Full Text AI-94-026 STRATEGIC PROGRAM FOR INNOVATIVE RESEARCH ON AIDS TREATMENT NIH GUIDE, Volume 23, Number 25, July 1, 1994 RFA: AI-94-026 P.T. 34 Keywords: AIDS 0765014 Immunotherapy Viral Studies (Virology) National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: September 20, 1994 Application Receipt Date: December 8, 1994 PURPOSE The Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID), invites applications for participation in the Strategic Program for Innovative Research on AIDS Treatment (SPIRAT). The objective of this Request for Applications (RFA) is to support innovative, integrated preclinical and clinical research to validate clinical therapeutic concepts for the treatment of HIV-1 infection. Applications in response to this RFA can emphasize research activities involving viral gene(s) or cellular factors required for HIV expression, novel immunotherapeutic approaches, or other approaches with the potential for effective therapy and disease modulation. Studies supported by this RFA may have greater conceptual risk than currently exercised for treating HIV-infected individuals, but are also expected to have greater potential for effective, long-term therapeutic returns. The SPIRAT program thus complements existing, more conservative preclinical and clinical programs for the treatment of HIV infection managed by the Division of AIDS/NIAID [National Cooperative Drug Discovery Groups for the Treatment of HIV Infection (NCDDG-HIV), AIDS Clinical Trial Groups (ACTG), DAIDS Treatment Research Initiative (DATRI), Community Program for Clinical Research on AIDS (CPCRA)]. Studies of therapies based on anti-HIV drugs or on opportunistic pathogens associated with AIDS are supported by other NIAID programs and are excluded from this RFA. Each SPIRAT will form an interdependent collaborative enterprise between preclinical and clinical scientists in the conceptualization and proof-of-concept of an identified therapeutic strategy. This will entail tightly coupled iterative research and data exchange between preclinical and clinical studies in order to maximally refine and improve the therapeutic concept. The Group must, therefore, possess the expertise necessary to (1) evaluate the proposed strategy in preclinical systems, and (2) conduct pilot clinical study(ies) in HIV-infected individuals (and uninfected volunteers, as appropriate) using the proposed therapeutic approach. Information derived from pilot clinical studies will feed into preclinical studies to further refine/revise the therapeutic approach. A SPIRAT must be dedicated to the expedited transition of advanced preclinical findings to applied clinical setting in HIV-infected individuals. Applications not proposing pilot clinical study(ies) will not be considered responsive and will be returned to the applicant without further review. A SPIRAT is encouraged to include investigators from academic, non-profit, and commercial (pharmaceutical, chemical, or biotechnological companies) organizations. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Strategic Program for Innovative Research on AIDS Treatment (SPIRAT), is related to the priority area of HIV infection. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, private and public, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Applications from minority individuals and women are encouraged. Applications from foreign institutions will be considered. Prospective foreign applicants should contact Dr. Nava Sarver at the address under INQUIRIES for additional details. MECHANISM OF SUPPORT The administrative and funding mechanism to be used to undertake this program will be the 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. Essential elements of the U19 mechanism include: (1) a minimum of three interrelated research projects organized around a central theme for the duration of the proposed study; (2) collaborative efforts and interaction among independent projects and their investigators to achieve a common goal; (3) one Principal Investigator who will be scientifically and financially responsible for the use and disposition of funds awarded; and (4) 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 overall research activities of the Group's effort. 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. Details of the responsibilities, relationships, and governance of a study funded under cooperative agreement(s) are discussed later in this document under the section Terms and Conditions of Award. The total project period for applications submitted in response to the present RFA may not exceed four years. The anticipated award date is August, 1995. At this time, the NIAID has not determined whether or how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE The estimated total funds (direct and indirect costs) available for the first year of support for awards under this RFA reissuance will be $2.5 millon; estimated total project costs (direct and indirect) over the four-year period will be $10.6 millon. In Fiscal Year 1995, two to three new awards are anticipated for project periods up to four years. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of individual awards will vary also. Awards are subject to a first year limit of $1.3 millon in total costs (direct plus indirect costs). Budget requests should be carefully justified and commensurate with the complexity of the project. Applications in excess of $1.3 million first year total cost will be returned without review. Although this program is provided for in the financial plans of the NIAID, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. The usual PHS policies governing grant administration and management will apply. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and availability of funds. In addition, recommended support beyond the second year of each SPIRAT is subject to determination by an external ad hoc review committee, convened by the NIAID, that stated goals (milestones) have been sufficiently met. The committee will evaluate: (1) accomplishment in executing the proposed studies as outlined in the research proposal; (2) preclinical achievements including quality and substance of findings; transition of such studies to clinical research; and (3) initiation of a clinical pilot study. The committee's recommendation resulting from the second year review will be used by NIAID staff to determine which groups will continue to be funded beyond two years for the full term of the award. It is noted that the NIAID's ad hoc committee is distinct from the Group's Scientific Advisory Panel (see DEFINITIONS). RESEARCH OBJECTIVES 1. Background The NIAID and the PHS are currently supporting comprehensive extramural and intramural projects for the study of the etiology, natural history, and demographics of AIDS; determining means of diminishing the risk of infection; screening of high risk individuals; developing prophylactic vaccines; developing therapies that may be useful chemopreventive or prophylactic agents; and developing therapies to treat