HIV VACCINE CLINICAL TRIAL UNITS Release Date: June 18, 1999 RFA: AI-99-009 National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: August 18, 1999 Application Receipt Date: October 14, 1999 PURPOSE The Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID) is soliciting applications for HIV Vaccine Trial Clinical Units (HVTUs) which are integral parts of an HIV Vaccine Trials Network (HVTN) designed to carry out a comprehensive scientific agenda on HIV vaccines. The HIV Vaccine Trials Network (HVTN) will be a cooperative network of NIAID awardees that will implement a comprehensive agenda of clinical research on HIV vaccines in the U.S. and abroad. The HVTN will have: o A single Vaccine Leadership Group (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 Principal Investigator (PI) of the Core. Applications for the VLG have been solicited under RFA AI-98-014 available at grants.nih.gov/grants/guide/rfa-files/RFA-AI-98-014.html o The HIV Vaccine Trial Clinical Units (HVTUs) being solicited by this RFA. The HVTUs will (1) contribute to the HVTN research agenda, (2) participate in domestic and international Phase I and II clinical trials of candidate HIV vaccines, and (3) participate in domestic and international Phase III efficacy trials of HIV vaccines. Potential applicants should refer to the following web site for further information on this initiative: http://www.niaid.nih.gov/daids/vtn-ptn 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 other prevention strategies to prevent HIV-1 transmission, domestically and internationally (RFA AI-98-015 available at grants.nih.gov/grants/guide/rfa-files/RFA-AI-98-015.html was released October 30, 1998) Clinical trials of vaccines focused on questions around maternal-infant transmission will be conducted within the HPTN in collaboration with the HVTN and, when desirable, the Pediatric AIDS Clinical Trials Network. 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 Trial Units, is related to the priority area of HIV infection. Potential applicants may obtain a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private institutions (such as universities, colleges, hospitals, laboratories, state and local governments) and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. An institution may submit more than one HVTU application, and/or a single application encompassing one or more scientific area's or approaches. An HVTU application may be a single site or may include multiple collaborating sites. In the case of collaborating sites, one institution will be the grantee and the other sites will be consortia. In all cases, justification should be provided in terms of (1) scientific, administrative, and fiscal management; (2) cost- effectiveness of the structure; and (3) adequacy of provisions for inter- organization coordination, oversight for the contributing/participating groups, subcontracts, or organizations. Documentation should be provided for any financial relationship between the applicant's organization and other researchers, organizations, consultants, etc. See Appendix A for instructions for Federal Agencies that wish to apply. 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 anticipated award date is June 2000. The total project period for applications submitted in response to this RFA may not exceed five years. At present, the NIAID is administratively limiting the duration of U01 cooperative agreements to four years; this administrative limitation may change in the future. At this time, the NIAID has not determined whether and how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE Approximately $13 million total costs (direct and indirect) will be available for the first year of support. NIAID estimates that 8 to 10 awards will be made. 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 four years of the grant will be contingent upon satisfactory progress during the preceding years, the numbers of participants needed for the research agenda, and availability of funds for this purpose. DEFINITIONS AIDS Vaccine Evaluation Group (AVEG) - Multi-institutional clinical infrastructure currently responsible for the conduct of Phase I/II HIV vaccines. This contract program is scheduled to terminate in fiscal year 2000 and will be extended to provide for a transition of ongoing trials to the HVTN. Central Laboratory (CL) - the HVTN component that will implement state-of-the-art assays and technologies that are essential for the completion of the vaccine research agenda. 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. Coordinating and Operations Center (CORE) - The VLG leadership (PI) and Operations Office. The CORE coordinates all aspects of the HVTN and has oversight for the CL and SDMC. Data and Safety Monitoring Board (DSMB) - An independent group of experts established by NIAID and charged with the responsibility of monitoring the progress of large clinical 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 these trials based on observed beneficial or adverse effects of the interventions under study. This board panel is funded and managed separately by NIAID. Division of AIDS (DAIDS) - The extramural Division that has the primary responsibility within the NIAID for the design, implementation and oversight of basic and clinical research programs