IMMUNOBIOLOGY OF XENOTRANSPLANTATION RELEASE DATE: August 6, 2004 RFA Number: RFA-AI-04-042 (Reissued as RFA-AI-09-035) (See Addendum in NOT-AI-04-054) EXPIRATION DATE: November 23, 2004 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENTS OF PARTICIPATING ORGANIZATION: National Institute of Allergy and Infectious Diseases (NIAID) (http://www.niaid.nih.gov) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov) CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: No. 93.855, Immunology, Allergy, and Transplantation Research No. 93.847, Diabetes, Endocrinology, and Metabolism Research LETTER OF INTENT RECEIPT DATE: October 22, 2004 APPLICATION RECEIPT DATE: November 22, 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 purpose of this RFA is to solicit applications from single institutions or consortia of institutions to establish cooperative interdisciplinary research programs for development of pre-clinical, porcine to non-human primate (NHP) models of xenotransplantation. The goals of this program are (1) to delineate the cellular and molecular mechanisms of xenograft rejection and the induction of tolerance and accommodation; (2) to develop effective strategies to improve xenograft survival; and (3) to characterize the physiological compatibility/limitations of xenografts. The long-term goal of this program is to develop novel and efficacious strategies for broad application of xenotransplantation in the clinic. RESEARCH OBJECTIVES Background Transplantation is the preferred therapy for the majority of end-stage organ diseases. In 2003, more than 23,000 organ transplants were performed in the United States, but over 84,000 patients were still on waiting lists. Although active donor recruitment and primary care education programs have resulted in a gradual increase in the number of donated organs, the number of patients on waiting lists greatly exceeds the number of available organs. The success of the "Edmonton Protocol" has established pancreatic islet transplantation as a viable therapy for type 1 diabetes in patients whose disease cannot be effectively managed with exogenous insulin therapy. As with solid organ transplantation however, the availability of human cadaveric islets is sufficient for only a small fraction of patients who could potentially benefit from islet transplantation. Xenotransplantation offers a potential solution to the severe shortage of human organs, tissues, and cells to treat patients with end-stage organ diseases. Currently, the swine is the primary species of interest as an unlimited source of donor organs, tissues, and cells for xenotransplantation due to its favorable reproductive capacity as well as anatomical and physiological similarities to humans. However, xenotransplantation poses significant challenges, including the immune response of the recipient against the xenograft (i.e. hyperacute, acute vascular, cellular, and chronic rejection), the physiological limitations of organs or tissues functioning in a xenogeneic environment, and potential transmission of xenogeneic infectious agents, such as porcine endogenous retrovirus (PERV), from the graft to the recipient. The first and the most challenging hurdle to xenotransplantation has been hyperacute rejection, which is caused by preformed xenoreactive natural antibodies (XNA) and which can destroy the xenograft within minutes to a few hours of reperfusion by the recipient’s blood. The primary target of XNA is the gal epitope (galactosyl alpha-(1,3)-galactosyl beta-1,4-N-acetyl glucosaminyl), a non-reducing trisaccharide group synthesized by New World monkeys and lower mammals, but not by humans, apes, and Old World monkeys. Over the past several years, advances made in genetic engineering of large animals allowed researchers to develop several lines of genetically modified pigs with diminished potential for hyperacute rejection. These pig lines include transgenic strains expressing various human complement regulatory proteins [i.e., decay accelerating factor (CD55), terminal complement inhibitor (CD59), and monocyte chemoattractant protein (CD56)] to minimize the deleterious effects of the complement cascade. Other transgenic pig strains express different glycosyltransferases which compete with alpha-1,3- galactosyltransferase, the enzyme that generates the gal epitope, to decrease the gal antigen expression. Additionally, transgenic pigs expressing a combination of a human complement regulatory protein and a glycosyltransferase have been developed. These strategies dramatically, but not completely, reduce the frequency of hyperacute rejection and prolong the survival of some xenografts in porcine to nonhuman primate transplantation models from a few hours to a few weeks; however, the gal epitope still contributes to delayed acute vascular rejection. To further reduce the risk of hyperacute rejection, two different strains of alpha-1,3-galactosyltransferase gene knockout pigs, which lack the expression of the gal epitope, were recently developed. The advent of genetically modified pigs provides opportunities for the development of strategies to overcome hyperacute rejection; to address other immunological barriers