AUTOIMMUNITY CENTERS OF EXCELLENCE RELEASE DATE: May 13, 2002 (see addendum NOT-AI-02-053) RFA: AI-02-006 - (Reissued as RFA-AI-08-010) PARTICIPATING INSTITUTES AND CENTERS (ICs): National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov) National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov/) Office of Research on Women's Health, NIH (http://www4.od.nih.gov/orwh) LETTER OF INTENT RECEIPT DATE: September 17, 2002 APPLICATION RECEIPT DATE: October 16, 2002 APPLICATIONS IN RESPONSE TO THIS REQUEST FOR APPLICATIONS (RFA) MUST BE PREPARED USING A MULTI-PROJECT GRANT APPLICATION FORMAT; SPECIFIC INSTRUCTIONS FOR COMPLETING THE APPLICATION ARE IN THE NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS" at http://www.niaid.nih.gov/ncn/grants/multibron.htm THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to become Principal Investigators o Special Requirements o Cooperative Agreement Terms and Conditions of Award o Where to send Inquiries o Letter of Intent o Submitting an Application o Special Instructions for Completion of Applications in Response to This RFA 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), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the Office of Research on Women's Health (ORWH) invite applications for Autoimmunity Centers of Excellence (ACEs). The purpose of this cooperative research program is to support integrated basic, pre-clinical and clinical research centers to: conduct single site and multi-site cooperative clinical trials and studies of mechanisms of action of tolerance induction and new immune modulation interventions in multiple autoimmune diseases; accelerate early translation of basic findings into clinical application; facilitate the utilization of clinical materials for basic research studies; enhance the exchange of information between basic scientists and clinicians and among various specialists involved in treating autoimmune diseases; and establish a collaborative approach to clinical and basic research among multiple institutions in various geographic areas. Each Center will include: 1) a clinical component, incorporating multiple clinical specialists to conduct trials and clinical studies of new immunotherapies for autoimmune diseases in cooperation with other Center clinical components; and 2) two or more multidisciplinary, interactive basic and/or pre-clinical research components, focused on elucidation of the basic mechanisms of autoimmunity, self tolerance and/or immune modulation. The basic and clinical components of all Centers will work cooperatively to select, design, and perform the clinical trials/studies and the adjunct basic mechanistic studies. All applicants must comply with the Cooperative Agreement Terms and Conditions of Award presented below. RESEARCH OBJECTIVES Background Autoimmune diseases result from direction of an immune response towards the body's own tissues. The most common of these diseases include systemic lupus erythematosus, multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. However, the immune response toward self can affect any organ or organ system, resulting in a wide variety of autoimmune diseases, including autoimmune myositis, thyroid disease, oophoritis and orchitis, hepatitis, hemolytic anemia, pemphigus, inflammatory bowel disease, and alopecia. Many of these autoimmune diseases by themselves are considered orphan diseases, but in toto autoimmune diseases disproportionately afflict millions of women in this country. The costs of these diseases are enormous, including hospitalizations, outpatient visits, lost productivity, and decreased quality of life for patients and their families. The underlying immune mechanisms of these multiple diseases may be overlapping. Self-reactive T cells play an important role in the immune responses leading to many of these clinically divergent diseases. The presence, number, activity, and specificity of these self-reactive cells are regulated by complex processes involving multiple molecules and mechanisms. These include: the binding and presentation of antigen by the molecules of the major histocompatibility complex (MHC); the number and affinity of specific T cell receptors for these complexes; the presence of co- stimulatory molecules, including the B.7 and CD40 families; the activity of regulatory T cells, both T helper and T cytotoxic cells; the presence and pattern of extracellular mediators including cytokines, lymphokines, and chemokines; and the intracellular pathways leading to apoptosis or cell death. Strategies to interrupt the immune response at any of these sites could prevent or down regulate the self-reactive response leading to autoimmune disease. In fact, agents which block co-stimulatory signals (anti-CD40L, CTLA4-Ig) or cytokines (anti-TNF-alpha, TNFR:Fc, IL-1Ra), interrupt or alter binding of antigen to MHC (antigen peptides, MHC peptides, peptide oligomers), or modulate the appearance and activity of regulatory cells (various cytokines and anti- cytokines) are now being evaluated for treatment of multiple autoimmune diseases. Equally, T cell independent mechanisms may be important mediators of B cell tolerance. Thus, approaches that target various molecules in these unique pathways, including complement, B cell receptor, PD-1, CD22, Fc?Rs, CD19, and B lymphocyte stimulator (BlyS), are under evaluation. Other approaches are likely to be discovered in the next few years. Clinical evaluation of new immune interventions in various diseases has often been performed without basic mechanistic studies to define the actions of the experimental agents. Closer interactions between clinicians and basic scientists should accelerate clinical testing of new approaches to tolerance induction and immune modulation and enhance understanding of their underlying mechanisms of action. Since the affected organ systems vary in different diseases, autoimmune diseases are usually treated by multiple clinical specialists. Thus, multiple sclerosis is treated by neurologists; type 1 