on HIV/AIDS. Executive Committee - Established and chaired by the PI of the VLG, this is the main governing body of the HVTN responsible for the conduct and overall activities of the HVTN. Membership of the Executive Committee will be determined by HVTN policies and procedures. HIV Network for Prevention Trials/HIV Network for Efficacy Trials (HIVNET) - Multi-institutional clinical infrastructure currently responsible for the conduct of Phase I-III clinical trials of non-vaccine prevention modalities and Phase II/III vaccine clinical trials. This contract program is scheduled to terminate in Fiscal Year 2000 and will be extended to provide for a transition of ongoing trials to the HPTN. HIV Prevention Trials Network (HPTN) - The HPTN will be a collaborative network of institutions comprised of the CORE, CL, HPTUs, and the SDMC, designed to carry out a comprehensive scientific agenda of HIV prevention research. The network will conduct domestic and international clinical and related laboratory research towards this objective. The mission will be to identify, prioritize, and conduct research on promising prevention intervention concepts for the prevention of HIV disease worldwide. HIV Prevention Trials Unit (HPTU) - An HPTU is a clinical site that is a member of the collaborating group of institutions comprising the HPTN. An HPTU may be organized as a single clinical site or a main site and several satellites (subunits) under the leadership of a Principal Investigator. HIV Vaccine Trials Network (HVTN) - The HVTN will be a collaborative network of institutions comprised of the CORE, CL, HVTUs, and the SDMC, designed to carry out a comprehensive scientific agenda on HIV vaccines. The network will conduct domestic and international clinical and related laboratory research towards this objective. The mission will be to identify, prioritize, and conduct research on promising vaccine concepts for the prevention of HIV disease worldwide. HIV Vaccine Trials Unit (HVTU) - An HVTU is a clinical site that is a member of the collaborating group of institutions comprising the HVTN. An HVTU may be organized as a single clinical site or a main site and several satellites (subunits) under the leadership of a Principal Investigator. 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 by subcontract under the cooperative agreement award to a HVTU. Subunits may be established to contribute to the scientific agenda and/or clinical trial accrual goals. 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; these three will be the core of the Executive Committee. Vaccine and Prevention Research Program (VPRP) - The VPRP is a unit within DAIDS that is responsible for the design, implementation, and oversight of HIV vaccine and prevention research programs funded by the Division. RESEARCH OBJECTIVES BACKGROUND The development of safe and effective HIV vaccines for worldwide use is one of the highest priorities to the NIAID. 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 (primarily the AVEG -AIDS Vaccine Evaluation Group) 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 will enter Phase I testing in the next five years. One Phase II trial has been completed with nearly 300 volunteers enrolled from heterogeneous populations, including those at high risk of exposure to HIV. The study was comprised of two HIV-1 gp120 subunit vaccines and evaluated their safety and immunogenicity. The impact of trial participation on high-risk activity in populations at risk for acquiring HIV-1 infection was also evaluated. A second Phase II trial, evaluating the safety and immunogenicity of live recombinant canarypox-HIV constructs (ALVAC vCP205 - Pasteur Merieux Connaught) administered with or without HIV-1 SF2 recombinant gp120 (Chiron Vaccines), is in the follow- up phase with 435 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, antibody-dependent cellular cytotoxicity (ADCC) and cytotoxic T lymphocytes (CTL) against selected HIV epitopes. Studies have also demonstrated that certain adjuvants are useful for inducing increased levels of antibody response. NIAID is now establishing the HVTN, a group of clinical and laboratory researchers that will have the capability and capacity to carry out a comprehensive HIV vaccine research agenda focused on the clinical evaluation of promising HIV vaccine candidates, and addressing key scientific questions related to vaccine research and development. Through this process the HVTN will transition ongoing studies from the AVEG and HIVNET and initiate new studies according to the network's scientific agenda and priorities. The HVTN needs capacity and capability to conduct Phase I and Phase II (safety and immunogenicity) trials of candidate HIV vaccines, domestically and in foreign 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. 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 other prevention strategies to prevent HIV-1 transmission, domestically and internationally (RFA AI-98-015 available at https://grants.nih.gov/grants/guide/rfa-files/RFA-AI-98-015.html was released October 30, 1998) Clinical trials of vaccines focused on questions around maternal- infant transmission will be conducted within the HPTN in collaboration with the HVTN and, when desirable, the Pediatric AIDS Clinical Trials Network. 