to xenotransplantation, including acute vascular and cellular rejection as well as chronic rejection; and to pursue regimens for immune tolerance induction to xenografts. Physiological incompatibility between organs, tissues, and cells and the xenogeneic environment is another potentially critical challenge to successful xenotransplantation. Initial observations in studies using solid organs from transgenic pigs transplanted into nonhuman primates (NHP) indicate that the xenografts may have basic physiological functions that are compatible with the recipient as long as the grafts survive. However, it is possible that some proteins produced by the xenograft, such as the liver, will not function or will be incompatible and thus interfere with normal metabolic processes in the recipient. Furthermore, although porcine insulin has been used to effectively treat diabetic patients, porcine islets transplanted into not only xenogeneic but also heterotopic environments (i.e. liver in human and under the kidney capsule and muscle in some NHP studies) may not function in a physiologically compatible manner. Therefore, each organ/tissue/cell xenograft is likely to face unique obstacles. Additionally, issues related to the longevity, growth, and development of xenografts remain to be addressed. While the heart or kidney of a juvenile miniature swine is of suitable size for transplant into human, the rate and extent of graft growth as well as the lifespan of the xenograft beyond the pig’s natural lifespan of 15 years, are undetermined. Successful strategies to overcome hyperacute rejection and prolong the survival of xenografts will also allow opportunities to investigate any physiological obstacles to xenotransplantation and the development of novel therapeutic approaches to address those limitations. The third major barrier to xenotransplantation is potential transmission of an infectious agent from the xenograft to the recipient and then more broadly to the general population. The animals used as the source of xenografts can be bred in specific pathogen-free conditions, vaccinated, caesarian derived, medicated, and routinely screened to eliminate most, if not all, known zoonotic agents. However, endogenous retroviruses (e.g. PERV), whose DNA is integrated into the donor genome, or new and yet unidentified infectious agents may not be removed by conventional means. Although the patients transplanted with porcine cells or tissues show no evidence of PERV infection thus far, the effects of long-term exposure to xenografts, especially in immunosuppressed recipients, are unknown. In the last few years, investigators have made significant progress in assessing the risk of PERV infection. Polytropic (PERV-A, B, and A/C) and ecotropic (PERV-C) classes of PERV and human receptors for PERV-A have been identified. These findings provide the basis for additional investigations critical to determine susceptibility to and pathogenic consequences of PERV infection, the most serious known risk of zoonoses following xenotransplantation. While insights gained from such studies would increase understanding of the infectious risks of xenotransplantation, such studies are beyond the scope of this RFA. In 2003, the National Center for Research Resources established the National Swine Research and Resource Center (NSRRC; http://www.nsrrc.missouri.edu/), which is co-sponsored by the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute. The purpose of the NSRRC is to provide the biomedical research community enhanced access to critically needed swine models for studies involving human health and diseases including xenotransplantation. The recent scientific advances in xenotransplantation and the advent of new and novel resources underscore the timeliness of research efforts focused on the vital issues facing xenotransplantation. Understanding cellular and molecular mechanisms of xenograft rejection and physiological compatibility between xenografts and recipients will facilitate the development of novel and efficacious strategies for broad clinical application of xenotransplantation. Research Scope This RFA will establish a cooperative research program to develop pre- clinical, porcine to NHP models of xenotransplantation to address immunological and physiological issues critical to the engraftment, survival, and function of xenografts. The research focus may include: (1) elucidation of cellular and molecular mechanisms of xenograft rejection, accommodation, and/or tolerance induction; (2) development of effective strategies to prolong xenograft survival, including immune tolerance induction; and (3) characterization of the biology of the xenograft post-transplantation. Examples of research topics may include, but are not limited to the following: o Elucidation of the mechanisms of acute vascular and cellular rejection as well as chronic rejection of xenografts o Characterization of the host innate and adaptive immune responses to the xenograft post-transplantation o Evaluation of the immune responses to xenografts from the same animal source but in different stages of development, e.g. neonatal islet-like clusters vs. adult islets o Approaches