those with all stages of HIV disease. Notwithstanding these efforts, effective, long-term therapies are lacking, and the number of HIV-infected individuals and AIDS cases is increasing. As of December 31, 1993, 361,509 cases of AIDS had been reported in the U.S. by the Centers for Disease Control (CDC) and more than 220,871 of these patients (60 percent) had died. Recent estimates indicate that 1,000,000 to 1,200,000 individuals in the U.S. are infected with HIV. The World Health Organization projection of worldwide HIV infection is placed at 30 to 40 million individuals by the year 2000. While significant advances in the biology and pathogenesis of HIV disease have been made, the disease, which is associated with severe immune dysfunction, remains intransigent. Currently FDA-approved therapies for HIV infection are associated with toxic side effects and emergence of HIV drug-resistant variants that preclude long term use. Moreover, no treatment has been identified to eradicate or curb HIV infection for extended time, and the disease is presently considered fatal. Given the emergence of reverse transcriptase and protease drug-resistant variants, it is expected that resistance to inhibitors directed against other viral targets will occur. The search for more effective and innovative therapies that may be less susceptible to the emergence of resistant HIV variants, is one of the highest priorities of the NIAID. In recent years, the base of scientific information on HIV has expanded and the number of technological breakthroughs has increased significantly; however, the translation of that knowledge to clinical and preventive activities has not been commensurate with this expansion. There is a need to apply these research advances to clinical research studies, an effort that requires tightly coupled research activities between preclinical and clinical investigators in the planning and implementation of studies whose ultimate goal is an effective clinical therapy for HIV-positive individuals. Significant scientific and clinical expertise exists throughout the country. A concerted effort to mobilize this expertise through SPIRAT can accelerate advances in the management, and ultimately the effective treatment, of the disease. The SPIRAT program, launched in 1993, is specifically designed to support refinement and proof-of-concept of innovative molecular intervention and immunotherapy strategies for the treatment of HIV infection. The SPIRAT program complements and balances present efforts pursued under existing NIAID programs, including the AIDS Clinical Trial Groups (ACTG), the Division of AIDS Treatment Research Initiative (DATRI), the National Cooperative Drug Discovery Groups for the Treatment of HIV Infection (NCDDG-HIV). Specifically excluded from this RFA are studies on anti-viral drugs, therapies involving the use of monoclonal antibodies, and opportunistic infections associated with AIDS. These efforts are supported by other NIAID programs. 2. Research Objectives and Scope The principal goals of this RFA are to (1) tightly couple innovative preclinical research with clinical proof-of concept; and (2) implement pilot clinical studies of a therapeutic strategy in HIV-infected individuals. In line with this objective, applicants for SPIRAT funding will already have an identified strategy that is based on creative and solid scientific rationale, and for which advanced preclinical data exist. Efforts are to be implemented through concerted and interdependent activities by components constituting the group. Each SPIRAT group will have a well-defined central research focus consistent with the research objectives of the Program as stated in the RFA. A SPIRAT application can focus its preclinical and clinical research activities on strategies directed against a viral gene or cellular component(s) required for HIV expression, pathogenic mechanisms of disease, novel cell-based immunotherapeutic approaches, or other pioneering approaches. (Studies involving traditional anti-HIV drugs or opportunistic pathogens associated with AIDS are not supported by this RFA.) The following approaches are provided as examples and are not intended to be inclusive or restrictive: o Strategies that target HIV gene expression via interference with HIV cis-acting elements, viral regulatory elements, viral structural components, or cellular factors required for HIV expression; strategies that interrupt steps in HIV/cell interaction (entry, subcellular transport, assembly/release); novel approaches unlikely to be compromised by emergence of escape or resistant HIV variants; o Strategies that integrate current understanding of HIV accessory proteins into a targeted therapeutic approach; o Intracellular delivery of genetic antagonists to curb pivotal events in HIV life cycle (protein-based suppressors, molecular competitors, RNA decoys, ribozymes) using ex vivo and in vivo delivery strategies; o Immune system reconstitution, including infusion of genetically modified lymphocytes, hematopoietic stem cells, xenogeneic transplantation (e.g., bone marrow, thymic); o Strategies that target non-T cells (e.g., dendritic cells, follicular dendritic cells, monocyte/macrophage, epithelial) believed to play an essential role in cell-free virus transport, trapping, cell-cell transmission, and general dissemination of HIV in the body; o Genetic immunization to augment immune response(s) via intracellular expression of HIV immunogen(s); o Cell or tissue based approaches designed to modulate or curtail the pathogenic course of infection; o Strategies that target the central nervous system and have the potential to prevent or reverse AIDS-related neurologic dysfunction and dementia o Innovative therapeutic strategies that specifically address pediatric HIV disease and pathogenesis. 3. Study components Studies will involve advanced preclinical refinements of the proposed strategy, evaluation and demonstration of therapeutic or immune benefit in laboratory animals, as appropriate, and implementation of pilot clinical studies in HIV-infected individuals. (1) Animal studies: Projects or cores with proposed animal models must be integrated with and required to attain the Group's objectives. Funds awarded for animal models will not be made available until the therapeutic strategy is ready for animal efficacy studies. Due to budgetary limitations, primate animal models should not be requested in the original application unless they constitute a necessary, integral component of the proposal. Requests for assistance in evaluation studies in primate animals may also be directed to the NIAID for consideration in conducting such studies in its primate model resources. The availability of these models will depend on the nature of the therapeutic approach. In all other cases, should the need for such models become evident during the course of studies under this cooperative agreement, the Principal Investigator may submit a competitive supplement request for the support of primate animal models. Funding