NON-HUMAN PRIMATE HEART/LUNG TRANSPLANTATION TOLERANCE RELEASE DATE: August 20, 2004 RFA Number: RFA-AI-04-049 (This RFA has been reissued, see RFA-AI-09-041) (This RFA has been reissued, see RFA-AI-06-018) EXPIRATION DATE: December 22, 2004 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Institute of Allergy and Infectious Diseases (NIAID) (http://www.niaid.nih.gov) CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: No. 93.855, Immunology, Allergy, and Transplantation Research No. 93.856, Microbiology and Infectious Diseases Research LETTER OF INTENT RECEIPT DATE: November 22, 2004 APPLICATION RECEIPT DATE: December 21, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements 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 Allergy and Infectious Diseases (NIAID) invites applications from single institutions or consortia of institutions to participate in the Non-Human Primate Immune Tolerance Cooperative Study Group (NHPCSG). The NHPCSG is a multi-center, cooperative program for research on non-human primate (NHP) models of kidney and islet transplantation, established in 1999 to evaluate preclinical safety and efficacy of existing and newly developed immune tolerance induction regimens and to elucidate the underlying mechanisms of the induction, maintenance, and/or loss of tolerance in these models. The long-range goal of this program is to develop and evaluate tolerance-induction regimens that will result in enhanced long-term graft survival in clinical transplantation of all organs and tissues. The purpose of this RFA is to expand the scope of transplantation models studied within the NHPCSG to include NHP models of heart and lung transplantation. RESEARCH OBJECTIVES Background Organ or tissue transplantation is the preferred treatment for many end-stage organ diseases when other therapies have failed or are unavailable. However, despite significant advances in immunosuppressive medications over the past 15 years that have led to one-year graft survival rates that approach or exceed 90% for most organs, long-term graft survival and, in many cases, patient survival remains poor for all organ transplants. In addition, life-long, global immunosuppressive therapy results in significant morbidity and has thus far not significantly enhanced long-term graft survival. The overwhelming leading cause of graft failure, both short- and long-term, is immune-mediated graft rejection. Advances in immune tolerance induction will eventually provide valuable new therapeutic strategies, which should eliminate the need for life-long, global immunosuppressive therapy, increase long-term graft survival and life expectancy, and improve health-related quality of life. For purposes of this RFA, immune tolerance is defined as the lack of a pathogenic immune response to allogeneic organs or tissues in the absence of ongoing immunosuppressive therapy. Research targeted to the induction of immune tolerance in solid organ and islet transplantation is a high scientific priority for the NIAID. In 1997, the NIAID initiated a scientific planning process designed to accelerate research in this area. The 1998 broad-based, long-range plan, entitled “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 at NIH in designing and directing major research programs in immune tolerance, particularly with respect to the application of tolerance induction strategies for the treatment of human disease. Two subsequent panels, the NIAID Expert Panel on Ethical Issues in Clinical Trials of Transplant Tolerance and the Expert Review Panel for NIAID's Extramural Transplantation Research Program, identified NHP 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, NIAID and the National Institute of Diabetes and Digestive Diseases (NIDDK) formally established a program in NHP models of kidney and islet transplantation in 1999 (RFA AI-99- 003, http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-99-003.html) and expanded the program in 2002 (RFA AI-01-006, http://grants1.nih.gov/grants/guide/rfa-files/RFA-AI-01-006.html). In addition, due to the rising costs and decreasing supply of specific pathogen free (SPF) Cynomolgus macaques and Indian Rhesus macaques, NIAID established breeding colonies of these monkey species to support the NHPCSG’s research efforts. The goals of the NHPCSG include: (1) development of novel donor-specific tolerance induction regimens; (2) assessment of the safety and efficacy of existing and newly developed immune tolerance regimens in preparation for human clinical trials; (3) definition of underlying mechanisms of action of the therapeutic approaches under investigation and the mechanisms of induction, maintenance and/or loss of tolerance; and (4) development and validation of biomarkers for the induction, maintenance and/or loss of immune tolerance. Currently, all studies within the NHPCSG are limited to NHP models of kidney and islet transplantation. A wide range of immune tolerance induction protocols are under evaluation and development. NIAID’s primary area of focus in organ and tissue transplantation research is the immunology of graft rejection and survival and the induction of immune tolerance. These immunological issues are shared across all organs and tissues, although specific aspects of the immunological processes involved may differ. Indeed, studies from each organ may offer unique insights into various facets of immune tolerance induction and graft rejection. Therefore, what is learned regarding tolerance induction and graft rejection for one organ may be informative to the development of therapeutic strategies for other organs and tissues. In FY 2004, NIAID expanded the scope of human clinical studies supported in tissue and organ transplantation beyond kidney and islets consistent with the view that graft rejection is an immunological disease. This first targeted research program to reflect this expansion was the establishment of a cooperative clinical trials and mechanistic studies program called the Clinical Trials