerance in humans, including: (1) clinical trials of tolerance induction in kidney transplantation, islet transplantation and autoimmune diseases; (2) integrated studies of the mechanisms underlying the induction, maintenance and loss of tolerance in humans; and (3) the development, evaluation and validation of biomarkers and assays to measure immune tolerance in humans. Close coordination among these two research programs will facilitate the development of safety, toxicity and potential efficacy data from nonhuman primate transplant models critical to the design and implementation of scientifically sound and ethically acceptable human trials for both existing and new tolerogenic approaches. Close coordination will also enable the application of findings from nonhuman primates to the clinical setting with respect to important immune/surrogate markers and reliable assays to measure tolerance. The annual meetings of the Nonhuman Primate Transplant Tolerance Cooperative Study Group Steering Committee will include a joint session with the Executive Committee of the Collaborative Network for Clinical Research on Immune Tolerance and involve dissemination and review of interim and final data, overall study progress, and approved but not implemented, ongoing and future studies relevant to the design of human clinical trials. The Request for Proposals to establish the Collaborative Network for Clinical Research on Immune Tolerance (RFP NIH-NIAID-DAIT-99-30) is available at the NIAID Contracts Management homepage (http://www.niaid.nih.gov/contract/rfp's/rfp9930.htm). In addition, the Principal Investigators of the Cooperative Study Group and the Chair of the Adjunct Studies Subcommittee will report on progress and future plans to the NIAID Advisory Committee for Research on Immune Tolerance at its annual meeting. This will include the preparation of data and other written materials addressing the current status of research projects, preliminary and final results, and proposed future investigations. 2. Data Coordination and Management Each Cooperative Study Group member institution will be responsible for its own data collection, management and quality assurance. Specific data analyses to be carried out will be determined by the Steering Committee, will be conducted by the Statistical Coordinator(s), and the results of those analyses will be delivered to the Steering Committee as the group responsible for determining if and what further analyses should be performed, how the results are interpreted, whether the results impact ongoing data collection or future studies, and how the findings should be disseminated. Applicants should request support for all data collection and analyses, including a Statistical Coordinator in their budget. B. Terms and Conditions of Award The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator 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 Multi- project Cooperative Agreement (U19), an "assistance" mechanism (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 Multi-project 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 NIAID Coordinator. 1. 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. Steering Committee Membership and Meeting Attendance Each Principal Investigator, additional investigators, where appropriate, and Statistical Coordinator from an applicant consortium will serve as a voting members of the Steering Committee and will participate in all scientific decisions. Each Steering Committee member will be responsible for attending all Steering Committee meetings, including not less than two meetings during the first 12 months of the study and annually thereafter, and participate in all other Steering Committee activities, e.g., conference calls, special subcommittee meetings as may be necessary, etc. Subcommittees of the Steering Committee may be established as necessary. At a minimum, the Steering Committee will establish an Adjunct Studies Subcommittee to provide advice to the Steering Committee with respect to research on immune/surrogate markers for induction, maintenance and loss of tolerance, graft function and graft survival, as described under the section "RESEARCH OBJECTIVES." The Adjunct Studies Subcommittee will be composed of two representatives selected by each Principal Investigator, as well as the NIAID Coordinator. This Subcommittee will meet annually in conjunction with the Steering Committee meeting. Protocol Development and Conduct The Steering Committee, or a separate Study Design Subcommittee, will define the objectives and approaches of all treatment protocols and adjunct studies and design the consensus protocols to be implemented by the Cooperative Study Group. Each institution participating in the Cooperative Study Group will follow the procedures required by the consensus protocol generated by the Steering Committee or its appointed Study Design Subcommittee regarding study conduct and monitoring, data collection and quality control. Data Coordination and Management Each Cooperative Study Group member institution will be responsible for its own data collection, management and quality assurance. Specific data analyses to be carried out will be determined by the Steering Committee, will be conducted by the Statistical Coordinator(s), and the results of those analyses will be delivered to the Steering Committee as the group responsible for determining which further analyses should be performed, how the results are interpreted, whether the results should influence ongoing data collection or future studies, and how the findings should be disseminated. Applicants should include in their budget requests support for all data collection and analyses, including a Statistical Coordinator. 