of competitive supplements will be from set-aside funds allocated to future RFAs for this initiative, and is not guaranteed. Consideration for funding will also depend on the competitive merit and justification of the competitive supplement relative to all other competing applications submitted in response to the RFA. (2) IND-related studies: Studies required for the IND-targeted preclinical development (formulation, toxicology) of proposed treatments are generally beyond the scope of this RFA, but such development through private venture capital is encouraged. Alternatively, a Group may request that the NIH assist in these developmental tasks using existing NIH/NIAID contract resources (see below). (3) Clinical studies: Pilot clinical studies must commence within two years of funding. Funds awarded for the clinical components of the SPIRAT application will not be available until the therapeutic strategy is ready to enter clinical phase. Only pilot clinical studies with limited number of patients (6 to 12) will be supported under this program. The NIAID has several programs for clinical evaluation of therapies for HIV/AIDS. These include the AIDS Clinical Treatment Units (ACTUs) for large phase I, Phase II, and Phase III clinical studies, and DATRI. It is envisioned that extended clinical studies of treatments developed by a SPIRAT group can be accommodated under the clinical trial mechanisms available through Division of AIDS. Queries about these programs should be directed to Dr. Nava Sarver, NIAID, address listed under INQUIRIES. SPECIAL REQUIREMENTS A. Minimum Requirements for SPIRAT Application Applicants for SPIRAT funding must have an identified therapeutic strategy that is proposed for pilot clinical evaluation, and for which advanced preclinical data already exist. The proposed strategy must be sufficiently advanced to permit initiation of pilot clinical studies within two years of funding. The proposed strategy must, therefore, identify provisions for tightly coupled and continuous flow of data between its preclinical and clinical components. All applications must consist of at least three interrelated and interdependent projects focusing on a unifying central theme conducted by at least three independent laboratories. For the purpose of encouraging new collaborations under this RFA, two (or more) projects within a single company will not be considered independent. Similarly, two (or more) projects within the same academic department will not be considered independent. This limitation on the number of independent projects from the same academic or private sector organization is intended to increase the diversity and multi-disciplinary expertise available to the Group from other than the parent institution or organization. A minimum 20 percent (time) effort by the Principal Investigator and each Project Leader should be devoted to the study. Applications with less than 20 percent efforts for the Principal Investigator and each Project Leader, and that do not offer compelling arguments for failing to comply with the 20 percent requirement, will be considered non-responsive and will be returned to the applicant without review. B. Definitions ADMINISTRATIVE CORE: An administrative facility that provides central operations and support for the overall management of the cooperative agreement and services shared by the Group as a whole. The Administrative Core should have a budget separate from that of the Principal Investigator's research project, but should be administered by the Principal Investigator's organization. The Administrative Core will have in its budget for each year travel costs for (1) two required meetings of individual members of the Group; (2) one meeting of representative of all Groups in the SPIRAT program; and (3) travel expenses for the Scientific Advisory Panel (see below). The Administrative Core will be responsible for allocating required travel expenses to appropriate members of the Group. Only SPIRAT-related travel will be supported under this RFA; travel funds to other domestic or foreign meetings is not provided under this RFA. (For additional details of required travel see SPECIAL REQUIREMENTS - TERMS AND CONDITIONS OF AWARD: C. Awardee's Rights and Responsibilities.) ARBITRATION PANEL: An NIAID-convened ad hoc panel that is formed to review scientific or programmatic activity that is impeding progress within a Group. It will be composed of a "Group" designee, one NIAID designee, and a third designee with expertise in the relevant area and chosen by the other two. The Arbitration Panel may help resolve both scientific and programmatic issues that develop during the course of work that restrict progress. COOPERATIVE AGREEMENT: An assistance mechanism in which substantial NIAID programmatic involvement is anticipated with the recipient organization during the performance of the planned activity. CORE LEADER: The leader of one of the Scientific or Administrative Cores of the SPIRAT. INVENTION: An innovative therapeutic approach that is or may be patentable under Title 35 of the United States Code. NIAID SPIRAT PROGRAM DIRECTOR: A Senior Scientist of the NIAID extramural staff who coordinates NIAID's participation in the SPIRAT program, oversees the entire SPIRAT program, maintains the overall scientific balance in the SPIRAT program commensurate with new research and therapeutic findings and emerging research opportunities, and who ensures that the SPIRAT program is consistent with the Division of AIDS and NIAID missions and goals. NIAID SCIENTIFIC COORDINATORS: Scientists of the extramural staff of the Division of AIDS, NIAID, who function as peers with the Principal Investigators and Project Leaders and who facilitate the partnership relationship between NIAID and each Group. Two Scientific Coordinators from the Division of AIDS - one from the Basic Research and Development Program, and one from the Clinical Research Program - will be assigned to each Group by the SPIRAT program director. The Scientific Coordinators are the immediate contact persons to the Group. PRINCIPAL INVESTIGATOR: The person who assembles the SPIRAT, is responsible for the performance of the Group as a whole and for that of each of the Project Leaders, and who is responsible for submitting the single application in response to this RFA. The Principal Investigator will coordinate Group activities scientifically and administratively and should preferably be project leader of one of the Research Projects of the Group. The awardee (Principal Investigator's) institution establishes and operates the Central Operations Office that funds Group members and is legally and fiscally accountable for the disposition of funds awarded. PROJECT LEADER: The leader of one of the scientific research projects of the SPIRAT, who is responsible for the scientific conduct of that project. RESEARCH PROJECT: A discrete, specified, circumscribed project that must relate to the overall theme of the SPIRAT. SCIENTIFIC ADVISORY PANEL: A panel, comprised of two to