in Organ Transplantation or CTOT (RFA AI-04-003, http://grants2.nih.gov/grants/guide/rfa-files/RFA-AI-04-003.html.), which is co-sponsored by the National Heart, Blood and Lung Institute (NHLBI) and the NIDDK. NHP transplantation studies are critical to the design of scientifically sound and ethically acceptable clinical trials, due, in part, to the close approximation of the NHP immune system and physiology to those of humans. NIAID intends to complement and support these human clinical trial efforts by expanding the scope of the NHPCSG to include models of heart and lung transplantation. Several aspects of heart and lung transplantation underscore the need for further research from an immunological standpoint. While three-year graft survival rates in the range of 77% in heart transplantation are similar to 81% graft survival seen in kidney transplantation, patient survival rates are more discrepant – 78% in heart, versus 91% in kidney – due, in part, to the availability of dialysis for those with a failed kidney, and the absence of a comparable life support system for heart recipients with a failed graft. In addition, chronic rejection in heart transplantation is often “silent,” with the initial presentation resulting in death; in contrast to kidneys, non-invasive monitoring of cardiac function is not sensitive to the development of chronic rejection. Lung transplantation has an extremely poor five-year graft survival rate of approximately 45%, with similarly poor patient survival rates. The lung plays a primary role in the host defense against airborne pathogens and, in the transplant setting, this unique immune environment may be related to a heightened chronic rejection in the lung. What is learned from studies of lung allograft rejection may prove to be significantly informative for the immune-mediated aspects of chronic rejection in multiple organs. The timely expansion of the NHPCSG will help meet the scientific needs of the transplantation research community and allow capitalization on recent and future opportunities in heart and lung transplantation. Research Objectives and Scope This RFA solicits grant applications to expand the scope of the current NHPCSG to include immune tolerance induction studies in NHP models of heart and lung transplantation. Currently the NHPCSG is funded exclusively for studies in islet and kidney transplantation. Because the long-range goal of this RFA is to develop and evaluate candidate tolerogenic approaches for transplantation in humans, NIAID expects that there will be reciprocal communication between the NHPCSG and NIH funded clinical trials programs. In addition, this interaction may result in potential opportunities to develop and participate in initial safety and efficacy pre-clinical studies. (See the Special Requirements and Collaborative Responsibilities sections below for additional discussion of potential opportunities and policies.) All research projects to be supported under this RFA are limited to NHP heart and/or lung transplantation models. Specifically, this RFA calls for the use of any NHP species for allogeneic studies of heart and/or lung transplantation. While individual research approaches may vary, the research scope of applications is restricted to one or more of the following areas: (1) Development of novel donor-specific tolerance induction regimens or refinement of existing regimens; (2) Assessment of the safety and/or efficacy existing or newly developed immune tolerance regimens either alone, in combination with immunosuppressive therapy, and/or in combination with withdrawal of immunosuppressive therapy; (3) Studies to define the underlying mechanisms of action of the therapeutic approaches under investigation, including changes in immune response and function, and the mechanisms of induction, maintenance and/or loss of donor- specific tolerance; and (4) Studies to develop, evaluate, and validate biomarkers for the induction, maintenance and/or loss of immune tolerance and/or for onset of acute or chronic graft rejection. All U01 and U19 applications must contain at least a single tolerogenic approach. This RFA will not provide support for the following: o Studies in animal models other than non-human primates o Xenotransplantation o Human studies or trials o Preliminary development of a non-human primate model of organ transplantation o Studies to improve the isolation, preservation, or supply of organs, tissues or cells o Hematopoietic stem cell transplantation, unless in the context of solid organ transplantation (i.e. tolerance induction through bone marrow chimerism) o Kidney or islet transplantation models o Studies of non-immunological side effects of an immuno-modulatory agent. MECHANISM OF SUPPORT This RFA will use the NIH single project cooperative agreement (U01) and/or multi-project cooperative agreement (U19), "assistance" mechanisms, rather than "acquisition" mechanisms. The applicant will be solely responsible for planning, directing, and executing the proposed project. 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 1, 2005. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. The NIH U01 and U19 are cooperative agreement award mechanisms in which 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" At this time, the NIAID has not determined whether or how this solicitation will be continued beyond the present RFA. The total project period for applications submitted in response to this RFA may not exceed five years. 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_2003/index.htm. Applicants for U19 grants must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS; this brochure is available via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm. Multi-project grant applications must have two or more individual projects and may include scientific cores and an administrative core. Scientific cores must serve at least two individual projects within the multi-project grant. Specific application details for multi-project grant applications are available at http://www.niaid.nih.gov/ncn/grants/multi/3aa.htm. FUNDS AVAILABLE The NIAID intends to commit approximately $2,000,000 in FY 2005 to fund 2 to 3 new grants in response to this RFA. An applicant may request a project period of up to five years and a budget for total first-year costs (directs and F&A) of up to $500,000 for U01 applications and total first-year costs (directs and F&A) of up to $1,000,000 for U19 applications. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the 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 meritorious applications. At this time, the NIAID has not determined whether or how this solicitation will be continued beyond the present RFA. ELIGIBLE INSTITUTIONS The applicant may submit (an) application(s) if the 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 institutions/organizations Foreign institutions are not eligible to apply as the applicant institution, but may enter into a consortium or subcontract with a domestic institution as the primary applicant. 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 their 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. SPECIAL REQUIREMENTS Applicants are encouraged to contact NIAID program staff well in advance of the application submission date, to discuss the proposed research program. These contacts help to ensure that applicants have a clear understanding of the goals, policies and priorities of this RFA. They also will allow staff to assess responsiveness to this RFA and provide appropriate guidance as needed, with regard to this initiative. 1. Steering Committee The Steering Committee will be the main governing body of the NHPCSG and membership on the Steering Committee is determined as described below under Cooperative Agreement Terms and Conditions of Award. Successful applicants will become members of the NHPCSG and participate in the collaborative program. The Steering Committee will meet at least once annually in Bethesda, MD. Proposed budgets should include funds to cover travel costs for these meetings. The Steering Committee will prioritize, develop and implement a scientific agenda for the group, and prioritize this agenda. All major scientific decisions will be determined by a majority vote of the Steering Committee. In the event that additional funds for collaborative opportunities, pilot projects, or pre-clinical safety and efficacy evaluation of new therapeutic regimens are made available to the NHPCSG, participation of all successful applicants will be required and determined by procedures instituted by majority vote of the Steering Committee. The Steering Committee will be responsible for the approval, conduct and monitoring of studies and study results. Any specific collaboration involving the resources of the NHPCSG will require approval by the Steering Committee. NIH will facilitate collaboration and coordination between the NHPCSG and the Immune Tolerance Network (ITN) and other clinical trials groups as needed. 2. Participation in a Productive Collaborative Program The applicant must provide a written commitment to: participate in the NHPCSG; serve on the Steering Committee; adhere to the decisions reached by the Steering Committee; participate in pre-clinical safety and efficacy evaluation of new therapeutic regimens or collaborative or pilot projects that are instituted and determined by majority vote of the Steering Committee, when and if funds become available for these additional studies; and accept the participation and assistance of NIH staff in accordance with the guidelines outlined under “Cooperative Agreement Terms and Conditions of Award: NIH Staff Responsibilities”. 3. Non-human Primate Resources Provision of NHPs from the NIAID Indian Rhesus macaque and Cynomolgus macaque breeding colonies is determined by availability, scientific priority, and recommendations by the Steering Committee. The NIAID Program Official will make final decisions regarding allocation of this resource. All non-human primates obtained from the NIAID colonies may be used only for the expressed purposes of the individual Cooperative Agreements funded through this RFA or proposals approved by the Steering Committee as discussed above under “Participation in a Productive Collaborative Program.” Costs for non-human primates from the NIAID breeding colonies will be assumed by the NIAID, but all shipping, handling, and special testing fees will be the responsibility of the grantee. It is possible that in future years NIAID will institute a partial cost recovery program for the NIAID non-human primate breeding colony monkeys for research use. However, for purposes of budget preparation, assume that non-human primates will not be provided by the NIAID breeding facility. Therefore, budgets will include the costs of non-human primate purchases for the proposed studies. The Steering Committee provides scientific advice and recommendations to the NIAID regarding breeding strategies and other considerations to assure the optimum long-range value of this resource to the research community. 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 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 NIH cooperative agreement (U01) or multi-project cooperative agreement (U19), "assistance", rather than an "acquisition", mechanisms, 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 NIAID Scientific 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. The Principal Investigators will determine and coordinate the project activities scientifically and administratively; set project goals and timelines to achieve the proposed goals; accept and implement common guidelines and policies set forth and approved by the Steering Committee; attend Steering Committee meetings; participate in all Steering Committee activities; and serve as a voting member of the Steering Committee, as outlined below under Collaborative Responsibilities; and participate in the cooperative nature of the group. Awardees will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. Data