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 Early publication of major findings is encouraged. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of both the Cooperative Study Group and NIH support. Analyses to be performed using the collective data from the Cooperative Study Group institutions will be determined and directed by the Steering Committee. Cooperative Study Group institutions wishing to perform analyses of local data will inform the Steering Committee of any such analyses prior to initiation in order to avoid duplication. 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 Subcommittee to serve this function. Monitoring Study Progress The Steering Committee will establish mechanisms for assessing performance of the Cooperative Study Group institutions. This includes quality, accuracy and timeliness of data collection and management, conscientious observance of study requirements, and presentation of study results at joint meeting with the Executive Committee of the Collaborative Network for Clinical Research on Immune Tolerance and the NIAID Advisory Committee for Research on Immune Tolerance. Federally Mandated Regulatory Requirements The PHS Policy on Humane Care and Use of Laboratory Animals requires that applicant organizations proposing to use vertebrate animals file a written Animal Welfare Assurance with the Office for Protection from Research Risks, establishing appropriate policies and procedures to ensure the humane care and use of live vertebrate animals involved in research activities supported by the PHS. The PHS policy stipulates that an applicant organization, whether domestic or foreign, bears responsibility for the humane care and use of animals in PHS-supported research activities. All institutions are required to comply, as applicable, with the Animal Welfare Act as amended (7 USC 2131 et sec.) and other Federal statutes and regulations relating to animals. These documents are available from the Office for Protection from Research Risks, National Institutes of Health, Bethesda, MD 20892, (301) 496-7163. 2. NIAID Staff Responsibilities NIAID staff assistance will be provided by the Chief of the Genetics and Transplantation Branch, Division of Allergy, Immunology and Transplantation, NIAID who will serve as NIAID's Coordinator. The NIAID Coordinator 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. Steering Committee Membership and Meeting Attendance The NIAID Coordinator will serve as a voting member of the Steering Committee, will attend all Steering Committee meetings, and will participate in other Committee activities, e.g., conference calls, special subcommittees. The NIAID Coordinator will also serve on the Adjunct Studies Subcommittee. Protocol Development As a member of the Steering Committee, the NIAID Coordinator and other NIH representatives will serve as a resource with respect to the design of treatment protocols and adjunct studies and will assist the Steering Committee in study development. Study Materials The NIAID Coordinator will be responsible for obtaining and distributing study materials to be used in the treatment protocol developed by the consensus of the Steering Committee. The NIAID is not responsible for obtaining or distributing of solid organs, tissues or cells to be used by the Cooperative Study Group. Monitoring Study Performance The NIAID Coordinator will provide assistance to the Steering Committee in the development of mechanisms and procedures for monitoring study performance. This includes the accuracy, quality and timeliness of data collection and management, consistency in observing study requirements, and presentation of study results at joint meetings with the Executive Committee of the Collaborative Network for Clinical Research on Immune Tolerance and the NIAID Advisory Committee for Research on Immune Tolerance. Data Coordination and Management Each Cooperative Study Group member institution will be responsible for its own data collection, management and quality assurance. Specific data analyses to be carried out will be determined by the Steering Committee, will be conducted by the Statistical Coordinator(s), and the results of those analyses will be delivered to the Steering Committee as the group responsible for determining if and what further analyses should be performed, how the results are interpreted, whether the results impact ongoing data collection or future studies, and how the findings should be disseminated. Applicants should include in their budget requests support for all data collection and analyses, including a Statistical Coordinator. 