three peers from the scientific community, whose mission is to provide the Principal Investigator with a comprehensive review of the Group's activities and progress, consult on future goals and strategies, and recommend alternative directions, as appropriate. Selection and appointment of the Panel is the responsibility of the Principal Investigator. SCIENTIFIC CORE COMPONENT: Laboratory facilities for equipment and services which are shared by two or more projects of the SPIRAT. Examples of core components are: biochemical, cell-based, virological, and immunological studies; animal model studies; pharmacology/toxicology studies; scale-up synthesis of the therapeutic agent. The core can be defined as a facility laboratory with established techniques and assays which performs a service function resulting in an economy of effort and savings in the overall costs of the Group. A CORE component cannot be considered toward fulfilling the three research projects requirement. The core unit is to be described with the same detail as the research projects to enable evaluation of its scientific merit. (See details for preparation of the budgets under "PREPARATION AND ORGANIZATION OF THE APPLICATION). STRATEGIC PROGRAM FOR INNOVATIVE RESEARCH ON AIDS TREATMENT (SPIRAT): In this RFA the terms STRATEGIC PROGRAM FOR INNOVATIVE RESEARCH ON AIDS TREATMENT (SPIRAT) and "Group" are synonymous. Each Group may consist of a number of scientific investigators from academic and/or non-profit research institutions as well as scientists from commercial organizations, performing research on interdependent projects whose central focus is development of effective clinical therapy for HIV-infected individuals. A CORE component cannot be used toward fulfillment of the three research projects requirement. C. Patent Coverage Because the implementation of innovative, effective clinical therapies for HIV/AIDS is the goal of this effort, and active involvement by private sector laboratories is facilitated by the existence of adequate patent coverage, it is essential that applicants provide plans to assure such coverage. Since several institutions may be involved, complex patent situations may arise. Each applicant Group must, therefore, provide a detailed description of the approach to be used for obtaining patent coverage and for licensing where appropriate, in particular where the invention may involve investigators from more than one institution. In addition each Group must provide a detailed description of the procedures to be followed for the resolution of legal problems that potentially may develop. Attention is drawn to the reporting requirements of 35 U.S.C. Parts 200-212 and 37 CFR Part 401 or FAR 55.227-11. Instructions were also published in the NIH GUIDE FOR GRANTS AND CONTRACTS, Vol. 19, No. 23, June 22, 1990. Note that non-profit organizations (including universities) and small business firms retain the rights to any patent resulting from Government contracts, grants or Cooperative Agreements. It is also noted that a Presidential memorandum of February 18, 1983 extended to all business concerns, regardless of size, the first option to the ownership of rights to inventions as provided in P.L. 96-517. As a result of this memorandum, the relationships among industrial organizations and other participants are simplified, since all Group members can now be full partners in the research and in any inventions resulting therefrom. The specific patenting arrangements among the institutions may vary, and could include joint patent ownership, exclusive licensing arrangements, etc. Applicants are encouraged to develop an arrangement that is most suitable for their own particular circumstances. The proposed patent plan among the institutions comprising the Group must be submitted with the application. This patent agreement, signed and dated by the organizational officials authorized to enter into patent arrangements for each Group member and member institution, must be delivered two weeks prior to submission of the application to Dr. Nava Sarver, Targeted Drug Discovery Section, Developmental Therapeutics Branch, Division of AIDS, NIAID, Solar Building Room 2C-11, 6003 Executive Boulevard, Bethesda, MD 20892. (For express mail or courier services, the address is Rockville, MD 20852.) Should the Group wish to place all inventions and discoveries resulting from these studies within the public domain, a letter to that effect must be submitted to Dr. Sarver in lieu of the patent agreement two weeks prior to submission of the application. The letter must be co-signed by the Principal Investigator, each of the Project Leaders, and each of the business officials representing the respective institutions. Federal regulation clause 37 CFR 401 and HHS Inventions regulations at 45 CFR Parts 6 and 8 require that NIH be informed of inventions and licensing occurring under NIH funded research. Invention and licensing reports must be submitted to Extramural Invention Reports office, Office of Extramural Research, Building 31, Room 5B41, NIH, 9000 Rockville Pike, Bethesda, Maryland 20892. D. 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. The following 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 [Part 92 is applicable when State and local Governments are eligible to apply], and other HHS, PHS, and NIH grant administration policies. The administrative and funding instrument used for this program is the 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. The U19 must contain a minimum of three interrelated research projects organized around a central theme. A Core resource or facility must be utilized by at least two research projects. 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 awardee(s) for the project as a whole, although specific tasks and activities in carrying out the study will be shared among the awardees and the NIAID Scientific Coordinator. 1. Awardee Rights and Responsibilities Awardees will have primary responsibility for defining the details for the project within the guidelines of the RFA and for performing the scientific activity, and agree to accept close coordination, cooperation, and participation of NIAID staff in those aspects of scientific and technical management of the project as described under "NIAID Staff Responsibilities". Specifically, awardees have primary responsibilities as described below: a. Meetings Two Group meetings are required per year. The Principal Investigator and Project Leaders of the Group, and one or both of the NIAID Scientific Coordinators, will meet twice per year to review progress, plan and design research activities, and establish priorities within the Group. The Principal Investigator will be responsible for scheduling the time and place (generally at one of the performance sites), notifying the NIAID at least 30 days prior to the meeting date, and preparing concise (3 to 4 pages) minutes or a summary, which will be delivered to members of the group, including the Scientific Coordinator, within 30 days after the