diabetes, Graves' disease, and Hashimoto's thyroiditis by endocrinologists; systemic lupus erythematosus, rheumatoid arthritis, and scleroderma by rheumatologists; idiopathic thrombocytopenia purpura by hematologists; and inflammatory bowel disease by gastroenterologists. Many of these diseases are treated by multiple specialists. Because all these diseases will be increasingly approached with immunologic interventions, a cooperative group with the capability to evaluate a new agent in any of a number of diseases offers considerable advantages. Increased interaction of clinical specialists in planning, performance, and evaluation of trials/studies should lead to a more coordinated approach to development of new immune-based therapies for all autoimmune diseases. Research Objectives and Scope The major goal of this program is to support an integrated basic and clinical research program focused on tolerance induction and immune modulation to prevent or treat autoimmune disease. The close interaction between basic researchers and clinicians will accelerate the translation of basic advances to the clinic and the utilization of patient materials for basic research. NIAID is seeking multidisciplinary centers that emphasize new ideas, novel approaches, and state of the art technology to increase our understanding of the basic mechanisms of autoimmunity and self tolerance and the translation of that knowledge to design and evaluate clinical interventions to prevent or treat autoimmune diseases. The clinical components of the Autoimmunity Centers of Excellence will perform pilot or exploratory clinical trials or clinical studies, hereafter designated clinical trials/studies, in patients with autoimmune disease(s) to test, evaluate, develop, or determine mechanism of action of agents or interventions to prevent or treat autoimmune disease by induction of tolerance or immune modulation. While industry has supported some translational activities, industry-supported trials have generally not focused on questions about the basic mechanisms of action of these agents. Collaboration of the Autoimmunity Centers of Excellence with industry in performance of clinical trials/studies and adjunct basic mechanistic studies is encouraged. Specific areas of interest include, but are not limited to: o clinical trials of tolerogenic and immunomodulatory approaches and agents to treat and prevent autoimmune disease, including co-stimulatory blockade, such as anti-CD40 ligand antibody and CTLA4-Ig; cytokines and anti-cytokine molecules, such as anti-TNF, IL-4, and IL-12; and peptide ligands, such as MHC peptides, antigen-specific peptides, or peptide oligomers; o clinical trials of novel approaches to modulate B cell tolerance, including anti-CD19, anti CD22, anti-BlyS, and anti-apoptotic agents; o immune ablation with or without reconstitution with hematopoietic stem cell or bone marrow transplantation for treatment of autoimmune disease; determination of course of development of tolerance and/or immunity, the cells that are necessary for tolerance induction, and the role of chimerism; o relationship of response to therapy and various parameters: stage of disease, subsets of disease (i.e., relapsing vs. chronic progressive multiple sclerosis), patient characteristics including race, ethnic background, and genetic background, route of administration of agents; o development of new clinically useful agents to modulate the immune response and modification of currently available agents to enhance agonist or antagonist activity, to enhance efficacy, and/or eliminate adverse effects; o determination of the mechanism of action of agents utilized: the role of cytokines, regulatory T cells, accessory cells (including macrophages, NK cells, dendritic cells, and B cells), shifts in T cell subset response, T cell anergy, T cell deletion, or induction of cell death pathways; o mechanisms responsible for tolerance initiation, maintenance, or loss; and o basic hypothesis driven research into mechanisms of self tolerance, the pathogenesis of human autoimmune disease and/or its modulation. MECHANISM OF SUPPORT This RFA will use the NIH Multi-project Cooperative Agreement (U19) mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. The anticipated award date is September 2003. The NIH (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." Essential elements of the multi-project cooperative agreement mechanism also include: (1) a minimum of three interrelated individual research projects organized around a central theme; (2) collaborative efforts and interaction among independent projects and their investigators to achieve a common goal; (3) a single Principal Investigator who will be scientifically and administratively responsible for the group effort; (4) a single applicant institution that will be legally and financially responsible for the use and disposition of funds awarded; and (5) support provided, as necessary, for "Core" resources or facilities, each of which is expected to be utilized by at least two research projects in order to facilitate the research effort. The total project period for applications submitted in response to this RFA may not exceed five years. At this time, the NIAID has not determined whether or how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE The estimate total funds, direct and facilitites and administrative (F & A), available from participating IC(s) for the first year of support of this program are $6.25 million. In fiscal year 2003, the sponsoring institutes intend plan to award 5 new and/or competitive continuation grants in response to this RFA. First year budget requests may not exceed $800,000 total costs for the basic projects and any proposed cores (excludes costs for clinical component). The additional funds of approximately $2.5 million (ACE Clinical Research Fund) will be available to successful applicants to support the clinical components and new clinical trials. Although the financial plans of the IC(s) 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. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution the following characteristics: o Domestic (US) 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 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 Each Autoimmunity Center of Excellence must have a clinical research component, two or more research projects and participate in cooperative and collaborative projects within each Center and among the Centers. For detailed information, see "Cooperative Agreement Terms And Conditions Of Award" and "SPECIAL INSTRUCTIONS FOR COMPLETION OF APPLICATIONS IN RESPONSE TO THIS RFA" below. 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 multiproject cooperative agreement (U19), an "assistance" mechanism rather than an "acquisition" mechanism, in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. 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 Research Coordinator. 1. Monitoring Clinical Studies When clinical studies or trials are a component of the research proposed, NIAID policy requires that studies be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study. Terms and Conditions of Award will be included with awards. NIAID policy was announced in the NIH Guide on February 24, 2000 and is available at: http://grants.nih.gov/grants/guide/notice-files/NOT-AI-00-003.html. The full policy including terms and conditions of award is available at: http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf All investigators proposing clinical research should comply with the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. DATA AND SAFETY MONITORING BOARD. The NIAID will appoint an independent Data and Safety Monitoring Board to monitor the endpoint and safety data for all trials/studies on an ongoing basis, but at least twice a year. This Board is advisory to the Institute staff; feedback is provided to investigators as well. This Board will be funded separately from the Centers. 2. Awardee Rights and Responsibilities Awardees will have primary responsibility for defining the details of the project within the guidelines of the RFA AI-02-006 and for performing the scientific activity, and agree to accept close coordination, cooperation, and participation of the NIAID staff in those aspects of the scientific and technical management of the project described below. Specifically, awardees have primary responsibility as described below. Designation of the Clinical Research Representative and the Basic Research Representative The Clinical Research Representative is the person responsible for the overall management of the clinical research component, including: coordination of the participating Center specialists, whether within a single institution or a consortium of institutions; design and submission of proposed protocols for clinical trials/studies; and implementation, monitoring, and data submission and analysis of clinical trials/studies. This person must be a physician with substantial training and experience in 1) clinical management of one or multiple autoimmune diseases, 2) clinical immunology, and 3) the design, implementation and evaluation of clinical trials. The Basic Research Representative is the person responsible for coordination of the Center's basic research scientists, whether within a single institution or a consortium of institutions, in: development of proposed clinical trials/studies and adjunct basic studies in cooperation with clinicians, conduct of the basic studies in conjunction with ongoing clinical trials/studies; and collaboration and sharing of basic resources and reagents within a Center and with other Centers. The collaboration of clinicians and/or basic scientists from different Centers is highly encouraged based on shared interests and complementary talents. Designation of the Clinical Research Representative and the Basic Research Representative is the responsibility of the Center Principal Investigator, who may serve as either representative, but not both. Steering Committee Membership and Meeting Attendance Each Center Principal Investigator will designate a Clinical Research Representative and a Basic Research Representative to serve as voting members of the Steering Committee and participate in all Committee activities and decisions including, but not limited to, conference calls and special subcommittees as may be necessary. The Steering Committee shall be responsible for determining the frequency of meetings and scheduling the time and location. The Steering committee will establish the procedures for the function of the Centers network, as outlined in section "Steering Committee." Data Coordination and Management Each awardee will be responsible for providing the NIAID with all primary study data for management, quality control and analysis, using procedures and standards determined by the Steering Committee. All data will be available to all awardees. Specific analysis to be performed by NIAID will be directed by the Steering Committee or its designee. The awardees will retain custody of and have primary rights to all data developed under these awards, subject to Government rights of access consistent with HHS and NIH policies. Publication and Presentation of Study Findings Early publication of major findings is encouraged. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of the Autoimmunity Centers of Excellence and NIAID support. Analyses to be performed using collective data from multiple centers will be determined by the Steering Committee. Centers wishing to perform analysis of local data or of single site studies should inform the Steering Committee prior to initiation to avoid duplication. The Steering Committee will establish the procedures and criteria for presentation and publication of data developed within the Centers network. Federally Mandated Regulatory Requirements Each institution participating in the Clinical component of an Autoimmunity Center of Excellence is required to meet DHHS regulations for the protection of human subjects and FDA requirements for the conduct of research using investigational agents. At a minimum, these include: o methods for assuring that each institution at which Autoimmunity Centers of Excellence investigators are conducting clinical studies has registered with the Office of Human Research Protections (OHRP; http://www.hhs.gov/ohrp/) and has a Federalwide Assurance; that study protocols are reviewed and approved by the responsible Institutional Review Board (IRB) prior to patient entry; that active protocols are reviewed at least annually by the IRB, and that amendments are approved by the IRB. o methods for assuring or documenting that each patient, or patient's parent/legal guardian, gives fully informed consent to participation in a research protocol prior to the initiation of the experimental intervention. 3. NIAID Staff Responsibilities NIAID staff assistance will be provided by an NIAID Autoimmunity Research Coordinator, who will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below. Steering Committee Membership and Meeting Attendance The NIAID Autoimmunity Research Coordinator will serve as a voting member of the Steering Committee, will attend all Steering Committee meetings, and will participate in other Committee activities, including, but not limited to, conference calls, subcommittees, and special committees. Monitoring Performance The NIAID Autoimmunity Research Coordinator will provide assistance to the Steering Committee in the development of procedures for monitoring the performance of the clinical trials/studies. This includes participation in periodic on-site monitoring with respect to compliance with protocol specifications, quality control and accuracy of data recording, and accrual. Clinical Data Coordination and Management The NIAID will be responsible for ensuring the provision of centralized data management and coordination assistance, including analysis support. Under the direction of the Steering Committee, the NIAID will provide technical assistance and data management services to the Autoimmunity Centers of Excellence with respect to quality control, uniformity of data collection, management of the collective data base, and data analysis. Publication and Presentation of Clinical Trials/Studies Findings The NIAID Autoimmunity Research Coordinator may contribute, through review, comment, analysis, and/or co-authorship, to reporting results of the clinical studies and trials/studies to the investigator community and other interested scientific and lay organizations. Co-authorship by the NIAID Autoimmunity Research Coordinator will be subject to approval in accordance with the NIH policies regarding staff authorship of publications resulting from extramural awards. NIAID Program Director The NIAID Autoimmunity Research Coordinator, who is an NIAID Program Director, will be responsible for normal programmatic stewardship and monitoring of this award. These duties include: The Government, via the NIAID Program Director, will have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. Information obtained from the data may be used by NIAID staff for the preparation of internal reports on the activities of the clinical trials/studies. However, awardees will retain custody of and have primary rights to all data developed under these awards. Study Materials: The NIAID may negotiate with companies interested in participating in trials or studies. The NIAID may facilitate the appropriate approvals (when necessary) from the Food and Drug Administration with respect to the use of investigational drugs. 4. Collaborative Responsibilities Each clinical and basic component of each Center must be willing to work cooperatively and collaboratively both within their Center and with other Centers. Steering Committee A Steering Committee will be established to serve as the main governing body of the cooperative network. At a minimum, the Steering Committee will be composed of the NIAID Autoimmunity Research Coordinator and two representatives from each of the Centers: one Clinical Research Representative and one Basic Research Representative. Each Basic and Clinical Research Representative will be expected to actively participate in all Steering Committee activities. The Chairperson of the Steering Committee will be selected by the Steering Committee from among the non-Federal members during one of the early meetings of the Committee to be convened by the NIAID Autoimmunity Research Coordinator. All major scientific decisions will be determined by the Steering Committee, with each Clinical Research Representative, Basic Research Representative, and the NIAID Autoimmunity Research Coordinator having one vote. The Committee will meet at least three times during the first 12 months of the program and at least semi-annually thereafter. The Steering Committee will have responsibility for facilitating the conduct of clinical trials/studies and basic research related to these trials/studies, promoting trans-Center collaboration among and between clinical and basic components, analyzing and interpreting Center-wide study data, and establishing procedures for reporting results of Center trials/studies. Proposed protocols for clinical trials/studies to be performed by a single Center or groups of Centers will be submitted to the Steering Committee for review and evaluation. Protocols to be implemented will be selected by the Steering Committee in accordance with criteria and procedures established by the Steering Committee. Timely review and evaluation are expected. After approval, those clinical investigators participating in the trial/study in collaboration with investigators from the basic components who will be performing adjunct basic mechanistic studies will develop detailed protocols. As needed, the Steering Committee may establish subcommittees for special purposes. It is expected that most of the work of the Steering Committee will be performed in these subcommittees. Clinical trials/studies will proceed into the implementation stage