sharing requirements are presented under Required Federal Citations below. NIAID intends to support the peer-reviewed studies proposed in the awarded grant applications. However, under special circumstances (e.g. duplicative or overlapping specific aims between two awardees), the Steering Committee will establish guidelines and review procedures, and will evaluate and determine redirection or modification of the peer-reviewed proposals or provide recommendations to the NIH when applicable and necessary. All NHPCG institutions, upon acceptance of an award, agree to participate in studies as specified by majority vote of the Steering Committee, if and when additional funds for these studies become available, including those studies that involve collaborations with biotechnology and pharmaceutical companies. In addition, the Steering Committee will establish guidelines for proposal and review procedures for new pilot or collaborative projects when applicable and necessary, if and when funds for such projects are available. These policies are in keeping with the terms and conditions of the cooperative agreement mechanism. 2. NIAID Staff Responsibilities An NIAID Program Official will be responsible for the normal program stewardship, including monitoring program progress and approving changes. The Government, via the NIAID Program Official, will have access to data generated under this 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. NIAID staff assistance will be provided by the Chief, Transplantation Basic Sciences Section, DAIT or his/her designee, who will serve as the NIAID Scientific Coordinator. The NIAID Scientific 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. An NIAID Program Official will be assigned to perform normal program stewardship responsibilities for this award. The Program Official may serve as the Scientific Coordinator. The NIAID Scientific Coordinator will serve as a voting member of the Steering Committee and will participate in all Committee activities. During performance of the award, the NIAID Scientific Coordinator, 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; advising in management and technical performance; or participating in the preparation of publications for collaborative programs when and if applicable. The NIAID Scientific Coordinator will serve as a liaison/facilitator between the awardee, pharmaceutical and biotech industries, and other government agencies and will serve as a resource of scientific and policy information related to the goals of the awardee's research. However, the role of 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 the NIH staff will be given the opportunity to offer input into this process. The manner of reaching this consensus and the final decision-making authority will rest with the Steering Committee. 3. Collaborative Responsibilities The Steering Committee The NHPCSG Steering Committee serves as the governing board for the cooperative group. Each member of the Steering Committee will have one vote. At a minimum, voting membership of the Steering Committee will include the NIAID Scientific Coordinator, the Program Officials for other participating ICs, each U01/U19 Principal Investigator, one sub-project investigator from each U19 award, and selected scientists other than the awardees when additional expertise is required for committee breadth and balance. The Steering Committee will appoint additional members by majority vote. In addition, the NIAID may appoint up to two members of an NIAID scientific advisory panel to the Steering Committee as non-voting members. Federal voting membership cannot exceed 25% of the total voting members. A Chairperson was selected from among the non-federal Committee members by majority vote of the current NHPCSG Steering Committee. When or if a new Chairperson is selected, the selection will also be from the non-federal Committee members determined by majority vote of the Steering Committee. Subcommittees of the Steering Committee may be established as necessary. Each Steering Committee member will be expected to participate in all meetings and activities, e.g., conference calls and special subcommittees as required, and will be required to accept and implement common guidelines and procedures approved by the Steering Committee. The Steering Committee or a designated subcommittee will prepare an annual report containing the following information: progress of ongoing and newly- initiated projects; manuscripts published, in press, and in preparation; presentations at regional, national, and international meetings; other activities of the group; data submitted to databases; and future plans. The first such report will be submitted to the NIAID Scientific Coordinator not later than 13 months after the initial notice of award, or a time agreed upon by the NIAID Scientific Coordinator and yearly thereafter. The NIAID Scientific Coordinator will schedule the meetings of the Steering Committee and actively assist the Chair in developing the meeting agendas. The NIAID Scientific Coordinator will ensure coordination of the Steering Committee’s activities and implementation of the group’s recommendations. In order to most efficiently utilize research resources and exchange scientific information to rapidly respond to new pre-clinical opportunities, it is anticipated that collaborations with other NIH funded programs, such as the Cooperative Clinical Trials in Organ Transplantation or the ITN, will be initiated in future years. These collaborations will be coordinated and facilitated by the NIAID Program Official. The Steering Committee will: o serve as the main governing board; o establish protocols and subcommittees, as needed, for the receipt, review, development and evaluation of potential new, pilot, or collaborative projects, if additional funds are provided and available for such projects; o advise NIAID on scientific opportunities, emerging needs, and impediments; o advise NIAID on maximizing the value of the NIAID macaque breeding colonies; o ensure the timely release of data through publication and/or release of data to public databases; o develop guidelines for publication of collaborative project results; o prepare annual reports; and o collaborate when appropriate with NIH clinical trials programs. 