meeting. NIAID staff will participate, but not chair Group meetings. One mandatory meeting of the entire SPIRAT program will be held each year (SPIRAT program annual meeting) at a site designated by the NIAID (usually the Washington DC vicinity) during which the Principal Investigators and Project Leaders of all the Groups will present significant findings and progress in symposium format. The NIAID SPIRAT program director will consult with the Groups' key personnel in formulating the overall agenda and in identifying key topics for discussion, with specific focus on inter-Group interaction and sharing information of general importance to the implementation of clinical studies. It is expected that NIH staff, members of established committees and advisory boards, and others active in the clinical application of innovative therapies for HIV/AIDS will also be invited. Applicants should include requests for travel funds specifically for and restricted to the above meetings when they prepare their budgets. Funds to cover operating costs of the SPIRAT program annual meeting may be contributed by one or more Groups; NIAID will provide administrative supplements for this purpose, as needed. This RFA will support only SPIRAT-related travel as specified above; no additional travel funds will be provided to attend other domestic or foreign scientific meetings under this RFA. b. Group's scientific advisory panel Each Group will designate a Scientific Advisory Panel of two to three investigators within six months of funding. The Panel will attend one or more of the Group's meetings. The Scientific Coordinator(s) will participate in all meetings of the Panel. The Panel will review the Groups's activities and advise the Principal Investigator on the Group's progress, timeliness of progress in individual projects relative to original projections, continued relevance of a given project to Group's goals, and recommendations for new directions, as appropriate. The Panel will provide the Principal Investigator with a comprehensive written review of the Group's activity in each year of funding, as specified under DEFINITIONS: SCIENTIFIC ADVISORY PANEL. A copy of the Panel's report will be submitted to the NIAID as a supplement to the annual progress report, or within 30 days of the report, whichever is earlier. Members of the Panel will not be affiliated with any of the institutions comprising the Group. c. Annual Progress Report The Progress Report must include basic information as instructed with PHS 2590 Noncompeting Continuation Application forms. In addition, each Progress Report must include a brief section outlining intra-Group interactions that have augmented activities, citing specific occurrences (e.g., construct X was made under Project 1 and transferred to Project 2 for clinical evaluation). Inter-Group collaboration with other SPIRATs should be specified, where applicable. Interaction with the Scientific Coordinator and the NIAID during the reporting period should be described. d. Publications and Presentation of Findings Early publication of major findings is encouraged. The Principal Investigator will be responsible for the timely submission to the Scientific Coordinator of all abstracts, manuscripts, and reviews (co)authored by members of the Group and supported in part or in total under this Agreement. The Principal Investigator and Project Leaders are requested to submit manuscripts to the Scientific Coordinator within three weeks of acceptance for publication so that an up-to-date summary of program accomplishments can be maintained. Publications or oral presentations of work done under this Agreement are the responsibility of the Principal Investigator and appropriate Project Leader. All publications (abstracts, peer reviewed manuscripts, reviews) and oral presentations of work supported in part or in total by the SPIRAT cooperative agreement must be acknowledged as part of the presentation and will include the mechanism, cooperative agreement number and Institute, for example, "This work was supported in whole (or in part) by the SPIRAT program, cooperative agreement number U19-AI-12345, NIAID." e. Rights to data While the NIAID Scientific Coordinator has a right of access to the data, the applicant will retain custody of and rights to the data. Information obtained from the data may be used by the Scientific Coordinator for the preparation of internal reports on the Group's activities. 2. NIAID Staff Responsibilities The NIAID shall participate as a member of the Group and shall be represented by a Scientific Coordinator(s) or the SPIRAT program director. The Scientific Coordinator(s) shall be selected from the Division of AIDS, which is an extramural programs of the NIAID. The NIAID Scientific Coordinator(s) will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination such as participating in the design of Group activities, advising in the selection of sources or resources, coordinating or participating in collection and/or analysis of data, advising in management and technical performance, or participating in the preparation of publications. However, the role of NIAID will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus of the Group and that NIAID staff will be given the opportunity to offer input to this process. The manner of reaching this consensus and the final decision-making authority will rest with the Principal Investigator. Examples of potential assistance to the Group include: (1) provision of needed resources and information that otherwise may not be available to the Group (e.g., reference compounds for standardization of test systems or as analytical standards); (2) testing in NIAID contract laboratories when the occasional need arises and when the main research activities of the Group do not require these resources on a regular basis (e.g., biochemical, cell-based assay, and animal model studies). On occasion, and under mutual agreements, NIAID may arrange for limited preclinical evaluations at other SPIRAT sites. The requesting Group is expected to provide sufficient material for such testing. Groups whose experimental approach involves studies that require testing in animals on a regular basis must budget for costs to be paid from award funding; (3) information concerning work conducted in other NIAID-supported extramural projects in order to reduce or prevent duplication of efforts; (4) further evaluation of the therapeutic strategy under a larger phase I clinical trial be conducted under other NIAID's sponsored clinical programs The NIAID will retain the option to cross-file or independently file an application for investigational clinical trial; e.g., an Investigational New Drug (IND) application to the United States Food and Drug Administration of any invention resulting from these NIAID-supported Cooperative Agreements. Reports of data generated by the Group or any of its members required for inclusion in INDs and Clinical Brochures and for cross-filing purposes will be submitted by the Principal Investigator