only with the concurrence of the Steering Committee and the NIAID Autoimmunity Research Coordinator. The Steering Committee will be responsible for management of the ACE Clinical Research Fund. 5. Arbitration Any disagreement that may arise on scientific or programmatic matters (within the scope of the award) between award recipients and the NIAID may be brought to arbitration. An arbitration panel will be formed to review any scientific or programmatic issue that is significantly restricting progress. This panel will be composed of three members -- one selected by the Steering Committee or by the individual awardee in the event of an individual disagreement, a second member selected by the NIAID, and a third member with expertise in the relevant area and selected by the two prior members. While the decisions of the Arbitration Panel are binding, these special arbitration procedures will in no way affect the awardee's right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, subpart D, and HHS regulations at 45 CFR Part 16. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Elaine Collier, MD Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases 6700-B Rockledge Drive, Room 5135, MSC-7460 Bethesda, MD 20892-7640 Telephone: (301) 496-7104 FAX: (301) 402-2571 E-Mail: ECollier@niaid.nih.gov Beena Akolkar, Ph.D. Program Director, Immunopathogenesis and Genetics of Type 1 Diabetes Division of Diabetes, Endocrinology, and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 681 Bethesda, MD 20892 Phone: 301 594-8812 FAX: 301 480-3503 Email: ba92i@nih.gov o Direct your questions about peer review issues; Priti Mehrotra, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2100, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 435-9369 FAX: (301) 402-2638 E-Mail: pm158b@nih.gov o Direct your questions about financial or grants management matters to: Ann Devine Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2118, MSC-7614 6700-B Rockledge Drive Bethesda, MD 20892-7614 Telephone: (301) 402-5601 Fax: (301) 480-3780 E-mail: ad22x@nih.gov 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: Priti Mehrotra, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room (insert), MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 435-9369 FAX: (301) 402-2638 E-Mail: pm158b@nih.gov 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). The PHS 398 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: Priti Mehrotra, Ph.D. Division of Extramural Affairs National Institute of Allergy and Infectious Diseases Room Number 2100, 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 the receipt date 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. It is highly recommended that the appropriate NIAID program contact be consulted before submitting the letter of intent and during the early stages of preparation of the application. (See program contact under INQUIRIES). 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. For this RFA, the description of each basic project is limited to 25 pages each. The description of the clinical component is also limited to 25 pages. Within the 25 page limit for the clinical component, the description of each proposed clinical trial is limited to not more than 10 pages each. CLINICAL RESEARCH COMPONENT. Each Autoimmunity Center of Excellence application must describe a SINGLE clinical research component that encompasses significant participation by multiple clinical specialists who have access to patient populations in which to conduct clinical trials/studies in autoimmune diseases. This component must include a minimum of three clinical specialties and demonstrate the ability to perform clinical trials/studies in at least three different autoimmune diseases. The clinical component may represent a single institution or a consortium of institutions. Diseases amenable to clinical intervention and of interest to the NIAID include, but are not limited to: systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, type 1 diabetes mellitus, idiopathic thrombocytopenia purpura, inflammatory bowel disease, and scleroderma. Specialists that could participate in the clinical component include, but are not limited to: endocrinologists, neurologists, rheumatologists, gastroenterologists, and hematologists. The multiple specialists in the clinical component must be willing and able to work collaboratively and cooperatively, both within their Center and with clinical and basic components of other Centers to facilitate clinical and adjunct basic studies. The application should include written letters of commitment to this principal. Applications proposing clinical components that do not meet the above criteria concerning the number of clinical specialties represented and available disease populations will be judged non-responsive and returned to the applicant without review. The application for the clinical component should describe the populations of patients available for utilization in clinical trials/studies, and demonstrate the ability to perform clinical trials/studies, including the ability to recruit and retain subjects for at least three different autoimmune diseases. The application should include two proposed clinical trial/study protocols for immune interventions for autoimmune diseases. These protocols should include the rationale for the agent(s) and disease(s) selected, patient population, study design, and primary and secondary outcome measures. These two protocols may utilize the same or different agents, but must intervene on different autoimmune diseases. Award of a Center does not imply that the proposed protocols will be implemented. Since the clinical trials/studies that are ultimately undertaken by the Centers will be selected by the Steering Committee (see TERM AND CONDITIONS OF AWARD), the trials/studies selected for implementation may not be identical to any single protocol submitted in response to this RFA. Funding for clinical components will be contingent upon participation in approved clinical