HIV VACCINE TRIALS NETWORK LEADERSHIP GROUP Release Date: October 23, 1998 RFA: AI-98-014 P.T. National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: November 30, 1998 Pre-application Conference: November 23, 1998 Application Receipt Date: February 12, 1999 PURPOSE The Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID) is soliciting applications for a HIV Vaccine Leadership Group (VLG) for a planned HIV Vaccine Trials Network (HVTN) to conduct clinical research on HIV vaccines. The development of safe and effective HIV vaccines is of the highest priority, and is the ultimate goal of vaccine research supported by the NIAID. The HVTN will provide the focus of clinical research towards this objective. The primary mission of the HIV Vaccine Trials Network will be to identify, prioritize, and conduct research on promising vaccine concepts for the prevention of HIV disease worldwide. The HVTN will require the immediate capacity/capability to conduct Phase I and Phase II (safety and immunogenicity) trials of candidate HIV vaccines, domestically and in developing countries. Utilization of data and biological specimens from these studies to expand basic knowledge on human immunology, viral pathogenesis, and vaccine design/development are highly encouraged. The HVTN must also be prepared to rapidly implement Phase II/III or III (efficacy) studies domestically and internationally, should one or more vaccine candidates merit such testing. Such larger capability should be accomplished by demonstrating linkages to domestic and international investigators with the capacity and willingness to perform such studies in close collaboration with the HVTN. The establishment of the HVTN will occur through two announcements: this RFA for a VLG and the second RFA for clinical sites that will serve as HIV Vaccine Clinical Trials Units (HVTUs). The purpose of this first RFA is to establish a single VLG consisting of three components -- the Coordinating and Operations Center (Core), the Central Laboratory (CL), and the Statistical and Data Management Center (SDMC) -- under the leadership of the PI of the Core. The VLG will plan and implement a comprehensive agenda of clinical research on HIV vaccines within a cooperative network of clinical trial sites (HVTUs). The HVTUs, which will implement the approved scientific agenda, will be solicited at a later date under a separate RFA. Applicants for the VLG must identify a Principal Investigator for the Core who will assume overall scientific and operational leadership of the group. The VLG should include multi- disciplinary teams of scientists. In addition to the HVTN, the NIAID is supporting the creation of the HIV Prevention Trials Network (HPTN), to perform Phase I, II and III trials of various non-vaccine strategies to prevent HIV-1 transmission, domestically and internationally (RFA AI-98-015, HPTN Leadership Group, will be published in the NIH Guide in the near future). Clinical trials of vaccines focused on questions around perinatal transmission will be conducted within the HPTN in collaboration with the HVTN and the Pediatric AIDS Clinical Trials Networks. Sites funded under the HPTN may serve as effective venues for the eventual implementation of larger HIV vaccine trials, therefore linkages between HPTN and HVTN, in addition to other scientific organizations, are strongly encouraged. 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, HIV Vaccine Trials Network Leadership Group, 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 Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, SDMC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private institutions, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign organizations are not eligible to apply. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The administrative and funding instrument to be used for these awards will be the cooperative agreement (U01). The cooperative agreement is an assistance mechanism in which substantial NIAID scientific and programmatic involvement is anticipated during performance of the activity. Under the cooperative agreement, the NIAID"s purpose is to support and encourage the recipients" activities by working jointly with the awardees in a partner role, but not to assume direction, prime responsibility, or dominance. Details of the responsibilities, relationships, and governance of the studies to be funded are described under the section entitled, SPECIAL REQUIREMENTS, "Terms and Conditions of Award." The total project period for each award is five years. The anticipated award date is September 1999. The NIAID has not determined whether and how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE The estimated total funds (direct and indirect costs) available for the first year of support for awards made under this RFA will total $12 million. The distribution of funds is projected as follows: the Core award at approximately $4 million including a discretionary fund not to exceed $1.5 million, the CL at approximately $5 million, and the SDMC award at approximately $3 million. The Core will have responsibility for transitioning the phase in/phase out of vaccine trials currently underway in the current AVEG/HIVNET system. Although a single CL will be designated for the purposes of co-ordination, it is recognized that the scope of the laboratory requirement will make it unlikely that a single laboratory will be able to respond. Applicants for the CL are encouraged to identify a network of laboratory sites, which may be potential HVTUs, which have capability and capacity to carry out the laboratory functions proposed within the research agenda. Applications for clinical trial sites (HVTU) within the HVTN will be solicited under a separate RFA. Approximately $13 million total costs are expected to be available for the first year of support for proposed clinical trials and trial sites under the subsequent HVTU RFA. The usual PHS policies governing grants administration and management will apply. 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, and the receipt of a sufficient number of applications of high scientific merit. Funding beyond the first and subsequent (5) years of the grant will be contingent upon satisfactory progress during the preceding years and availability of funds for this purpose. DEFINITIONS AIDS Vaccine Evaluation Group (AVEG) - Multi-institutional clinical infrastructure currently responsible for the conduct of Phase 1/2 HIV vaccines. This contract program is set to expire in fiscal year 2000. Central Laboratory (CL) - The CL is the central laboratory that will enable the HVTN to implement state-of-the-art assays and technologies that are essential for the completion of the vaccine research agenda, as defined in the HVTN VLG Application. In addition to the performance of these assays for the HVTN, this laboratory may investigate the feasibility, validity, and standardization of the assays and techniques. The cooperative agreement award for the CL will be made as part of the HVTN VLG and will provide support for protocol related studies only. Collaborating Institution - A collaborating institution of the HVTN may be the CORE, the CL, the SDMC, or a HVTU. Cooperative Agreement - A cooperative agreement is an assistance mechanism in which substantial NIAID programmatic involvement with the recipient is anticipated during performance of the planned activity. Coordinating and Operations Center (CORE) - The CORE consists of the VLG leadership (PI) and Operations Office. The CORE coordinates all aspects of the HVTN and has oversight for the CL and SDMC. CORE Principal Investigator (PI) - The CORE Principal Investigator is responsible for the leadership and coordination of all HVTN activities both scientifically and administratively, and serves as the Principal Investigator for the CORE Award. The CORE PI may or may not be associated with a HVTU. The CORE PI responsibility may be transferred during the period of the award according to election procedures outlined by HVTN bylaws, in which case a new PI will be nominated and voted upon by the HVTN Executive Committee to lead the CORE. Data and Safety Monitoring Board (DSMB) - The DSMB is an independent group of experts established by NIAID and charged with the responsibility of monitoring the progress of trials, the safety of participants, and the efficacy of treatments being tested. The DSMB also makes recommendations to NIAID concerning continuation, termination or modification of the trials based on observed beneficial or adverse effects of any of the interventions under study. This panel is funded separately by NIAID. Division of AIDS (DAIDS) - The Division within the NIAID that has the primary responsibility for support of basic and clinical research on HIV/AIDS. Executive Committee - The Executive Committee, established and chaired by the PI of the VLG, represents the main governing body of the HVTN. This committee will be responsible for the conduct and overall activities of the HVTN. (Refer to "SPECIAL REQUIREMENTS, Awardee Rights and Responsibilities" in the RFA.) HIV Network for Prevention Trials/HIV Network for Efficacy Trials (HIVNET) - Multi-institutional clinical infrastructure currently responsible for the conduct of Phase 1-3 clinical trials of non-vaccine prevention modalities and Phase 2/3 vaccines. This contract program will expire in Fiscal Year 2000. HIV Prevention Trials Network (HPTN) - The HPTN will be a collaborative network of institutions involved in the conduct of all phases of non-vaccine HIV prevention. Included in this scope of activities are clinical studies evaluating topical microbicides, interruption of perinatal transmission, behavioral studies with biological endpoints, preventive treatment of sexually