to immune tolerance induction o Approaches to reducing host toxicity (i.e. hepatosteatosis) in xenotransplantation models o Delineation of the mechanisms of accommodation and/or tolerance induction o Development and characterization of life-supporting models of xenotransplantation o Development of effective strategies, including genetic modifications of organs/tissues/cells or utilization of encapsulation, to prolong xenograft survival and to eliminate or minimize the use of immunosuppressive drugs o Characterization of physiological interactions between the xenograft and the host and development of strategies to overcome physiological incompatibilities This RFA will not support: o Studies on zoonotic agents or strategies to circumvent zoonoses o Small animal models of xenotransplantation, such as rodent models, unless a novel rodent animal model(s) is proposed only as an in vivo bioassay of large animal immune function (e.g. trans in vivo DTH assay) o Clinical trials or clinical studies on xenotransplantation MECHANISM OF SUPPORT This RFA will use the NIH cooperative agreement (U01) and/or the NIH multi- project cooperative agreement (U19), "assistance" mechanisms, rather than an "acquisition" mechanism. 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 June 30, 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/U19 is a cooperative agreement award mechanism 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". The total project period for applications submitted in response to this RFA may not exceed five years. This RFA uses just-in-time concepts. 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. FUNDS AVAILABLE The NIH intends to commit approximately $4M in FY2005 to fund 2 to 6 new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to 5 years. 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 and the NIDDK provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. At this time, the NIH 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 o Foreign institutions are not eligible to apply but are eligible for inclusion as collaborators or subcontracts with sufficient justification. 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 NIH Program staff well in advance of the application submission date to discuss the proposed research program. This contact allows staff to assess responsiveness to this RFA and provide appropriate guidance as needed. 1. Description of Research Projects Applications must propose a 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 studies responsive to this RFA. 2. Development of a Productive Collaborative Program Each U01 or U19 application must demonstrate the organization’s ability to participate effectively in the NIH Immunobiology of Xenotransplantation Cooperative Research Program. The applicant must include a written commitment to: participate in the NIH Immunobiology of Xenotransplantation Cooperative Research Program; serve on the Steering Committee; adhere to the decisions reached by the Steering Committee; 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.” For a U19 multi-project cooperative agreement, the application must provide: a clear and concise plan that depicts the interrelationships among the research groups, their relevant experience/expertise, and the contribution of each to fulfillment of the objectives of this RFA; an organizational chart of the U19 cooperative group showing the name, organization, and scientific discipline of the PI and of all key scientific and technical personnel. If the application is from a consortium of institutions, the applicant must provide a plan to assure the maintenance of close cooperation and effective communication among members of the U19 cooperative group. In the event that additional funds for collaborative opportunities, pilot projects, or establishment of resources (e.g. swine islet isolation core) are made available to the Immunobiology of Xenotransplantation Cooperative Research Program, procedures for the solicitation and review of proposals will be instituted by majority vote of the Steering Committee. In addition, the Steering Committee will establish procedures for the approval, conduct and monitoring of studies and study results as well as any specific collaborations involving the resources of the Immunobiology of Xenotransplantation Cooperative Research Program. 3. Steering Committee The NIH will establish a Steering Committee within 60 days of award to serve as the governing body of the Immunobiology of Xenotransplantation Cooperative Research Program. At a minimum, the Steering Committee will be composed of the U01/U19 Principal Investigators, one subproject investigator of each U19 award, and the NIH Scientific Coordinators. The Steering Committee will meet at least twice the first year and annually thereafter. At least one of the meetings in the first year and the annual meetings will be in Bethesda, MD. Proposed budgets should include funds to cover travel costs for these meetings. Each Steering Committee member will be expected to participate in all meetings and activities, e.g., conference calls and special subcommittees as required. 