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. The Government, via the NIAID Coordinator, will have access to data generated under this Multi-project Cooperative Agreement and may periodically review the data and progress reports. NIAID 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. Publication and Presentation of Study Findings The NIAID Coordinator and other NIH representatives may contribute, through review, comment, analysis, and/or co-authorship, to reporting results of the studies conducted by the Cooperative Study Group to the investigator community and other interested scientific and lay organizations. Co-authorship by the NIH staff will be subject to approval in accordance with NIH policies regarding staff authorship of publications resulting from extramural awards. Organizational Changes Certain organizational changes require the prior written approval of the NIAID Coordinator. These changes include the addition or replacement of a scientific investigator, affiliate, component, or research base that is associated with this study. A change in the Principal Investigator, or in any key personnel identified on the Notice of Award, must have the prior written approval of the NIAID Grants Management Specialist in consultation with the NIAID Coordinator. Program Review The NIAID Coordinator will review the progress of the Cooperative Study Group through consideration of annual progress reports, periodic reports on ongoing progress, findings and future plans presented during meetings and conference calls, publications, site visits, etc. This review may include, but is not limited to, compliance with the study protocols, adherence to uniform data collection procedures and participation in Steering Committee and other committee meetings as necessary. The NIAID reserves the right to terminate or curtail the study (or any individual award) in the event of (a) a major breech of the protocols, (b) substantive changes in the agreed-upon protocols to which the NIAID does not agree, and/or (c) reaching a major study endpoint substantially before schedule with persuasive statistical significance. 3. Collaborative Responsibilities A Steering Committee, composed of the Principal Investigators, additional investigators, the Statistical Coordinators, and the NIAID Coordinator will be the main governing body of the Cooperative Study Group and will have primary responsibility for all scientific decisions, including: defining protocol objectives and approaches; designing and implementing protocols; developing procedures for data collection, management and quality control; establishing procedures for assessing performance with respect to adherence to protocols and adjunct studies; analyzing and interpreting study data; and publishing/presenting study findings. Each member of the Steering Committee will have one vote. The chairperson will be selected by the Steering Committee from among the non-federal members. Subcommittees will be established by the Steering Committee, as it deems appropriate. At a minimum, the Steering Committee will establish an Adjunct Studies Subcommittee to provide advice with respect to the mechanistic research and immune/surrogate marker studies as described under "RESEARCH OBJECTIVES." Cooperative Study Group institutions will be required to accept and implement the common treatment protocols, adjunct studies and procedures approved by the Steering Committee. Studies will proceed into the implementation stage only with the concurrence of the Steering Committee, the NIAID Coordinator and other NIH representatives. 4. Arbitration Any disagreement that may arise on scientific or programmatic matters (within the scope of the award) between award recipients and the NIAID may be brought to arbitration. An arbitration panel will be composed of three members -- one selected by the Steering Committee (with the NIAID member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by the NIAID, 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. 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 NIAID 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. LETTER OF INTENT Prospective applicants are asked to submit, by March 15, 1999, a letter of intent that includes a descriptive title of the overall proposed research; the name, address and telephone number of the Principal Investigator and all collaborators; and the number and title of this RFA. Although the letter of intent is not required, is not binding, does not commit the sender to submit an application, and does not enter into the review of subsequent applications, the information that it contains allows NIH staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Bela Gulyas at the address listed under INQUIRIES. APPLICATION PROCEDURES Applicants for U19 cooperative agreements must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS (September 1997); this brochure is available via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 435-0714, email: grantsinfo@nih.gov. Application kits are also available on the World Wide Web at: http://www.nih.gov/grants/forms.htm. For purposes of identification and processing, item 2 on the face page of the application must be marked "YES" and the RFA number "AI-99-003" and the words "Non-human Primate Transplant Tolerance Cooperative Study Group" must be entered on the face page. Applications must be received by May 6, 1999. Applications that are not received as a single package on the receipt date or that do not conform to the instructions contained in PHS 398 (rev. 4/98) Application Kit (as modified in, and superseded by, the special instructions below, for the purposes of this RFA), will be judged non-responsive and will be returned to the applicant. The RFA label available in the application form PHS 398 must be affixed to the bottom of the face page. 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. If the application submitted in response to this RFA is substantially similar to a grant application already submitted to the NIH for review, but that has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will different review committees review essentially identical applications. Therefore, an application that is essentially identical to one that has already been reviewed cannot be submitted in response to this RFA. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. It is highly recommended that the appropriate NIAID program contact be consulted before submitting the letter of intent and during the early stages of preparation of the application. (See program contacts under INQUIRIES). Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-sided 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 exact copies of the grant application and all five sets of any appendix material must be sent to Dr. Bela Gulyas at the address listed under INQUIRIES. DUE TO THE EXPEDITED NATURE OF THIS RFA, FAILURE TO SEND THESE ADDITIONAL COPIES COULD RESULT IN AN APPLICATION NOT BEING INCLUDED IN THE PEER REVIEW PROCESS. Minimum Requirements for Application To promote the development of a collaborative program among the award recipients, a minimum number of issues need to be addressed in the applications, as outlined below. 1. The application must include a broad-based scientific agenda designed to evaluate the safety, toxicity and efficacy of various tolerogenic approaches in nonhuman primate models of kidney and islet transplantation with the goal of inducing immunosuppression free, donor-specific tolerance to improve graft function, graft survival and prevent graft rejection, and to delineate the mechanisms involved in the induction, maintenance and loss of tolerance as an integral part of the treatment protocols. The scientific agenda shall include the following: a) A discussion of the state-of-the-art of research focused on elucidating the underlying mechanisms of immune tolerance and on evaluating tolerogenic approaches in nonhuman primate studies and human clinical trials. b) A description of gaps in knowledge and scientific opportunities relevant for the application of tolerogenic approaches to nonhuman primate studies and human clinical trials in kidney and islet transplantation. c) A plan to accelerate research on immune tolerance in nonhuman primate models of kidney and islet transplantation, including: (1) A conceptual framework delineating approaches to tolerance induction to improve graft survival and prevent graft rejection, priorities among various approaches and the rationale for such priorities, including potentially promising reagents and molecules in development; (2) The relevance of each approach to human kidney and islet transplantation; (3) A conceptual framework for delineating underlying mechanisms of tolerogenic approaches through studies conducted as an integral part of the nonhuman primate treatment protocols; (4) A description of promising nonhuman primate treatment protocols, including the rationale for the selection of tolerogenic approaches, and overall study design; and (5) A description of promising mechanistic studies to be incorporated as an integral part of the nonhuman primate treatment protocols, including the rationale for the selection of the mechanistic studies, proposed techniques, and the overall design of such studies. (6) A plan detailing the acquisition and preparation, if applicable, of the solid organs, tissues or cells to be used in the studies. All costs required for this must be included in the application and fully justified. 2. The application must also include: (1) a 1-2 page synopsis for each of two proposed pilot treatment protocols to assess safety and efficacy and incorporating two mechanistic studies, and (2) a 1-2 page synopsis for each of two proposed efficacy treatment protocol incorporating 3 mechanistic studies (all synopses are to be included as appendices). Since the actual treatment protocols to be performed will be selected by the Steering Committee, the final protocols implemented by the Cooperative Study Group may not reflect any protocol submitted in response to this RFA. Budget requests should reflect and fully justify all costs associated with the conduct of the above studies. 3. The application must include at least two proposed adjunct studies, each focused on the development, evaluation and validation of sensitive immune and/or surrogate markers of the induction, maintenance or loss of tolerance and short- and long-term graft function, survival and/or rejection. Proposed adjunct studies are to include: identification of and rationale for the immune and/or surrogate markers selected, including published data from laboratory, animal and human studies; description of and rationale for the proposed source, quantity and number of samples required; methodologies proposed to collect and analyze samples; and a discussion of how the results of the proposed adjunct studies will contribute to improvements in the capacity to utilize immune and surrogate markers to predict the induction, maintenance or loss of tolerance, graft function and graft survival. Proposed studies using new technologies, including minimally and non-invasive approaches are encouraged. Since the actual adjunct studies to be performed will be selected by the Steering Committee, the final studies carried out by the Cooperative Study Group may not reflect any single adjunct study submitted in response to this RFA. All costs required for the proposed adjunct studies must be included in the application and must be fully justified. These include the additional costs for all proposed adjunct studies and data collection and analyses. 4. The application must identify the single applicant organization that will be legally and financially responsible and accountable for the use and disposition of funds awarded on the basis of this RFA to other institutions participating in the consortium, if applicable, and show availability of personnel and facilities capable of performing and supporting the administrative functions necessary. 