transmitted diseases, and chemoprophylaxis. HIV Vaccine Trials Network (HVTN) - The HVTN will be a collaborative network of institutions comprised of the CORE, CL, HVTUs, and the SDMC. This group conducts all phases of HIV vaccine clinical trials and laboratory studies. HIV Vaccine Trials Unit (HVTU) - A HVTU is a clinical site that is a member of the collaborating group of institutions comprising the HVTN. A HVTU may be organized as a main clinical site or a main site and several subunits under the leadership of one Principal Investigator. Operations Office - The Operations Center is a unit within the CORE that will take responsibility for coordinating HVTN administrative activities including technical assistance with research and protocol development, budgetary activities, preparation of technical reports and SAER reporting. The CORE PI will serve as PI for the Operations Center, with the award made to the Operations Center. Prevention Leadership Group (PLG) - The Prevention Leadership Group consists of the Principal Investigator for the CORE, the Principal Investigator for the SDMC and the Principal Investigator for the CL. Other members of the PLG group may be designated by the HVTN in the future. Prevention Sciences Review Committee (PSRC) - An internal DAIDS review committee with the responsibility of evaluating clinical protocols in the context of relevance to the mission of NIAID as well as on the basis of sound methodology, reasonable feasibility, safety and ethics. Statistical and Data Management Center (SDMC) - The SDMC is the component of the HVTN that is responsible to the VLG leadership for the statistical aspects of study design and analysis and management of the HVTN database. Subunit - A subunit is an institution supported under the fiscal and managerial umbrella of a HVTN. Subunits may be established to support the scientific agenda and/or accrual goals. All subunits are subject to the same policies and procedures mandated by Federal regulations, DAIDS and NIAID policies, and the bylaws of the HVTN. Vaccine Leadership Group (VLG) - The Vaccine Leadership Group consists of the Principal Investigator for the CORE, the Principal Investigator for the SDMC and the Principal Investigator for the CL. Other members of the VLG group may be designated by the HVTN in the future. Vaccine and Prevention Research Program (VPRP) - The VPRP is a program within the DAIDS that is responsible for the scientific, administrative, and operational management of clinical vaccine and prevention research funded by the Division. SOLICITATION PROCESS Each proposed VLG will submit a group package consisting of up to three individual applications that address the three components of this RFA: (1) A COORDINATING AND OPERATIONS CENTER (CORE) headed by a PRINCIPAL INVESTIGATOR (PI) who heads the VLG, (2) A CENTRAL LABORATORY (CL) and (3) A STATISTICAL AND DATA MANAGEMENT CENTER (SDMC). A group may choose to combine two components (the CORE and SDMC) and apply as a COORDINATING CENTER. Either two or three separate awards will be made in support of these three major components of the VLG. When applying for VLG components (CL or SDMC), each applicant must identify the VLG CORE with whom they propose to work and must coordinate the preparation of their application with all other components of the VLG. Unaffiliated applications will not be accepted. The application for the PI who heads the VLG team and Operations Center"s (CORE) should address the RESEARCH OBJECTIVES AND SCOPE and the Vaccine Leadership Group (CORE) Responsibilities (in Terms and Conditions of Award) stated below. The HVTU application process will occur approximately 4-6 months after the VLG application process. At the time of the HVTU submission, it is unlikely that the VLG will have been awarded. Therefore, potential HVTU applicants are encouraged to communicate with VLG applicants and to attend the VLG Pre-Application Meeting (see APPLICATION PROCEDURE below). The responsibilities for the Central Laboratory and for the Statistical and Data Management Center are stated below in the Terms and Conditions of Award. These responsibilities should be addressed in the relevant applications. RESEARCH OBJECTIVES BACKGROUND As the pandemic of the Acquired Immunodeficiency Syndrome (AIDS) continues to grow, the importance of developing safe and effective vaccines and other prevention modalities to prevent infection with the Human Immunodeficiency Virus (HIV) and the development of AIDS assumes increasing importance. In pursuit of this goal, the Vaccine and Prevention Research Program (VPRP), DAIDS, NIAID, supports a comprehensive program of basic and applied research directed toward the development of safe and effective AIDS vaccines and other prevention interventions. NIAID-funded HIV vaccine research groups have thus far evaluated the safety and immunogenicity of twenty candidate AIDS vaccines in Phase I trials in over 1750 volunteers who are at low risk of exposure to and infection with HIV-1. Several additional new candidate vaccines await Phase I testing. One Phase II trial has been completed. This trial enrolled nearly 300 volunteers from heterogeneous populations, including volunteers at high risk of exposure to HIV, and studied two HIV-1 gp120 subunit vaccines, comparing their immunogenicity and effect on high-risk activity in populations at risk for acquiring HIV-1 infection. A second Phase II trial, studying the safety and immunogenicity of live recombinant canarypox-HIV constructs (ALVAC vCP205 - Pasteur Merieux Connaught) with or without vaccination with HIV-1 SF2 recombinant gp120 (Chiron Vaccines), is underway with 420 enrolled volunteers. NIAID-sponsored trials of HIV vaccine candidates have demonstrated the safety of candidates tested thus far, including recombinant envelope proteins (e.g., gp120, gp160, and gp41), a variety of pox virus recombinants, alone and in combination with recombinant envelope proteins, and a DNA vaccine product containing gag/pol structural proteins. A number of these candidate vaccines have elicited binding antibodies and neutralizing antibodies to homologous virus. These studies have also demonstrated the ability of certain vaccine products, (e.g., pox virus/HIV recombinants) to elicit cellular immunity as demonstrated by lymphoproliferation, ADCC and CTLs against selected HIV epitopes. Studies have also demonstrated that certain adjuvants are useful for inducing increased levels of antibody response. In spite of these advances, many critically important questions remain unanswered including: 1) whether a vaccine product or combination of vaccine products can elicit protective immune responses, 2) whether immunological responses can prevent the establishment of HIV-1 infection following exposure, 3) whether vaccine-induced immunological responses can inhibit HIV replication in individuals who become infected with HIV, and 4) the relevance of viral (e.g., clade) and host (e.g., HLA) genetic factors in the development of HIV vaccines. RESEARCH OBJECTIVES AND SCOPE The objective of this RFA is to establish a Vaccine Leadership Group (VLG) for a comprehensive multi-centered HIV Vaccine Trials Network (HVTN). The VLG will have the expertise to set the overall scientific agenda to guide the HVTN in addressing the questions listed above as well as other key questions regarding HIV vaccine development and testing, leading to the development of effective HIV vaccines. Research to be implemented by the HVTN, under the leadership of the VLG should address the following broad scientific needs and considerations: Clinical Trials of HIV Vaccines o Identify and prioritize the clinical evaluation of vaccine concepts and adjuvant formulations, as well as routes of administration, and dosage schedules that can elicit broad and long-lasting humoral and/or cellular immune responses to homologous and heterologous strains of HIV-1 at systemic and/or mucosal levels to achieve protection from infection or disease, o Conduct Phase I and II multi-site trials, domestically and internationally, to evaluate the safety, toxicity, immunogenicity and efficacy of experimental HIV vaccines under Investigational New Drug applications, o Perform clinical trials of candidate HIV vaccines in populations at risk for acquiring HIV infection, both domestically and internationally, to determine whether underlying health conditions or other factors in these populations will affect the safety or immunogenicity of candidate vaccines, o Develop plans for community outreach, education, and participation on HIV vaccines in communities where HIV vaccine clinical trials will be conducted, o Prepare for and conduct large-scale, Phase II/III and Phase III vaccine clinical trials, in U.S. and in developing countries. Such plans should include: -- proposing linkages with sites capable of performing large-scale, Phase II/III and Phase III vaccine efficacy trials (including the criteria used to select these sites), -- ensuring that the key investigators from selected sites outside the HVTU will be integrated within the HVTN organizational structure (e.g., will be familiar with the participating HVTN investigators, the HVTN bylaws and decision-making process, and the data arising from HVTN studies relevant to implementing a large vaccine trial, and -- identifying and addressing the needs associated with implementation of large scale vaccine studies, including methodological research on trial design. HIV Vaccine Research within the Context of Clinical Trials o Identify and test improved, standardized, quantifiable, reproducible and accurate methods to evaluate immunological responses to vaccination through basic and clinical studies, -- Conduct laboratory studies to identify correlates of immune protection