to the Scientific Coordinator upon request. Such reports will be in final draft form and include background information, methods, results, and conclusions. They will be subject to approval and revision by NIAID and may be augmented with test results from other Government-sponsored projects prior to submission to the appropriate regulatory agency. The principal end product of SPIRAT activities will be the development of an innovative, effective clinical therapy for HIV/AIDS. Preclinical and clinical development through private sources is encouraged. Alternatively, the Group may request that further clinical studies be sponsored by NIAID. In this case, it will be necessary for the Principal Investigator, appropriate Project Leaders and the NIAID Scientific Coordinators to collaborate in the analysis, summary preparation, and subsequent presentation of data to the Division of AIDS and other NIAID staff and NIAID advisory committees, such as the AIDS Clinical Drug Development Committee (ACDDC), DATRI Executive Group, or AIDS Research Advisory Committee (ARAC). The NIAID has several programs for clinical evaluation of therapies for HIV/AIDS. These include the AIDS Clinical Treatment Units (ACTUs) for large phase I, Phase II, and Phase III clinical studies, and DATRI. It is envisioned that extended clinical studies of treatments developed by SPIRAT groups can be accommodated under the clinical trial mechanisms available through Division of AIDS. Queries about these programs should be directed to Dr. Nava Sarver, NIAID, address listed under INQUIRIES. It is understood that the Government supports studies in the interest of promoting the transition of effective, innovative therapies to the clinic, and that identified therapies that have been derived via government support mechanisms will be offered to the public at reasonable costs. 3. Arbitration Process Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIAID may be brought to arbitration. An arbitration panel will be composed of three members - one Group designee, one NIAID designee, and a third designee with expertise in the relevant area and chosen by the other two. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. STUDY POPULATIONS INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 9, 1994 (FR 59 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by September 20, 1994, a letter of intent that includes a descriptive title of the overall proposed research, the name, address and telephone number of the Principal Investigator, the number and title of this RFA, and a list of the key investigators and their institution(s) and projects. Although the letter of intent is not required, is not binding, does not commit the sender to submit an application, and does not enter into the review of subsequent applications, the information that it contains allows NIAID staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Dianne Tingley at the address listed under INQUIRIES. APPLICATION PROCEDURES Applications are to be submitted on the standard research grant application form PHS 398 (rev. 9/91). For purposes of identification and processing, item 2a on the face page of the application must be marked "YES" and the RFA number and the words "STRATEGIC PROGRAM FOR INNOVATIVE RESEARCH ON AIDS TREATMENT (SPIRAT)" must be typed in. Applications must be received by December 8, 1994. Applications from multi-component consortia must contain a single face page, an overall budget page, and separate budget pages for each institution involved. Each consortium institution is allowed 25 pages for the research plan if different plans are proposed by the different member institutions. Because of the multi-institutional nature of and the special requirements in this RFA, additional instructions regarding format are contained in NIAID POLICY ON MULTIPROJECT APPLICATIONS (PROGRAM PROJECT GRANTS AND MULTIPROJECT COOPERATIVE AGREEMENTS), which is included with this package and is also available from the program staff listed under INQUIRIES. If a conflict exists between instructions as presented in the program policy guidelines and this RFA, this RFA takes precedence. The instruction that follow are in addition to and not in lieu of instructions contained in the "NIAID PROGRAM PROJECT GRANTS AND MULTIPROJECT COOPERATIVE AGREEMENTS." The application forms may be obtained from the institution's office of sponsored research or its equivalent and from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone (301) 710-0267. Applications must address the requirements below as outlined in the section "SPECIAL REQUIREMENTS: Minimum Requirements for Application." A. Composition of First Section of the Application 1. The application must provide: a clear and concise plan - in narrative and diagrammatic form - that depicts the interrelationships among the members of the SPIRAT Group, their relevant experience/expertise, and the contribution of each to fulfillment of the objectives and scope of this RFA; an organizational chart of the SPIRAT Group showing the name, organization, and scientific discipline of the PI and of all key scientific, technical and administrative personnel; and a mechanism for selecting and replacing key professional or technical personnel. 2. Applications are to provide a plan to ensure maintenance of close collaboration and effective communication among members of the Group. The application should include plans for scheduling Group meetings, notifying Group members including the NIAID Scientific Coordinator, and documenting and disseminating Group meeting proceedings. 3. The application must include a written commitment to accept the participation and assistance of NIAID Scientific Coordinators in accordance with the guidelines outlined under "Terms and Conditions of Award: NIAID Staff Responsibilities." 4. Applications are to provide a rationale for the innovative therapeutic strategy proposed and the body of preclinical data in support of this approach. 5. Applications should present the anticipated unique advantages to be expected from the Group operating within the proposed collaborative efforts, how the projects are mutually reinforcing, and how collectively they will further the stated goals of the proposed research. B. Organizational and Administrative Structure of the SPIRAT The application should describe in detail - in narrative and diagrammatic form - the chain of responsibility for decision-making and administration starting at the level of the Principal Investigator and including the different research Project Leaders and other investigators. This description should indicate where in the chain of responsibility will the advisory group be used and its role in contributing to the quality and caliber of the research efforts. C. Consortium Arrangements An application that includes research activity involving institutions other than the sponsoring organization is considered a consortium effort. It is imperative that care be taken in preparing any consortium application so that the programmatic, fiscal, and