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. SCOPE The objective of this RFA is to solicit applications from clinical sites (HVTUs) that will implement the scientific agenda of the HVTN and contribute to updating that agenda as necessary. As such, responses to this RFA are required, at a minimum, to address three major areas: (1) scientific ability to contribute to the HVTN research agenda, (2) capability and clinical expertise of a site to conduct Phase I and II clinical trials of candidate HIV vaccines, domestically and/or internationally, and (3) ability to expand to recruit participants for large, multi-center efficacy trials of one or more HIV vaccine candidates. 1.Contribute to the HVTN research agenda. Applicants should describe their expertise, experience and capacity to conduct vaccine research in the U.S. and foreign countries, as it relates to the HVTN scientific agenda. Applicants should demonstrate their ability to lead, contribute to, and prioritize vaccine clinical research, including their scientific contributions to the design and conduct of HIV vaccine or related trials and the conduct of laboratory research ancillary to HIV vaccine trials, such as the development or applications of new assays, or addressing basic research questions utilizing vaccine trial specimens. 2. Phase I and II Vaccine Trials. The capability and experience to implement and manage a Phase I and/or II vaccine clinical trial based in the U.S. and/or a foreign country as it relates to the HVTN scientific agenda should be described. Applicants should assume that they will be participating in four to six domestic phase I trials and one phase II domestic trial at any time, and/or in one phase 1 or phase II trial at international sites, at any time Requirements for HVTUs are presented in A. Awardee Rights and Responsibilities in TERMS AND CONDITIONS OF AWARD below. 3. Efficacy trials. Applications should describe a plan for transition from Phase I and II vaccine study activity to vaccine efficacy trial recruitment, enrollment, immunization, and short-term and long-term follow-up, consistent with the requirements of the HVTN research agenda. 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 HVTUs. Specific tasks and activities in carrying out the activity will be shared among the awardees, DAIDS staff and its contractors. A. Awardee Rights and Responsibilities Awardees will have responsibility for conducting the research within the guidelines of the RFA, and agree to the participation of NIH staff in those aspects of scientific and technical management of the project described in these terms and conditions. The organization or individual awarded cooperative agreement by NIH that is responsible and accountable for the use of the funds provided and for the performance of the grant-supported project or activities. The grantee is the entire legal entity even if a particular component is designated in the award document. The grantee is legally responsible and accountable to NIH for the performance and financial aspects o of the grant- supported project. Specifically, awardees have primary responsibilities as described below. 1. The awardee accepts and will abide by the Bylaws of the HVTN, the research priorities of the HVTN scientific agenda, and accepts the performance standards established by the HVTN. 2. The awardee will follow the International Conference on Harmonization's (ICH) Guideline for Good Clinical Practice (GCP). In addition, each HVTU will have experienced physician investigators associated with the project who have demonstrated expertise in multi-center clinical trials. Plans for adequate staffing will be included, such as the required nursing, pharmacy, and data management and outreach personnel needed to recruit and screen potential participants, implement clinical research protocols, perform protocol required assessments, including laboratory assessments, perform protocol specific assays for safety monitoring, dispense investigational agents and appropriately document clinical data, to meet all data reporting requirements of the HVTN and DAIDS. Plans will also include the necessary coordination and support of research activities, including medical/clinical procedures and/or social services, quality assurance, laboratory procedures, and secretarial and administrative support. For applicants proposing sub-sites to a main clinical unit, or a consortia of sites, provide for a co-investigator(s) at an appropriate level of effort who shall provide scientific leadership and shall be responsible for development and implementation of mechanisms to ensure local government (if international) and community preparedness for, and involvement in, clinical trials research plans and activities in concert with the Principal Investigator of the main unit. 3. The awardee will develop and implement strategies for recruitment, retention and long-term follow-up of study participants for Phase I and Phase II trials of experimental HIV vaccines, both in the U.S. and/or in foreign countries with high HIV seroincidence. The awardee make every effort to recruit volunteers for domestic or international Phase I trials who are representative of the geographic region, paying particular attention to gender and members of minority groups (e.g., in the U.S. inclusion of African-Americans, Latinos/Latinas, Asians and Pacific Islanders, and Native Americans). Phase II trials may require recruitment of both healthy volunteers at low risk of HIV-1 infection, as well as individuals more representative of the populations at higher risk for acquiring HIV-1 infection (e.g., men who have sex with men, injection drug users, and women and men at increased risk due to heterosexual contacts). Appropriate HIV counseling of potential volunteers regarding HIV-1 transmission and methods to prevent transmission shall be provided, as shall mechanisms to educate the relevant communities about HIV-1 and HIV vaccine trials. 