against establishment of HIV infection or disease progression, utilizing data and specimens obtained from the vaccine trials conducted by the HVTN and the most advanced methodology available, -- Expand the scope of the current global HIV vaccine effort. For example, investigate the relevance of viral (e.g. clade) and host (e.g. HLA) genetic factors in the development of HIV vaccines. -- Identify and develop practical and reliable laboratory assays to screen vaccine trial participants for HIV infection, and to assess suppression of infection in vaccine recipients who become infected, both domestically and in the developing world, and -- Collaborate with investigators using simian models of retroviral infection and disease to systematically address the correlative relationship between human and animal studies. While it is not the intent of NIAID to fund simian based vaccine research within this award, collaborations which may assist in the ultimate development of an HIV vaccine may strengthen an application for the VLG SPECIAL REQUIREMENTS TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the award statement and provided to each Principal Investigator as well as the institutional officials at the time of award. These terms are in addition to, not in lieu of, otherwise applicable Office of Management and Budget (OMB) administrative guidelines, HHS Grant Administration Regulations at 45 CFR Part 74 and 92, and other HHS, PHS, and NIH Grants Administration policy statements. The administrative and funding instrument used for this program is the cooperative agreement (U01), 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 the cooperative agreement concept, the dominant role and prime responsibility for the planned activity resides with the awardees for the HVTN. Specific tasks and activities in carrying out the activity will be shared among the awardees, DAIDS staff and its contractors. The cooperative agreement funding mechanism will require collaboration among: the DAIDS Associate Director for VPRP, the CORE PI, the Principal Investigator of the CL and the Principal Investigator of the SDMC. The DAIDS will assist in coordinating the activities of the HVTN as defined below and will facilitate the exchange of information. I. Awardee Rights and Responsibilities Awardees will have primary responsibility for defining the research objectives, approaches and details of the projects within the guidelines of the RFA, and for performing the scientific activity. Awardees have primary responsibility as described below. A. Vaccine Leadership Group (CORE) Responsibilities 1. Research Agenda -- The Principal Investigator (CORE PI), in collaboration with other HVTN investigators constituting the key scientific and managerial leadership (Executive Committee), will be responsible for implementing, monitoring, and updating the HVTN scientific vaccine research agenda. The VLG will assume responsibility for further developing the scientific and managerial guidelines of the HVTN, in consultation with the Executive Committee (see below), through the development of the HVTN bylaws and governance. These research goals will be reviewed on a mutually agreed upon schedule with the Associate Director, VPRP, DAIDS or designee. 2. Transition Plan -- The VLG, in conjunction with the leadership of the current HIVNET and AVEG, will develop a detailed transition plan that adequately addresses the transition from the current AVEG and HIVNET vaccine research activities to the proposed HVTN. This plan will delineate the transition of ongoing clinical trials, propose procedures, timeline and planning for the phase in and phase out of clinical sites, statistical center and central laboratory contracts. The Plan will be completed and implemented with sufficient time to ensure timely completion of all ongoing studies. 3. Bylaws/Operating Procedures -- The PI of the VLG CORE will be responsible for ensuring that well-documented policies, procedures, and bylaws are developed, implemented, and when necessary updated to guide all aspects of the cooperative HVTN activities. 4. Executive Committee -- An Executive Committee will be established as the main governing body of the HVTN and must include at least one DAIDS staff representative. 5. Administrative Support -- The VLG will be responsible for coordinating, administrating, and supporting all research activities. These activities include but are not limited to: (i) protocol development, distribution of information, and training, (ii) administrative support for the VLG, the Executive Committee, community advisory board, and all other HVTN committees, (iii) maintenance of group administrative records and archives, (iv) coordination of efforts with DAIDS regarding group meetings, and (v) preparation of administrative and scientific reports. 6. Protocol Development -- The VLG will have the responsibility to assure that the HVTN will initiate the development of protocols only when there is sufficient commitment among the HVTN Principal Investigators and other scientific leaders within the group to proceed expeditiously. Early notification that the HVTN is considering a trial must be provided to the DAIDS to allow for comment on scientific rationale, feasibility, costs, and compatibility with overall NIAID research priorities and activities. The HVTN must have clear procedures for designating members of protocol teams, selecting sites for limited-site trials, and providing protocol-specific training. The HVTN must develop a mechanism to monitor progress, from study initiation through publication, and provide status reports to the DAIDS, on each study, in a mutually agreed upon format and on a schedule. 7. Broad Community Participation -- In formulating and implementing the research plan, provision should be made for broad community participation at both domestic and international sites. This plan should include consideration that the process of building a research relationship with a community takes time and commitment. There should be opportunities for education and training for researchers and community members. Researchers work more effectively with communities if they have knowledge of ethics, cultural competency, and participatory research techniques. Community members could be more effective with knowledge of research processes. The following specific issues need to be considered: (i) the need to develop model programs that not only include health research goals but also community capacity-building goals for conducting specific research activities, (ii) community training to improve understanding of research, (iii) support for the development of local organizations, and (iv) community mobilization skills. 8. Study Oversight Responsibility -- The VLG must establish procedures to: (i) assure adequate protection of the rights and safety of subjects involved in clinical investigations, (ii) guarantee the quality and integrity of the resulting data, and (iii) maintain accurate and timely information on each study. This oversight must include compliance with all Federal regulations, and DAIDS/NIH policies and procedures as outlined in the "Serious Adverse Experience Reporting Manual for the Vaccine and Prevention Research Program" available from Dr. MaryAnn Luzar (see Inquiries). 9. Federally and Internationally Mandated Regulatory and Ethical Requirements -- The HVTN must be in compliance with all Federal regulations and NIH policies applying to the conduct of research involving human subjects. These include, but are not limited to, Title 21 CFR 50, 56, 312, and Title 45 CFR 46. The HVTN must assure that: (i) each institution conducting HVTN trials has a current, approved Assurance Number on file with the NIH Office for Protection from Research Risks (OPRR), (ii) each protocol and informed consent is approved by the responsible Institutional Review Board (IRB) prior to subject entry, (iii) each investigator has supplied a completed (including curriculum vitae) FDA 1572 to DAIDS for each protocol conducted at each site, and (iv) each subject (or legal representative) gives written informed consent prior to entry on study. For trials conducted in foreign countries, the HVTN must assure compliance with the host country regulations for human subjects and AIDS research and must assure that the trials are conducted according to the International Ethical Guidelines for Biomedical Research Involving Human Subjects (CIOMS). 