4. Organizational Changes Certain organizational changes require the prior written approval of the NIAID Program Official. 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 Program Official. 5. Arbitration: Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and NIAID may be brought to arbitration. An arbitration panel will be composed of three members – one chosen by Steering Committee (with the NIH representation not voting) or one selected by the individual awardee in the event of an individual disagreement, a second member selected by NIAID, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. 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: Kristy Kraemer, Ph.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases Room 3043, MSC-6601 6610 Rockledge Drive Bethesda, MD 20892-6601 (FedEx: Bethesda, MD 20817) Telephone: 301-496-5598 Fax: 301-480-0693 e-mail: email@example.com o Direct questions about peer review issues to: Madelon Halula, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3116, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 402-2636 FAX: (301) 402-2638 Email: firstname.lastname@example.org o Direct questions about financial or grants management matters to: Ann Devine Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2114, MSC-7614 6700-B Rockledge Drive 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: Madelon Halula, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3116, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Bethesda, MD 20817 (for express mail or courier service) Telephone: (301) 402-2636 FAX: (301) 402-2638 Email: firstname.lastname@example.org SUBMITTING AN APPLICATION Applicants for U19 grants must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS; this brochure is available via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm. 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 D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The D&B 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) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS: 1. All applications must include a broad-based research program designed to evaluate the safety and efficacy of tolerogenic approaches in non-human primate models of heart and/or lung transplantation with the goal of inducing immunosuppression-free immune tolerance and delineating the mechanisms involved in the induction, maintenance and loss of tolerance as an integral part of the treatment protocols. All U19 and U01 applications must contain at least a single tolerogenic approach. The research plan must 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 non-human primate studies and human clinical trials. b) A description of gaps in knowledge and scientific opportunities relevant for the application of tolerogenic approaches to non-human primate studies and human clinical trials. c) A plan to accelerate research on immune tolerance in non-human primate models of lung and/or heart transplantation, including: o A conceptual framework delineating approaches to tolerance induction and their relevance to human transplantation, priorities among the various approaches and the rationale for such priorities, including potentially promising reagents and molecules in development; o A description of promising non-human primate treatment protocols, including the rationale for the selection of tolerogenic approaches and overall study design; o A description of promising mechanistic studies to be incorporated as an integral part of the non-human primate treatment protocols, including the rationale for the selection of the mechanistic studies, proposed techniques, and the overall design of such studies; and o A plan detailing the acquisition and preparation, if applicable, of the solid organs, tissues or cells to be used in the studies. All related costs required should be included in the application and fully justified. 2. All applications must propose clear research plan(s) and project goal(s) to be completed during the award period. The applicant must clearly state the interim objectives to be achieved during the project, identify impediments or critical decision points that could require a revision in the work plan, and provide a detailed timeline for the attainment of each goal. The application must also demonstrate the scientific and technical expertise required to design, conduct and analyze NHP studies responsive to this RFA. 3. All applications must also include a 1-2 page synopsis (to be included as appendices) of the proposed treatment protocol(s) to assess safety and efficacy and incorporating the proposed mechanistic studies. Budget requests should reflect and fully justify all costs associated with the conduct of the above studies. 4. Any application may include, in addition to the tolerogenic approach(s) and mechanistic project(s), the development, evaluation and validation of sensitive immune and/or surrogate biomarkers of the induction, maintenance, or loss of tolerance. Proposed tolerance assay studies should include: identification of and rationale for the immune and/or surrogate markers selected, including published data from in vitro or in vivo 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 studies will contribute to improvements in the capacity to utilize immune and/or surrogate biomarkers to predict the induction, maintenance or loss of tolerance. Use of new technologies, including minimally and non-invasive approaches, is encouraged. All costs required for the proposed tolerance and biomarker assays must be included in the application and must be fully justified. 5. U19 multi-project applications only 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; and 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. 