4. Intellectual Property Rights Institution’s rights in inventions made under this funding mechanism and the reporting requirements for such inventions will be governed by Public Law 96- 517 (the Bayh-Dole Act of 1980), 35 U.S.C. Secs. 200-212, 37 C.F.R. Part 401, and 45 C.F.R. parts 6 and 8. Institutions and investigators are expected to share research resources developed under this funding agreement for research purposes, e.g., with other participating institutions as required to carry out the aims of the collaborative projects. In the event of a joint invention involving multiple institutions under this funding agreement, the funding recipient institution is expected to cooperate with any such co- inventor's institution(s) in developing a plan to achieve practical application of the technology. Applicants are expected to abide by the “Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources,” as published in the Federal Register December 23, 1999, Volume 64, Number 246, Pages 72090-72096. The Steering Committee will develop a policy on publication and sharing data obtained by the collaborative efforts of the Immunobiology of Xenotransplantation Cooperative Research Program. 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 cooperative agreement (U01) and the multiproject cooperative agreement (U19), "assistance", rather than an "acquisition", mechanism, in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the research will be shared among the awardees and the NIH Scientific Coordinators. 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 approved by the Steering Committee; attend Steering Committee meetings and serve as a voting member of the Steering Committee; and participate in the cooperative nature of the group. It is recognized that goals may require revision and re-negotiation during the course of the project period. Release of each funding increment by NIH will be based on a review of progress towards achieving the previously agreed upon research goals. 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. NIH 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 for modification of the peer- reviewed or initiation of new projects, and will evaluate and determine opportunities for collaboration with outside investigators and redirection of resources when applicable and necessary. This policy is in keeping with the terms and conditions of the cooperative agreement mechanism. 2. NIH Staff Responsibilities NIH staff assistance will be provided by a Program Director from the Transplantation Basic Sciences Section, Transplantation Immunobiology Branch, Division of Allergy, Immunology, and Transplantation (DAIT), who will serve as NIAID's Scientific Coordinator and a Program Director from the Division of Diabetes, Endocrinology and Metabolic Diseases (DDEM), who will serve as NIDDK’s Scientific Coordinator. The NIH Scientific Coordinators will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination above and beyond normal program stewardship for grants, as described below. During performance of the award, the NIH Scientific Coordinators, with assistance from other scientific program staff who are designated based on the research topic and their relevant expertise, may provide appropriate assistance, advice, and guidance by: participating in the design of the activities; advising in the selection of sources or resources (e.g., determining where a particular reagent can be found); coordinating or participating in the collection and/or analysis of data; advising in management and technical performance; or participating in the preparation of publications. The NIH Scientific Coordinators or his/her designee will serve as a liaison/facilitator between the awardee, pharmaceutical and biotech industries, and other government agencies (e.g., FDA, USDA, CDC) and will serve as a resource of scientific and policy information related to the goals of the awardee's research. However, the role of 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 Principal Investigator and the Steering Committee. In addition, the NIH Program Directors will be responsible for normal programmatic monitoring and stewardship for the award. The NIH Program Directors will approve changes in proposed research objectives and redirection of research projects. The NIH reserves the right to terminate or curtail a study (or any individual award) in the event of (a) substantial shortfall in progress, data reporting, quality control, or other major breach of the protocol; (b) substantive changes in the consensus protocol to which the NIH does not agree; (c) reaching a major study endpoint substantially before schedule with persuasive statistical significance; or (d) animal welfare issues that may dictate a premature termination. 