10. Reporting Requirements -- The HVTN will submit to DAIDS requisite information in order to meet administrative, oversight, and regulatory needs. a. Administrative: The VLG, under the leadership of the CORE PI will assume responsibility for assuring required administrative information is submitted to DAIDS. Types of information will include, for example, lists of investigators and other key personnel, affiliated sites, protocol abstracts and tracking data, patient accrual and demographics, and publication information. Some information such as protocol enrollment/accrual status may be required weekly, some less often. Submission by electronic means, whenever possible, is preferred. b. Performance: The Executive Committee will establish procedures for evaluating the performance of all HVTN components and provide DAIDS with reports. Procedures will include processes for the addition, reduction, expansion or elimination of clinical sites, labs or other components based on scientific contribution, protocol participation, observance of protocol requirements, data management/quality, and subject accrual/retention. This mechanism will include a procedure for recommending to DAIDS an adjustment of institutional funds based on level of contribution and performance. A system for establishing such procedures in a timely manner must be implemented by the VLG. c. Annual Report: The VLG will submit to DAIDS an annual report summarizing HVTN activities (including accrual and demographic data), accomplishments, performance evaluations and future directions. A system for providing such information in a timely manner must be implemented by the VLG. d. Regulatory - Reporting requirements will be in agreement with Federal regulations and NIAID procedures for clinical trials. Prior to the date specified, the VLG will submit to DAIDS data summary reports of HVTN activities that are required of Investigational New Drug (IND) sponsors to by the Food and Drug Administration (FDA). The VLG will submit to DAIDS a narrative summary of the data contained in these reports and future plans for each study one month in advance of each IND report"s due date. A system for providing such information in a timely manner must be implemented by the VLG. 11. Publication of Data -- Prompt and timely presentation and publication in the scientific literature of major findings is essential. Publications or oral presentations of work performed under this cooperative agreement will require acknowledgment of NIAID/NIH support. Prior to the submission of manuscripts for publication a copy must be provided to DAIDS. The awardee retains the rights to the data consistent with current HHS, PHS, and NIH policies, however, DAIDS under this cooperative agreement will have access to all data generated and may periodically review it. 12. Collaborative Responsibilities -- The VLG is expected to develop scientific collaborations that can expand the scope of the HVTN. The VLG should develop a process that would make data and biological specimens available to the general scientific community to further investigations in HIV vaccine discovery and development, including the objective review of such requests. 13. National Meetings -- It is anticipated that at least 2 national meetings/year will be required. The VLG is expected to hold at least one national meeting per year in the Washington, D.C. metropolitan area. They may chose to meet jointly with other HIV vaccine clinical trials groups, or groups engaged in non-vaccine prevention of HIV transmission. Portions of these meeting are open to the public. Responsibility for logistical support and scientific content will reside with the VLG. 14. Conflict of Interest -- The VLG will assure the development and implementation of a Conflict of Interest Policy (COI), acceptable to the NIAID, addressing any conflicts of interest that may occur through financial interest or other associations between members of the HVTN and the private sector. 15. Discretionary Funds -- The Operations Office will maintain and manage a Discretionary Fund for support of HVTN research projects. These funds will be expended only upon approval by the Executive Committee. The Executive Committee will develop criteria and review procedures for allocating discretionary funds, based on scientific and administrative needs and priorities of the group. Appropriate uses may include innovative pilot studies, supplementing budgets of collaborating institutions which are undertaking resource intensive studies, facilitating the initiation of large efficacy studies, accommodating non-routine protocol mandated requirements on an as needed basis, and supporting additional clinical or laboratory sites needed by the group. 16. Linkages with HIV Prevention Trials Network -- The HIV Prevention Trials Network (HPTN) will be established contemporaneously with the HVTN. The HPTN may be a unique scientific resource and offer a desirable capacity for conducting population-based studies. It is likely that any large-scale study of HIV vaccines will involve at least some HPTN sites. The VLG, in concert with the leadership of the HPTN (PLG) will develop and maintain linkages between the HVTN and the HPTN. These linkages will allow for ongoing exchange of information and planning to allow for rapidly including HPTN Sites in studies, should that be desired. The VLG may propose a number of different mechanisms and approaches to meet this need. These mechanisms may include ongoing activities such as having joint membership in leadership groups or identifying specific individuals responsible for assuring information sharing. There may also be specific activities such as joint protocol development or common scientific meetings. B. Central Laboratory Responsibilities 1. Conduct of Laboratory Assays and Research -- The Central Laboratory will be responsible for the following: (i) performing timely laboratory studies as needed for specific clinical trials, (ii) providing laboratory based scientific leadership and consultation for the HVTN and collaborating institutions and organizations, (iii) collaborating at all stages of protocol development concerning laboratory testing and implementation, (iv) conducting/overseeing quality assurance of laboratory assays performed at HVTN clinical and laboratory sites in order to improve the planning, design, conduct and interpretation of HVTN trials, and (v) work with the statistical center to assure transfer of quality laboratory data to the data center for preparing summary tables and data analyses for use in NIAID and IND annual reports as well as interim submissions to the NIAID, FDA, and the DSMB. 2. Organization/Management of the Central Laboratory -- The VLG will contain a single CL with responsibility for providing appropriate and coordinated laboratory support for HVTN investigations. It is anticipated that the CL will not possess the technical capability/capacity to perform all the required laboratory assays in house. The CL may organize, through a series of subcontracts, a network of laboratories (subsites) with various immunologic and virologic expertise to address the laboratory needs inherent in the research agenda. These laboratories should demonstrate both scientific excellence in clinical based assays and interest in participating in the research agenda defined by the HVTN. These laboratories may include, but are not limited to, cellular, humoral, mucosal immunology studies, viral studies, as well as assay and reagent development. The scope of the laboratory research should include immunologic and virologic assays relevant to HIV vaccine development. The CL will coordinate and oversee the quality assurance of assays performed at subsites and assure that a common laboratory data management system is utilized for specimen tracking and data transmission. C. Statistical and Data Management Center (SDMC) Responsibilities 1. Study Design, Conduct, Analyses, and Publications -- The SDMC will be responsible for: (i) providing statistical leadership for the HVTN and for all stages of protocol development and conduct, (ii) performing timely interim analyses of safety and efficacy for protocol teams and/or DAIDS and/or DAIDS DSMB, (iii) generating executive summaries of preliminary analyses for use by the protocol team, DAIDS, DSMBs, and collaborators, (iv) conducting final analyses and participating on publication writing teams, (v) producing study monitoring reports (such as accrual and AERs) for the VLG and DAIDS, (vi) conducting analyses and summaries for annual and interim reports for DAIDS INDs, and (vii) suggesting and, when agreed upon by VLG leadership, performing additional analyses of data obtained from HVTN vaccine trials, based upon the intimate familiarity of SDMC investigators with both the HVTN data set and the key scientific issues relevant to HIV vaccine development. 2. Data Management -- The SDMC will: (i) provide central registration and randomization for all study subjects, (ii) develop case report forms and standardized criteria for clinical endpoint verification, (iii) design and implement systems for the efficient tracking and transfer of clinical and laboratory data from clinical sites to the central database, (iv) provide data management training to the clinical sites and DAIDS" Clinical Site Monitoring Contractor, (v) provide for central storage, security, processing and retrieval of study results, (vi) demonstrate the means by which it will ensure that all data, patient questionnaires, consent forms, and all other records containing the volunteers name will be maintained in a confidential and secure manner at all times (e.g., no materials containing the volunteers name may be sent to vaccine manufacturers or to other individuals outside the HVTN), (vii) prepare selected public access databases for DAIDS, as provided for in the approved plan for providing public access in a reasonable time after the primary analysis and publications (see 1. above), (viii) provide for an electronic mail system capable of exchanging messages through the Internet, to facilitate communication among HVTN"s, other HVTN components and DAIDS, (ix) provide recruitment, retention and other relevant summary data to the sites and protocol teams as designated by the VLG, and (x) assume responsibility for ongoing maintenance of the modified ICD system for classifying and coding the types of serious adverse experiences. 3. Collaborations -- Develop processes for facilitating and monitoring HVTN Executive Committee-approved collaborations with investigators external to the HVTN. Such plans should be included in the SDMC application and address: (i) the capacity to assist external collaborators with the design of their studies, (ii) the monitoring plans for overseeing the status and availability of HVTN biological specimens in the NIAID AIDS Specimen Repository, and (iii) the plans for monitoring the progress of external collaborations, and reporting such progress to the HVTN Executive Committee. When collaborating with other HIV vaccine or non-vaccine prevention clinical study groups, procedures of conduct will be determined by the Associate Director, Vaccine Research and Prevention Program (VPRP), DAIDS and the leadership of each participating group. Generally, the procedures of the lead sponsor will be followed. 