administrative considerations are fully explained. The policy governing consortia is described in the NIH Guide for grants and Contracts (Vol. 14, No. 7, June 21, 1985), which should be available at the sponsoring institution's office of sponsored research, or in the Office of Grants Information publication entitled "Guidelines for Establishing and Operating Consortium Grants", January 1989, which may be obtained by calling (301) 710-0267. D. Patent Coverage Agreement 1. The application should provide a description of the Group's plan for assuring adequate patent coverage of new inventions that may arise as a result of Government funding of this U19. "Invention" is defined as a new drug or innovative treatment that is or may be patentable under Title 35 of the United States Code. A copy of the proposed patent plan among the institutions comprising the Group must be submitted with the application. The original patent agreement, signed and dated by the organizational officials authorized to enter into patent arrangements for each Group member and member institution, must be delivered two weeks prior to submission of the application to Dr. Nava Sarver at the address listed under INQUIRIES. 2. Should the Group wish to place all inventions and discoveries resulting from these studies within the public domain, a letter to that effect must be submitted to Dr. Sarver in lieu of the patent agreement prior to submission of the application. The letter must be co-signed by the Principal Investigator, Project Leaders, and each of the business officials representing the respective institutions. E. Individual Research Projects 1. The strength of the complete application package will be judged mainly on the basis of the quality of each research project. Reviewers will expect each project to be described in the same detail as for a regular research grant application to enable the reviewers to judge the technical and scientific merit solely on the basis of the written applications. 2. The portion of the application for each component research project should be prepared in the same manner as an R01 application, following carefully the instructions found in the grant application form PHS 398 (rev. 9/91). F. Scientific Core Support 1. The application should describe the role and importance of the core as a resource to the SPIRAT as a whole and the specific service(s) such core support will provide and the projects it will serve. The facilities, techniques, and professional skills that the core will provide should be described. The role of the Core Leader and each of the key participants should be described. The portion of the application describing each scientific core should be prepared with the same level of detail as an R01 application in order for the technical merit and appropriateness of each core to be evaluated. 2. Core support may be provided as consortia if performed at institutions different from that of the Principal Investigator. 3. The budget for each scientific core should be presented according to the instructions of the form PHS 398 (rev. 9/91); see also NIAID POLICY ON MULTIPROJECT APPLICATIONS (PROGRAM PROJECT GRANTS AND MULTIPROJECT COOPERATIVE AGREEMENTS). It is highly recommended that Dr. Nava Sarver, Chief, Targeted Drug Discovery Section, Division of AIDS, NIAID, be contacted in the early stages of preparation of the application. (See program contact in INQUIRIES below.) All components, subparts and sections of the application must be collated into the complete application, and the packages sent to the Division of Research Grants (DRG) and to the NIAID must each be complete in themselves. Applications that are not received as a single package from the Principal Investigator and that do not conform to the instructions contained in PHS 398 (rev. 9/91) applications kit will be returned to the applicant. The RFA label in the application form PHS 398 must be affixed to the bottom of the face page of the application. 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 2a of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the checklist; and three signed, exact, single-spaced photocopies in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, also submit two additional exact copies of the application, and five sets of the appendix and reprints directly to Dr. Dianne Tingley at the address listed under INQUIRIES. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or Principal Investigator should be included with the application. Applicants from an institution receiving government funds under General Clinical Research Center (GCRC), Center for AIDS Research (CFAR), AIDS Clinical Trial Unit (ACTU), AIDS Vaccine Evaluation Unit (AVEU), DATRI, and CPCRA programs, should describe how these programs are integrated with the proposed studies, and ensure that no scientific and budget overlap exists with the SPIRAT proposal. Applications must be received by December 8, 1994. If an application is received after that date, it will be returned to the applicant without review. The DRG 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 DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS A. General Considerations Upon receipt, applications will be reviewed for completeness by DRG and responsiveness by the NIAID. Incomplete applications will be returned to the applicant without further consideration. If NIAID staff find that the application is not responsive to the RFA, it will be returned without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAID in accordance with the review criteria stated below. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the principal investigator/program director and the official signing for the applicant organization will be promptly notified. The second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council. All applications will be judged on the basis of the scientific and technical merit of the proposed projects and the documented ability of the investigators to meet the RESEARCH OBJECTIVES of the RFA. Applications with first year total costs (direct and indirect) in excess of $1.3 millon will be returned without review. Applications will also be reviewed for minimum requirement described in the SPIRAT RFA. Those not meeting all the requirements will be considered not responsive and will be returned without further review. B. Review Criteria Scientific Considerations The application must be directed toward attaining the programmatic goals as stated under RESEARCH OBJECTIVES. The following criteria will be used by peer review groups to evaluate these applications: 1. The scientific and technical merit of the application as a whole and of each individual research project and core component. Emphasis will be placed on the innovative aspect and uniqueness of the proposed therapeutic strategy, and on the caliber of the preclinical and clinical activities described to realize the overall objective. Each project must be supportable on its own merit; 2. The likelihood that innovative preclinical therapeutic