6. All applications must also include a written commitment to: participating in the cooperative study group; serving on the Steering Committee and adhering to the decisions reached by that Committee, including following the consensus treatment protocols and adjunct studies; and accepting the participation and assistance of NIH staff in accordance with the guidelines outlined under "Terms and Conditions of Award: NIH Staff Responsibilities." 7. All applications must include a written commitment to design and conduct non-human primate research, in addition to the studies funded in the initial application, under circumstances in which such additional research is of significant importance to further the field of immune tolerance and if and when funds become available. Such circumstances include the evaluation of safety and efficacy and studies of underlying mechanisms for: existing tolerance induction treatment strategies in non-human primate models to produce data of critical importance to the design and conduct of scientifically sound and ethically acceptable human clinical trials; and newly discovered molecular targets for the induction of immune tolerance identified through fundamental research in small animal models. This written commitment must also include the awardee’s willingness and agreement to: (1) prepare scientific proposals for the design, conduct and analysis of such additional studies and budget requests for all associated costs; (2) submit proposals for scientific evaluation by NIH staff, the NHPCSG Steering Committee, and, when appropriate, non-Federal experts identified by the sponsors of this research program; and (3) accept additional funding from NIH and non-Federal organizations to support such additional investigations. The time frame within which such additional projects can be initiated and completed will be negotiated and agreed upon jointly between the awardees and the sponsors. 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 exact copies of the grant application and all five sets of any appendix material must be sent to: Madelon Halula, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3116, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 BETHESDA, MD 20817 (for express mail or courier service) Applications that are not received as a single package on or before the December 21, 2004 or that do not conform to the instructions contained in PHS 398 (rev. 5/01) Application Kit (as modified in, and superseded by, the NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS" for U19s), will be judged non-responsive and will be returned to the applicant. SPECIAL INSTRUCTIONS FOR COMPLETION OF U19 APPLICATIONS IN RESPONSE TO THIS RFA: Applicants for U19 cooperative agreements must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS; this brochure is available from NIAID listed under INQUIRIES via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm. This brochure presents specific instructions for sections of the PHS 398 (rev. 5/01) application form that should be completed differently than usual. For all other items in the application, follow the usual instructions in the PHS 398. 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. The NIH 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. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. CONCURRENT SUBMISSION OF AN R01 AND A COMPONENT PROJECT OF A MULTI-PROJECT APPLICATION: Current NIH policy permits a component research project of a multi-project grant application to be concurrently submitted as a traditional individual research project (R01) application. If, following review, both the multi-project application and the R01 application are found to be in the fundable range, the investigator must relinquish the R01 and will not have the option to withdraw from the multi-project grant. This is an NIH policy intended to preserve the scientific integrity of a multi-project grant, which may be seriously compromised if a strong component project(s) is removed from the program. Investigators wishing to participate in a multi-project grant must be aware of this policy before making a commitment to the Principal Investigator and awarding institution. 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIAID. Incomplete and/or nonresponsive 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 NIAID in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of 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 Advisory Allergy and Infectious Diseases Council REVIEW CRITERIA Review Criteria for U19 Applications: The general review criteria for U19 multi-project cooperative agreement applications are presented in the NIAID brochure entitled "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS” at http://www.niaid.nih.gov/ncn/grants/multibron.htm. Review Criteria for U01 Applications: 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 scientific review group will address and consider each of these criteria in assigning the application’s overall score, weighting them as appropriate for each application. 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: 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. ADDITIONAL REVIEW CONSIDERATIONS SHARING RESEARCH DATA: Applicants requesting $500,000 or more 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: November 22, 2004 Application Receipt Date: December 21,2004 Peer Review Date: April, 2005 Council Review: June, 2005 Earliest Anticipated Start Date: September, 2005 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 ANIMAL WELFARE PROTECTION: Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable. SHARING RESEARCH DATA: Investigators submitting an NIH application seeking $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. 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. 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. 93.855, 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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