4. Statistical Methodology -- Develop innovative HIV vaccine clinical trial designs and analysis methodologies consistent with and in support of the VLG research agenda. D. HVTU Clinical Sites While the HVTU Clinical Sites will be solicited under a separate RFA, the VLG applicants should be aware that HVTU responsibilities will include: 1. Volunteer enrollment, retention and follow-up, 2. Standard clinical laboratory assays (e.g. CBC) for patient assessment, 3. Individual quality assurance plans for Investigational Drug Management and internal data generation, and 4. Community Advisory Board plans. II. NIAID Responsibilities The NIAID will have substantial scientific programmatic involvement during the conduct of this activity, through technical assistance, advice, and coordination. The role of DAIDS staff described throughout these terms of cooperation is to assist and facilitate. Although communication primarily will be with the VLG Leader, substantial communication is anticipated with all members of the HVTN Executive Committee. The following are specific responsibilities of DAIDS staff in terms of interventional clinical research, and the NIAID"s role as an IND sponsor as defined in 21 CFR Part 312. 1. Scientific Role in NIAID Sponsored Clinical Research -- The Associate Director for VPRP, or designee, will be a member of the Executive Committee to assure that the research efforts are consistent with the NIAID agenda for HIV clinical research and complement those of other NIAID and NIH programs. The DAIDS will serve as a liaison/facilitator between pharmaceutical companies, the FDA, and HVTN investigators. DAIDS will serve as a resource of scientific and policy information related to the goal of the HVTN. DAIDS will also independently support a Data and Safety Monitoring Board (DSMB) that will oversee vaccine trials. 2. DAIDS Role in Protocol Development -- In order for a clinical study to be initiated, the protocol must be approved by the Associate Director, VPRP. Once notified that a study is under consideration, the Prevention Sciences Research Committee (PSRC) will evaluate the proposal relative to: (i) the NIAID research agenda and other NIAID/NIH clinical studies, (ii) subject safety, (iii) compliance with Federal regulations, (iv) study oversight and monitoring, (v) feasibility of timely completion, and (vi) when appropriate, plans for interim monitoring and analysis. The Associate Director, VPRP or designee will return comments and recommendations to the group within 30 days after review. If a protocol is disapproved, DAIDS will not provide investigational products or permit expenditure of NIAID funds for the proposed investigation. 3. DAIDS Involvement in Investigational New Drug Applications -- The DAIDS will have the option to file an IND on investigational agents evaluated in HVTN studies. Appropriate DAIDS staff will advise the investigators on specific regulatory requirements for IND sponsorship. In situations where DAIDS is the IND sponsor, they will also assemble, review, and submit the required regulatory documents to the FDA. A DAIDS pharmacist will participate on the protocol team, consult on the pharmaceutical aspects of protocol development, and will interact with pharmaceutical companies to ensure product availability. 4. Clinical Trials Agreements (CTA) -- When a pharmaceutical collaborator provides an investigational agent to DAIDS, a CTA will be negotiated describing respective responsibilities and rights. The agreement will include, but is not limited to, IND sponsorship, safety and data monitoring, and access to data. The VLG Core PI generally will be consulted on the terms prior to the execution of the CTA. Pharmaceutical collaborators generally request that patentable inventions discovered in the studies be brought to their attention, and the company has rights of first refusal provided that the collaborator has rights to the background patent. In general, terms in the CTA covering data access and sharing will conform to policies developed jointly by the VLG and DAIDS. 5. DAIDS Role during Study Conduct -- DAIDS will provide Regulatory Training at the annual meeting held in Washington, D.C. DAIDS will also provide ongoing and start-up training to international collaborators or for vaccine studies being conducted in international settings. A DAIDS Medical Officer will monitor the safety and efficacy of the intervention(s) for ongoing studies, and will be provided with interim and final reports. For protocols in which DAIDS is the IND sponsor, DAIDS will assign medical monitors. When a protocol is sponsored by a collaborating institution or research group, monitoring activities will be conducted by their medical representatives. 6. DAIDS Role in Protocol Closure -- The Associate Director, VPRP, or designee, will monitor the progress of the studies by reviewing reports submitted to DAIDS by the Data Safety and Monitoring Board, and through regular meetings with the VLG Leadership. NIAID, upon reviewing the recommendations from the DSMB, may find it necessary to terminate an ongoing study for the any of the following reasons: (i) risk to subject safety, (ii) the scientific question is no longer relevant or the objectives will not be answered, (iii) slow accrual, or (iv) the objectives of the study have been met. 7. Access to Data -- The Associate Director, VPRP, or designee will have access to all data generated under this cooperative agreement, and may review the data as recorded on the case report forms or in the central database. Data must be available for external checking against the original source documentation as required by federal regulation and DAIDS as the IND sponsor. The awardees will retain the primary rights to the data consistent with HHS, PHS, and NIH policies, but are encouraged to provide public access to selected data sets generated with the use of public funds within a reasonable time after the primary analysis and publication. 8. Site Monitoring -- The DAIDS has an external Clinical Site Monitoring Contract to evaluate good clinical research practice, regulatory compliance, accurate protocol implementation, internal quality assurance, and test agent accountability. The monitoring contractor will visit performance sites periodically to review selected protocols, provide training on general protocol conduct, review internal QA/QC plans, audit pharmacies, and document error resolution. 9. Review of Performance -- The performance of all group components will be reviewed at least annually by the Associate Director, VPRP, using the comprehensive annual progress report, clinical site evaluations developed by the Executive Committee, and site monitoring reports provided to DAIDS by its contractor. DAIDS staff will assist the VLG in developing evaluation instruments. Substandard data, insufficient subject accrual or retention, inadequate progress in fulfilling the research agenda, non-compliance with federal regulations or these Terms of Award may result in a reduction in budget, withholding of support or termination of award. 10. SAE Reporting -- In order to provide for consistent reporting of serious adverse experiences across clinical trial groups, DAIDS has established policies and procedures delineated in the "Serious Adverse Experience Reporting Manual for the Vaccine and Prevention Research Program." III. Collaborative Responsibilities 1. Group Governance -- The VLG will establish an Executive Committee as the central decision making body for the Group. The Committee will include the Associate Director, VPRP, or designee, as a voting member. A Chairperson, other than the DAIDS Official, will be elected by the Group membership as defined in the Bylaws. IV. Arbitration Any disagreement that may arise on scientific or programmatic matters (within the scope of the award) between award recipients and the NIAID may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the Executive Committee (with the NIAID member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by the NIAID, and the third member with expertise in the relevant area selected by the first two members to review any scientific or programmatic issue that is significantly restricting progress. While the decisions of the Arbitration Panel are binding, these special arbitration procedures will in no way affect the awardee"s right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, subpart D, and HHS regulations at 45 CFR Part 16. Cooperative agreements are subject to the administrative requirements outlined in OMB circulars A-102 and A-110. All pertinent HHS, PHS, and NIH grant regulations, policies and procedures, with particular emphasis on PHS regulations at 42 CFR Part 52 and HHS regulations at 45 CFR Part 74, are applicable. These special terms and conditions pertaining to the scope and nature of the interaction between the NIAID and the investigators will be incorporated in the Notice of Grant Award. However, these terms will be in addition to, not in lieu of, the customary programmatic and financial negotiations that occur in the administration of cooperative agreements. 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, compelling rationale, and justification are provided that inclusion is inappropriate with respect to the health of the subjects of 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 research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research", published in the Federal Register of March 28, 1994 (FR 59 14508- 14513) and the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, which is available at http//grants.nih.gov/grants/guide/notice-files/not94-105.html. Investigators may obtain copies from these sources or from Dr. Margaret Johnston at the address listed under INQUIRIES. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. For the purpose of this RFA adults are defined as persons 18 years of age and older. The NIH has other programs for HIV clinical research in children under 18 years of age. LETTER OF INTENT Prospective applicants are asked to submit, by November 30, 1998, a letter of intent that includes a descriptive title of the overall proposed research, the name, address and telephone number of the Principal Investigator, and the number and title of this RFA. Although the letter of intent is not required, is not binding, does not commit the sender to submit an application, and does not enter into the review of subsequent applications, the information that it contains allows 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 The individual applications that together make up the VLG package must be submitted on the standard research grant application form PHS 398 (rev. 5/95). Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda MD 20892-7910 telephone (301) 710-0267, Email: grantsinfo@nih.gov. The RFA label available in the PHS 398 application form 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 ("HVTN LEADERSHIP CORE" and/or "HVTN CENTRAL LABORATORY" and/or "HVTN STATISTICAL AND DATA MANAGEMENT CENTER") and number (AI-98-014) must be typed on line 2 of the face page of the application for and the YES box must be marked. Submit a signed, typewritten original of each application, including the Checklist, and three signed exact photocopies. Each group application for the CORE, CL, and SDMC (or CORE/Coordinating Center and CL) must be submitted 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 copies of the application package and all five copies of appendices must also be sent to: Dr. Dianne Tingley Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4C07, MSC 7610 Bethesda, MD 20892-7610 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. The deadline for the receipt of applications is February 12, 1999. Applications received after this date will be considered non-responsive to this RFA and will be returned without review. SPECIAL INSTRUCTIONS FOR THE PREPARATION OF COOPERATIVE AGREEMENT APPLICATIONS I. Identification of Potential Applicants and Formation of the VLG It is the responsibility of potential applicants for the CORE award, CL award, and SDMC award as components of the VLG to identify themselves to each other and to establish affiliations. II. Pre-Application Meeting November 23, 1998 A preapplication meeting will be held at the Marriott Hotel at Dulles Airport in Herndon, VA on November 23, 1998. The purpose of this meeting is to provide potential applicants with: (1) additional information about the structures and functions of DAIDS clinical research programs, (2) the opportunity to ask questions and obtain clarifications, and (3) the opportunity to establish affiliations. All applicants who are seriously considering a response to this RFA are strongly encouraged to attend this preapplication meeting. Investigators who are considering applying to become a site in the HVTN are also encouraged to attend this meeting. For further information, contact Dr. Margaret Johnston at the address listed under INQUIRIES. Questions and answers resulting from this meeting will be available, for individuals who are unable to attend, at the following website: http://www.niaid.nih.gov/research/DAIDS.htm III. Application Preparation All applications must be submitted on the grant application form PHS 398 (rev. 5/95). All component applications for each VLG must be submitted in one package. The structure of the VLG requires close integration among the components, under the leadership of the PI of the CORE. Thus, applicants for each VLG are strongly encouraged to interact and collaborate during the preparation of their applications. Successful applications for HVTN components (CORE, CL, and SDMC) will be awarded as separate cooperative agreements to the sponsoring institutions and will include the Terms and Conditions of Award specified in this RFA. Each individual application must contain a detailed budget for the first 12- month period and a budget for the entire proposed project period for direct costs. On page 11 of the PHS 398 application brochure, in the section entitled PERSONNEL, it is imperative that all applicants list ALL individuals and their institutions participating in the scientific execution of the project in the specified format, including those with no requested salary support. All applicants must ensure that the list is complete using as many continuation pages as necessary. Biographical sketches and other Support pages should be placed at the end of each individual application with the Principal Investigator first, followed by other key personnel in alphabetical order, biographical sketches are limited to two pages each. A key feature of this RFA is that it requires a CORE application to be submitted by a CORE Principal Investigator of the HVTN CORE. The Central Laboratory and Statistical and Data Management Center components should be submitted as separate applications within the same VLG package. The use of tables (e.g., accrual and protocol type), diagrams, and organization and flow charts is strongly encouraged throughout the preparation of all applications. Under a separate RFA application which will be announced, all HVTUs seeking membership in a collaborative group must submit a separate application and identify the CORE with which they are planning to affiliate. In summary, applications in response to this RFA must include, but are not limited to, the minimum requirements: A. HIV Vaccine Coordinating and Operations Center (CORE) Application The CORE application is not subject to the page limitations in the PHS 398 Form. This section of the application should not exceed 150 pages. When preparing your application use the topics listed below and the items under Vaccine Leadership Group (CORE) Responsibilities (Special Requirements, Terms and Conditions of Award) as a guide for writing the research plan in lieu of items a-d on pages 16-17 of the PHS 398 application kit. However, the "Gender and Minority Inclusion for Research Involving Human Subjects", "Participation of Children" and "Human Subjects" must be included in the Research Plan. The PI of the CORE should take overall responsibility in the CORE application for ensuring that the overall representation of study population, HVTN-wide, will be appropriately inclusive of under-represented populations. Research Plan and Scientific Agenda -- The application should present the proposed research agenda and should discuss the PI"s plan, process, and timeline to implement this agenda. The research agenda must clearly identify the priority areas in depth. The application should also identify and name the scientific and managerial leadership required for the VLG and the HVTN to effectively and efficiently carry out its research plan. The applicant must demonstrate, in the preparation of the research plan, scientific and administrative linkages with the CL and SDMC components. For committees (e.g., Executive Committee) include an outline of proposed expertise and plans for determining membership (including, where available, gender and minority status for individuals who choose to be self-identified) and responsibilities of this committee. Operations and Management - The application should provide well-documented, clearly defined policies, and operating procedures (e.g., protocol development, review, initiation, training, conduct and closure, data collection, and publication etc.). An outline or specific examples of policies, procedures and bylaws should included in the application (e.g., delineating the requirements and expectations of collaborating institutions, membership criteria and process for new site consideration by the HVTN, standards of performance, and procedures for removing institutions due to poor performance). The CORE application should also include the principles and procedures that will guide the transition (transition plan) from the current AVEG and HIVNET to the proposed VLG and HTVN. An outline and timeline for development and implementation of a Conflict of Interest Policy and development of the guidelines for scientific collaborations (including making samples and datasets available) should be included. In addition to a discussion of the support needed for the Operations Office, each CORE application should include a plan and a budget, developed by the CORE PI, for administrative/managerial support. The CORE, CL, and SDMC components must show evidence of ongoing cooperation in the preparation of their applications. Operations Office Procedures - The application must describe the steps that the CORE PI will take to ensure internal and external management between the Operations Office, CL, SDMC, HVTUs, and collaborating institutions (e.g. DAIDS). Community Participation - The application must describe the mechanisms and procedures that will be put in place for monitoring community participation and accrual efforts at the individual HVTUs. The application must also describe the steps taken to establish ongoing involvement in community outreach, including ability to establish and maintain an active community advisory board. Discretionary Funding - The CORE PI may also request a discretionary budget in this application that will be used to: fund innovative pilot studies, supplement the budgets of collaborating institutions undertaking resource intensive studies, facilitate the initiation of large