3. Collaborative Responsibilities The Steering Committee A Steering Committee will serve as the governing board of the cooperative group of researchers. At a minimum, voting membership of the Steering Committee will include the NIAID Scientific Coordinator, the NIDDK Scientific Coordinator, 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. Each member of the Steering Committee will have one vote. A Chairperson will be selected by the Steering Committee from among the non-federal Committee members. The Steering Committee may appoint additional members by majority vote. Subcommittees of the Steering Committee may be established as necessary. In addition, the NIH may appoint up to two members of an NIH scientific advisory panel to the Steering Committee as non-voting members. Federal votes cannot exceed 25%. Program Directors from other sponsoring Institutions will serve on the Steering Committee as either voting or non- voting members, dependent upon federal votes not exceeding 25%. Awardee members of the Steering Committee will be required to accept and implement common guidelines and procedures approved by the Steering Committee. The NIAID Scientific Coordinator will schedule the meetings of the Steering Committee and actively assist the Chair in developing the meeting agendas. The Committee will meet at least twice the first year and annually thereafter. At least one of the meetings in the first year and the annual meetings will be in Bethesda, MD. The NIAID Scientific Coordinator will ensure coordination of the Steering Committee’s activities and implementation of the group’s recommendations. 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; and future plans. The first such report will be submitted to the NIH Scientific Coordinators no later than 13 months after the initial notice of award and yearly thereafter. The Steering Committee will: o Evaluate progress of the xenotransplantation projects and provide guidance to investigators regarding study implementation and conduct; o Establish protocols and subcommittees for evaluation, recommendation, and modification of ongoing xenotransplantation studies from cooperative group members; o Establish protocols and subcommittees, as needed, for the solicitation, receipt, review, development, and evaluation of potential new, pilot, or collaborative projects or potential resource sharing opportunities, if additional funds are available for such projects; o Advise NIH on scientific opportunities, emerging needs, and impediments; o Prepare Annual Reports; and o Develop guidelines for publication of collaborative project results. Cooperation with Other NIH-Sponsored Programs In order to most efficiently utilize research resources and rapidly exchange scientific information to promote xenotransplantation objectives, it is anticipated that cooperation or opportunities to collaborate with other NIH funded programs will be initiated in future years and will be coordinated and facilitated by the NIH Program Directors. 4. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award) between award recipients and I/C may be brought to arbitration. An arbitration panel will be composed of three members – one chosen by the awardee, a second member selected by the NIH, 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: Crystal Y. Koh, Ph.D Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases Room 3026, MSC-6601 6610 Rockledge Drive Bethesda, MD 20892-7640 Telephone: 301-496-5598 FAX: 301-480-0693 Email: email@example.com Thomas L. Eggerman, M.D., Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Room 697, MSC-5460 6707 Democracy Boulevard Bethesda, MD 20892-5460 Telephone: (301) 594-8813 FAX: (301) 480-3503 Email: firstname.lastname@example.org o Direct questions about peer review issues to: Mercy Prabhudas, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3256, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 451-2615 FAX: (301) 402-2638 Email: email@example.com 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: firstname.lastname@example.org 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: Mercy Prabhudas, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3256, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 451-2615 FAX: (301) 402-2638 Email: email@example.com 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 DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. 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: Mercy Prabhudas, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3256, 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 November 22, 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"), will be judged non-responsive and will be returned to the applicant. SPECIAL INSTRUCTIONS FOR COMPLETION OF 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 and the NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration or review. 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 NIH 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 an appropriate national advisory council or board. 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: October 22, 2004 Application Receipt Date: November 22, 2004 Peer Review Date: March 15, 2005 Council Review: May 25, 2005 Earliest Anticipated Start Date: June 30, 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 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. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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; No. 93.847, Diabetes, Endocrinology, and Metabolism 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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