studies or trials. In addition to the two proposed clinical trials/studies submitted with the application, proposals for adjunct basic studies related to these clinical trials/studies should be included in the application. The submitting Center's basic components do not necessarily need to include the expertise to perform these studies, however, the studies must be feasible, i.e., the techniques must be established. BASIC RESEARCH COMPONETS. Each Autoimmunity Center of Excellence application must include TWO or more basic research components. The basic components must be multi-disciplinary, interactive basic or pre-clinical research projects focused on elucidation of the basic mechanisms and pathogenesis of autoimmunity, self tolerance, and/or immune modulation. In addition, the basic research components must have the interest and capability to carry out adjunct basic studies related to clinical trials/studies in the context of an overall Centers' program; work cooperatively with basic and clinical components from their and other Centers; work with clinicians in development of clinical trials/studies; and attend biannual Centers' meetings. These basic research projects may utilize animal models, but must also incorporate basic research in humans. To promote the development of an interactive integrated network, a minimum number of issues need to be addressed in the applications, as outlined below. a. Intra- and Inter-Institutional Arrangements Single institutions or consortia of institutions may submit applications. However, the application must identify a single applicant organization that will be legally and financially responsible and accountable for the use and disposition of funds awarded to the other institutions. The development of Centers, which include multiple institutions and geographic areas, is encouraged when such an institutional arrangement provides the most appropriate mixture of clinical and basic science components. Evidence that the components can work together effectively must be provided in all applications regardless of whether the applicant is a single institution or a consortium of institutions. b. Cooperative and Collaborative Responsibilities Each clinical and basic component of each Center must be willing to work cooperatively and collaboratively both within their Center and with other Centers. The application must indicate commitment/willingness to the collaborative organization, steering committee, and participation of NIAID staff as described in the Cooperative Agreement Terms And Conditions Of Award. The Steering Committee as defined in section entitled "Steering Committee" will be the main governing body of the Centers network and will have responsibility for establishing procedures for the selection of clinical trials/studies and adjunct basic studies to be performed; developing procedures for prioritization of use of samples from patients for basic studies; implementing clear, inclusive, and effective communication among the components of all Centers; establishing procedures for the monitoring of performance and progress of the clinical trials/studies, including accrual, timely submission and quality of data and samples, and conscientious observance of protocol requirements; and instituting procedures for data collection, management, quality control, and reporting results of clinical trials/studies. c. Budgets All costs requested for the proposed basic studies must be included in the application. Requested budgets should include: 1) travel for three one-day Steering Committee meetings during the first 12 months of the program and semiannual Steering Committee meetings thereafter for the Clinical and Basic Research Representatives of each Center; and 2) travel for the Principal Investigator of the Center components to a two-day biannual meeting (usually in Washington, DC area), beginning in the second year. Funding for clinical trials (including basic mechanistic studies associated with that trial) will be provided out of the ACE Clinical Research Fund.The Steering Committee must approve all clinical trials and will administer the ACE clinical research fund. 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 Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIAID. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIAID in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique 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 second level review by the National Advisory Allergy and Infectious Diseases Council. REVIEW CRITERIA 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 In addition, the following review criteria specific to this RFA will be used in evaluation of applications: o the scientific and clinical expertise of the Principal Investigator, Project Leaders, and key personnel; o a documented commitment to the clinical and basic study of multiple autoimmune diseases by the investigators and their institutions; o willingness to work cooperatively and collaboratively both within the proposed Center and with other Centers and to accept the participation and assistance of the NIAID staff in accordance with the guidelines outlined under "Terms and Condidtions of Award." ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data. o 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: September 17, 2002 Application Receipt Date: October 16, 2002 Scientific Review Date: February 12, 2003 Advisory Council Date: May 29, 2003 Earliest Date of Award: September 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm 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 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 PA 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 in the following citations: No. 93.855, Immunology, Allergy, and Transplantation Research, No. 93.847, Diabetes, Endocrinology, and Metabolism Research, and . 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. 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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