efficacy studies, accommodate non-routine protocol mandated requirements on an as needed basis, and support any additional clinical or laboratory sites needed by the group. The Discretionary Funds may not exceed $1,500,000 total costs per year. The application must describe how the funds will be used (including examples of studies), what review procedures will guide the Executive Committee for distributing the funds, and what criteria will be used for distribution of funds. Budget - As a part of the proposed detailed overall first year budget and summary budgets for future years, the applicant should demonstrate evidence that the budget requests for the CL and SDMC are consistent with the work scope of the scientific agenda. A composite budget should be included, followed by individual budgets. At a minimum the budget request should include four categories: (i) Operations Center, (ii) administrative support for the VLG Leader, scientific committees and annual meetings, (iii) projected transitioning costs for ongoing clinical trials, and (iv) discretionary funds not to exceed $1.5 million of the total cost budget request. Linkages - CORE applicants should include in their application their current linkages and or specific plans for linkages with other relevant HIV research related efforts. The following support linkages are either REQUIRED as specified or strongly ENCOURAGED when not specified: a. Community Advisory Boards [REQUIRED]: U.S and international b. HIV Prevention Trials Network Leadership [ENCOURAGED]: c. Acute Infection and Early Disease Research Network [ENCOURAGED] d. Centers For AIDS Research (CFARs) [ENCOURAGED] e. International Research Groups [ENCOURAGED] - UNAIDS/WHO, IAVI, etc B. Central Laboratory Application The CL application is not subject to the page limitations as stated in the form PHS 398. However, the Research Plan must be limited to 75 pages. Appendices may be used for SOPs and other detailed information, with the understanding that these may not be made available to all reviewers. When preparing your application, use the topics listed below and items under (Special Requirements, Terms and Conditions of Award) Central Laboratory Responsibilities as a guide for writing the research plan in lieu of items a- d listed on pages 16-17 of the PHS 398 application brochure. However, the "Gender and Minority Inclusion for Research Involving Human Subjects", "Participation of Children" and (e) "Human Subjects" must be included in the Research Plan. The workscope and activities proposed by the CL must be consistent with the research agenda proposed by the CORE. The CL application should clearly describe the role, experience and expertise in the development/execution of laboratory work in the context of the scientific research agenda. The CL budget must show linkage to the research priorities in the CORE application. Principal Investigator and Coordinating and Operations Center (CORE) Affiliate - The PI for the CL will indicate in the CL application the CORE with which they plan to affiliate. The CORE affiliate must be stated both in a cover letter and in the application. The applications should be included in the same package with the affiliated CORE and SDMC. Laboratory Expertise - The application must provide documentation of plans and standard operating procedures for carrying out laboratory studies in the area of virology and immunology that would be necessary for anticipated clinical trials in the HVTN. This would include procedures for supplying scientific, administrative and regulatory reports to the Executive Committee and DAIDS. Organizational Structure/Management Plan - The CL application must include an organizational chart, procedures for communicating with the Operations Office and other collaborating institutions, and availability of experienced laboratory staff including areas of laboratory based scientific expertise. The management plan must address areas of responsibility of key personnel. The justification for staffing levels for each category of staff should relate to projected workload in terms of study size, study phase, number, and complexity of protocols. If the CL is organized as a network, justification for each of the subsites, as it relates to the scientific research agenda, and including a budget justification, needs to be included. Additionally, a detailed management plan to assure the coordinated functioning of the CL network should be included. A plan for transition from current sites should be included, if appropriate. Central Laboratory Capabilities - Each application for a CL must provide evidence of laboratory research and assay capabilities by describing SOPs that address: (a) plans for laboratory administration, (b) procedures for collection and testing of laboratory specimens including quality control procedures, (c) plans for coordinating with the HVTN statistical center developing/maintaining laboratory tracking systems, centralized storage and retrieval of specimens, (d) interface with HVTN statistical center for tracking laboratory specimens and merger of laboratory data with clinical data, and (e) plans for training clinical site laboratory personnel to carry out some laboratory testing as defined in specific protocols. The application should describe, in detail, the laboratory requirements and expectations to be imposed on the HVTUs and other collaborators. C. Statistical and Data Management Center Application The SDMC application is not subject to the page limitations as stated in the form PHS 398. However, the Research Plan must be limited to 100 pages. Appendices may be used for SOPs and other detailed information, with the understanding that these may not be made available to all reviewers. When preparing your application, use the topics listed below and items under SDMC Responsibilities (Special Requirements, Terms and Conditions of Award) as a guide for writing the research plan in lieu of items a-d listed on pages 16-17 of the PHS 398 application brochure. However, the "Gender and Minority Inclusion for Research Involving Human Subjects", "Participation of Children" and (e) "Human Subjects" must be included in the Research Plan. The SDMC should address in its application how it will ensure that the conditions of the new Guidelines for Gender and Minority Representation and Inclusion of children, when appropriate, are met with regard to clinical trials design (e.g., stratifications, sample sizes, levels of statistical significance required according to what is previously known about gender/ethnicity/age effects), and how it will conduct appropriate analyses of any data collected. The workscope and activities proposed by the SDMC must be consistent with the research agenda proposed by the CORE. The SDMC budget must be consistent with the research agenda and priorities in the CORE application. Principal Investigator and Coordinating and Operations Center (CORE) Affiliate - The Principal Investigator for the SDMC application must indicate affiliation with only one HVTN CORE application, and the CORE affiliate must be stated in both a cover letter and in the application. The applications should be included in the same package with the affiliated CORE and CL. Statistical Expertise - The application must provide documentation of plans and standard operating procedures for the timely interim analyses of safety and efficacy, final analyses for publication, and procedures for supplying scientific, administrative and regulatory reports to the Executive Committee and DAIDS. Samples of protocols should be provided in the appendices to demonstrate experimental design, methods of analysis, and sample size calculations. If the SOPs and protocols are not available, this information should be described in detail in the text of the application. Organizational Structure/Management Plan - The application must include an organizational chart, procedures for communicating with the Operations Office and other collaborating institutions, availability of experienced biostatisticians and other key statistical scientific leadership. The management plan must address areas of responsibility of key personnel. The justification for staffing levels for each category of staff should relate to projected workload in terms of study size, study phase, number, and complexity of protocols. The application should also include plans for developing the processes related to collaborations with investigators external to the HVTN and plans for providing public access to selected datasets in a timely fashion. Data Management Capabilities - Each application for a SDMC must provide evidence of data management capabilities by describing SOPs that address: (a) plans for database design and administration, (b) procedures for data collection, management, analysis and quality control, (c) plans for developing/maintaining subject randomization systems, centralized storage and retrieval of data, (d) interface with HVTN Central Lab and HVTN site laboratory personnel for tracking laboratory specimens and merger of laboratory data with clinical data, (e) plans for training site personnel and DAIDS Clinical Site Monitoring contractor, and (f) plans for providing an electronic mail system. In addition, the application should describe, in detail, plans for transition, if necessary. The application should also describe, in detail, any hardware and software requirements and expectations to be imposed on the HVTUs and other collaborators. REVIEW CONSIDERATIONS Review Procedures Upon receipt, applications will be reviewed for completeness by the Center for Scientific Review (CSR) and for responsiveness by NIAID staff. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration or review. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAID in accordance with the review criteria stated below. The review of the HVTN CORE, CL, and SC applications will focus on each applicant"s ability to contribute to the HVTN scientific agenda, as well as the ability to provide leadership and expertise in the conduct of vaccine clinical trials. The second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council (NAAIDC). General Review Criteria The criteria to be used in the evaluation of grant applications are listed below. Criteria specific to this RFA are included with the general criteria. To put these criteria in context, the following information is contained in instructions to the peer reviewers. The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. Specific Review Criteria Coordinating and Operations Center (CORE) Application 1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? -- Quality of the scientific research agenda to address current and evolving needs in vaccine development, including the proposed ranking of the research priorities and justifications. -- Evidence that the research agenda reflects a broad understanding of HIV vaccine research within the changing context of the HIV/AIDS epidemic and of the implications/consequences of vaccine research worldwide. 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? -- Adequacy of the proposed research plans including the approach to set/redirect priorities, initiate studies, transition ongoing clinical trials, and govern Group activities, and criteria for affiliated HVTN clinical sites nationally and internationally. -- Adequacy of proposed procedures for protocol development, implementation, and oversight, committee management, and fiscal management. -- Strength and adequacy of the proposed management plan including: -- bylaws for governance including the election of HVTN Leadership and committee membership, -- mechanism for effective communication, -- operational plans for the delegation of authorities, decision making, and fiscal management, and -- performance evaluation plans and standards for participating institutions including corrective measures and principles of resource reallocation. -- Adequacy of outreach plan to ensure the inclusion of women, children, minorities and community representatives in all aspect of the proposed research and Group activities. -- Adequacy and feasibility of plans to foster participation of new investigators, especially women and racial/ethnic minorities, in activities at all levels of the HVTN. -- Adequacy of the plan for establishing and maintaining linkages with sites capable of performing Phase II/III and III HIV vaccine trials domestically and internationally, and for the plans to rapidly implement such Phase II/III and III trials when they become necessary. 3. Innovation. Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? -- Evidence that the research agenda addresses innovative approaches to the development and clinical evaluation of HIV vaccines, and the ability to respond to changing scientific priorities nationally and internationally. 4. Investigator. Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? --Adequacy of the qualifications, research experience, and time commitment of the PI for the CORE award. Adequacy of the qualifications and research experience of the proposed scientific leadership, including but not limited to, previous experience with design, administration, management, and coordination of multi-center clinical trials. 5. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? Central Laboratory Application 1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? -- Strength of the proposed scientific contributions of the CL to the HVTN scientific agenda. 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? -- Adequacy of the plans for achieving the proposed CL scientific contributions, including and the criteria for the selection and expertise of the proposed laboratories.. -- Adequacy of the proposed linkage among the various components that comprise the HVTN, as well as the ability to carry out the proposed responsibilities. -- Adequacy and quality of the CL network management plan, if appropriate. 3. Innovation. Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? -- Quality of the plan to develop and implement new assay technologies. 4. Investigator. Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? -- Adequacy of the qualifications, experience and availability of the key personnel to achieve the stated scientific goals and administrative responsibilities of the CL. 5. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? -- Adequacy of available facilities and resources to conduct the proposed work. Adequacy of proposed plans to provide or to obtain core laboratory services as required in the CORE application as needed to carry out the HVTN research agenda. Statistical and Data Management Center Application 1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? -- Strength of the proposed scientific contributions of the SDMC to the HVTN scientific agenda. 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? -- Adequacy of the proposed linkage among the various components that comprise the HVTN, as well as the ability to carry out the proposed responsibilities. -- Quality of the plan for both clinical and laboratory database designs, administration, data collection, security, and site-specific training, quality of sample protocols. -- Adequacy of the plan, including sample protocols, for developing and maintaining systems for patient randomization, receiving, recording and reporting of adverse events, and providing timely data analysis. -- Adequacy of plans to ensure the inclusion of women, children, minorities and community representatives in all aspect of the proposed research and Group activities. 3. Innovation. Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? -- Strength of experience in the development of innovative trial designs and analyses, quality of sample protocols. -- Quality of the plan to evaluate and implement new technologies and data collection procedures. 4. Investigator. Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? -- Strength of the qualifications and experience of the Principal Investigator and staff in providing statistical, analytical and data management expertise for multi-center clinical studies. -- Availability of the proposed SDMC director as well as other biostatisticans and data system personnel to provide statistical leadership. 5. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? Review Criteria for Protection of Human Subjects and for Gender and Minority and Children Representation The following section expands upon review criteria for the Protection of Human Subjects and for Gender and Minority and Children Representation. This section applies to all applications responding to this RFA. 1. Adequacy of the proposed means for protecting against adverse effects of the research upon humans, animals or the environment, where such are involved. 2. In clinical studies, if there is inadequate representation of any gender and/or racial/ethnic minorities and/or children in a study design AND this affects the potential to answer the scientific question(s) addressed, such inadequacy will be considered deficient in the study design. The deficiency will be reflected in the priority score, unless a convincing justification is provided by the investigator to explain the inadequate representation. AWARD CRITERIA The predominant criteria for funding priorities will be the scientific and technical merit of the group package as determined by peer review. Consideration will be given to the cost-effectiveness of the proposed studies, the availability of funds, and the ability of the VLG/HVTN to adequately address all needs of the scientific agenda. INQUIRIES Inquiries concerning this RFA are strongly encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Margaret I. Johnston, Ph.D. Division of AIDS National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 2A07 Bethesda, MD 20892-7620 Bethesda, MD 20852 (for express/courier service) Telephone: (301) 496-8200 FAX: (301) 480-4582 Email: pj7p@nih.gov Direct inquiries regarding regulatory affairs and oversight information to: MaryAnn Luzar, Ph.D. Division of AIDS National Institute of Allergy and Infectious Diseases Solar Building 6003 Executive Boulevard, Room 2B10 Bethesda, MD 20892-7620 Bethesda, MD 20852 (for express/courier service) Telephone: (301) 435-3737 FAX: (301) 480-5703 Email: ml29g@nih.gov Direct inquiries regarding review issues and special instructions for application preparation, address the letter of intent to, and mail two copies of the application and all five sets of appendices to: Dianne Tingley, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4C07 Bethesda, MD 20892-7610 Bethesda, MD 20852 (for express/courier service) Telephone: (301) 496-2550 FAX: (301) 402-2638 Email: dt15g@nih.gov Direct inquiries regarding fiscal matters to: Ms. Ann Devine Grants Management Branch National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4B23 Bethesda, MD 20892-7610 (For express mail or courier us 20852) Bethesda, MD 20852 (for express/courier service) Telephone: (301) 496-5601 FAX: (301) 480-3780 Email: ad22x@nih.gov Schedule Letter of Intent Receipt Date: November 30, 1998 Pre-Application Meeting: November 23, 1998 Application Receipt Date: February 12, 1999 Scientific Review Date: June 1999 Advisory Council Date: September 1999 Earliest Award Date: September 1999 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.855 and 93.856. Awards are made under authorization 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 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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