strategies will be refined and pilot clinical research implemented within two years of award date; 3. Demonstration of experience in the planning, design, and conduct of clinical research with a small number (6 to 12) of HIV-infected individuals (in-patient and out-patient). Relevant prior experience should be noted. The plan for clinical data management and adverse event reporting (AER) should be described; 4. The cohesiveness, multi-disciplinary and multifaceted scope of the program and the coordination and interdependence of the individual projects and core(s); plans for effective intra-Group communication and for assuring cohesiveness within the Group as a whole; 5. The justification for, and usefulness to the various research projects of the core facilities. The relationship of each core to the central focus of the overall program. Each core unit must provide essential facilities or service for two or more approved individual research projects; 6. The leadership, scientific ability, and administrative competence of the Principal Investigator for the development, implementation, and management of a comprehensive preclinical and clinical research program; and the Principal Investigator's commitment to devote substantial time and effort to the program; 7. The qualifications, experience, and commitment of the investigators responsible for the individual research projects or core(s) (Project Leaders) and their contribution to the program, including their ability to devote adequate time and effort to the Group. It is anticipated that, due to the complexity and time required to maintain a well-coordinated and productive research effort, a minimum 20 percent (time) effort by the Principal Investigator and each Project Leader should be devoted to the study, unless there are compelling arguments to the contrary; 8. Research training, experience and accomplishments of other participating investigators and support personnel in the Group in the research areas outlined in the RFA; 9. Provisions for the protection of human subjects and the humane care of animals; adequacy of biohazard containment facilities; 10. Adequate representation of women and/or minorities in clinical research populations; Administrative considerations 1. The academic, clinical, and physical environment in which the research will be conducted, including the adequacy of space, equipment, animal facilities, biohazard containment facilities; access to HIV/AIDS patient care; and the potential for interaction with active scientists from other departments and/or institutions in relevant disciplines including infectious diseases, virology, molecular biology, immunology, gene therapy, hematology. The availability of a GCRC (General Clinical Research Center) should be noted. The responsible IRB (Institutional Review Board) should be identified; 2. Documented commitment of Institutions represented by Group members; documented capability of Principal Investigator's Institution to serve as the Central Operations Office for the Group; 3. Soundness of the institutional administrative and organizational structure that facilitates attainment of the objective(s) of the program, including fiscal responsibility and management capability to assist the PI and staff in following PHS policy; 4. Description of the laboratory capabilities in immunology and virology with particular emphasis on ability to detect changes in parameters related to HIV infection. Pharmacological capabilities should also be described, when relevant; 5. Arrangements for internal quality control of on-going research, allocation of funds, day-to-day management, contractual agreements, and mechanism for selecting and replacing key professional or technical personnel, if required, on an interim or permanent basis; 6. Documented commitment of the sponsoring institution to the cooperative agreement and willingness to accept the participation and assistance of NIAID staff (Scientific Coordinator) as stated under TERMS OF AWARD; 7. Appropriateness of the budget in relation to the proposed program. For budgetary consideration, assume that the duration of the annual SPIRAT meeting will be four days. Funds to cover expenses incurred by the Panel (see VII: SPECIAL REQUIREMENTS, Part D - Awardee's Rights and Responsibilities, page 11) should be included in the Administrative Core component of the application and will be restricted solely for this purpose. The initial review group can make recommendations regarding appropriateness of the applicant's specific aims to programmatic goals, deletion of projects or cores not essential to the overall thematic objective, and administrative oversight by program staff. The initial review group will review each project and core within the application individually, followed by scoring of the application as a whole. Council Review Stage The second level review will be conducted by the National Advisory Allergy and Infectious Diseases Council. Factors that will be considered in this review include: 1. Results of the initial scientific and technical merit review; 2. Significance to NIAID program goals in infectious diseases, allergy, transplantation immunology, immunologic diseases, or AIDS; 3. National needs and NIAID program balance; 4. Policy and budgetary considerations. AWARD CRITERIA Award criteria will be made on the basis of scientific and technical merit as determined by peer review, program needs and balance, and the availability of funds. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify issues or questions about the RFA from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Nava Sarver, Ph.D. Division of AIDS National Institute of Allergy and Infectious Diseases Solar Building, Room 2C-11 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-8197 FAX: (301) 402-3211 Direct the letter of intent and inquiries regarding application preparation and review to: Dianne Tingley, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C16 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-0818 FAX: (301) 402-2638 Direct inquiries regarding fiscal matters to: Ms. Pamela Greenwald Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B22 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-7075 FAX: (301) 480-3780 For all express mail or courier services to Solar Building, use the following address: 6003 Executive Boulevard, Rockville, MD 20852 Schedule Letter of Intent Receipt Date: September 20, 1994 Application Receipt Date: December 8, 1994 Scientific Review Date: March 1995 Advisory Council Date: June 1995 Anticipated Award Date: August 1995 AUTHORITY AND REGULATIONS This program is described in the catalog of Federal Domestic Assistance, 93.856 - Microbiology and Infectious Diseases Research and 93.855 - Immunology, Allergy and Transplantation Research. Awards are made under the authority of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 122372 or Health Systems Agency review. The Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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