5. The application must name a single Principal Investigator (PI) who will have scientific responsibility for the application as a whole, including all consortium-related research activities, if applicable. The PI must be a senior scientist with substantial experience related to the scope and objectives of the RFA. In addition, applications from a consortium of institutions must designate a single investigator for each participating institution who will be responsible for on-site scientific implementation, direction and management of the studies, as well as the coordination of requirements for adjunct studies of underlying mechanisms and immune/surrogate markers. 6. Applications must also demonstrate the scientific and technical expertise required to design, conduct and analyze treatment protocols, mechanistic studies and assay development and validation. 7. Applications must provide: a clear, concise plan, in narrative and diagrammatic form, that depicts the interrelationships among the research projects and the scientific and technical staff, their relevant experience/expertise, and the contribution of each to fulfillment of the objectives of this RFA; an organizational chart of the consortium showing the name, organization, and scientific discipline of the PI and of all key scientific, technical and administrative personnel; and a mechanism for selecting and replacing key professional or technical personnel. 8. If the application is from a consortium, it must provide a plan to assure the maintenance of close cooperation and effective communication among members of the consortium, including letters of commitment to this plan from all participating institutions. 9. The application should discuss the capability of the applicant organization and each institution in a consortium, if applicable, to participate and interact effectively in cooperative, multi-center studies. 10. The application must include a written commitment to accept the participation and assistance of NIH staff in accordance with the guidelines outlined under "Terms and Conditions of Award: NIAID Staff Responsibilities." The application must also include a written commitment to the cooperative organization and willingness to serve on the Steering Committee and adhere to the decisions reached by that Committee, including following the consensus treatment protocols and adjunct studies. REVIEW CONSIDERATIONS Review Procedures Upon receipt, applications will be reviewed for completeness by the Center for Scientific Review (CSR) and for responsiveness by NIAID staff. 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 NCRR in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Advisory Allergy and Infectious Diseases Council. Review Criteria The review criteria for U19 multiproject cooperative agreement applications are presented in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS (September 1997); this brochure is available via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm. The initial review group will also examine: the appropriateness of proposed project budget and duration, the provisions for the protection of animal subjects; and the safety of the research environment. AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program balance, and the availability of funds. The earliest anticipated date of award is September 10, 1999. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic (research scope and eligibility) issues to: Stephen Rose, Ph.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4A14 Bethesda, MD 20892-7640 Telephone: (301) 496-5598 FAX: (301) 402-2571 Email: Steve_Rose@nih.gov Jerry A. Robinson, Ph.D. Comparative Medicine National Center for Research Resources 6705 Rockledge Drive, Suite 6030 Bethesda, MD 20892 Telephone: (301) 435-0744 FAX: (301) 435-3819 Email: jerryR@ep.ncrr.nih.gov Joan T. Harmon, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Building 45, Room 5AN-18G Bethesda, MD 20892 Telephone: (301) 594-8813 FAX: (301) 480-3503 Email: Joan_Harmon@NIH.GOV Direct inquiries regarding review issues and special instructions for application preparation; address the letter of intent to; and mail two copies of the application and all five sets of appendices to: Dr. Bela Gulyas Division of Extramural Activities National Center for Research Resources 6705 Rockledge Drive, Room 6018 Bethesda, MD 20892-7965 Telephone: (301) 435-7965 FAX: (301) 480-3660 Email: bg22s@nih.gov Direct inquiries regarding fiscal matters to: Pamela G. Fleming Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4C25 Bethesda, MD 20892-7610 Rockville, MD 20852 (for express/courier service) Telephone: (301) 402-6580 FAX: (301) 480-3780 Email: pf49e@nih.gov Schedule Letter of Intent Receipt Date: March 15, 1999 Application Receipt Date: May 6, 1999 Scientific Review Date: June-July 1999 Advisory Council Date: September 2, 1999 Earliest Award Date: September 10, 1999 AUTHORITY AND REGULATIONS This program is supported under authorization of the Public Health Service Act, Sec. 301 (c), Public Law 78-410, as amended. The Catalogue of Federal Domestic Assistance Citation is Sec. 93.856, Microbiology and Infectious Diseases Research, No. 93.855 - Immunology, Allergy, and Transplantation Research, insert additional citations for cosponsors. Awards will be administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems review. The Public Health Service strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or, in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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