4. The awardee will provide long-term follow-up for volunteers who become infected with HIV after trial enrollment. Each site will refer an infected volunteer to qualified physicians or clinics for medical care after HIV infection is determined. In addition, the awardee will provide information on availability and location of clinical trials with potentially beneficial treatments for HIV-1 infection and disease to the infected volunteers. 5. Quality Assurance: Investigational Drug Management. The awardee performing clinical studies sponsored by the NIAID must comply with all Federal regulations for investigational agents, and with DAIDS Standard Operating Procedures. Before clinical studies are initiated, a unit must submit and receive approval from DAIDS of a site registration plan, a pharmacy plan, and the individual protocols. 6. Quality Assurance: Internal Data Quality Control. The awardee must establish an internal quality assurance and quality management plan to assess the quality of the research recording and operating procedures. These plans are subject to approval by the HVTN leadership and DAIDS, and apply to both the main unit and any affiliated sites. 7. Quality Assurance: External Data Quality Control. The awardee shall cooperate with the DAIDS Clinical Site Monitoring contractor, and other federally supported site monitoring staff, who will inspect records to assure compliance with all federal regulations and IHC's GCP guidelines, and NIH policies on patient safety, data completeness and accuracy, and quality control. 8. Quality Assurance: Local Clinical Laboratory. The awardee will follow the standards set forth by the HVTN for laboratory certification. 9. Participation of New Investigators, Women and, Minorities. The awardee will establish procedure and opportunities to ensure the participation of new investigators, especially women, and racial/ethnic minorities, in all aspects of the research effort. 10. Community Advisory Board (CAB). The awardee will have a CAB as required of all NIAID funded sites to ensure community input into the research process and to foster a partnership between researchers and the community, particularly the population served by the individual unit and/or research study. 11. Federally Mandated Regulatory Requirements. The awardee shall 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 awardee must be able to demonstrate that: (i) each institution conducting trials has a current, approved Project 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 their legal representative) gives written informed consent prior to entry on study. In addition, DAIDS has established policies and procedures delineated in the "Serious Adverse Experience Reporting Manual for the Vaccine and Prevention Research Program" (A copy of this document can be requested by contacting Dr. MaryAnne Luzar, listed under Inquiries. The awardee must comply with all SAE reporting requirements. 12. For trials conducted in foreign countries, the awardee 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 Council for International Organizations of Medical Sciences (CIOMS). 13. Reporting Requirements. The awardee will adhere to HVTN Executive Committee policies for reporting. Reports may include volunteer recruitment and retention rates, volunteer demographics, timeliness and completeness of all data, including adverse events, completeness and quality of laboratory data, etc. 14. Publication of Data. The awardee will comply with the rules and regulations set forth by the HVTN leadership, DAIDS, and manufacturers, regarding presentation and publication in scientific literature of major findings. 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 will have access to all data generated under this cooperative agreement and may periodically review it. 15. National Meetings - The awardee's Principal Investigator will attend two 2- day national meetings/year. The HVTN is expected to hold at least one of the two national meetings in the Washington, D.C. metropolitan area. B. NIAID Staff Responsibilities The NIAID will have substantial scientific and programmatic involvement during the conduct of this activity, through technical assistance, advice, and coordination. The role of DAIDS staff is to assist and facilitate. Although communication primarily will be with the Executive Committee of the HVTN, substantial communication is anticipated with all members of the HVTN. 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 HVTN Executive Committee to assure that the research efforts are consistent with the NIAID agenda for HIV clinical research and complements those of other NIAID and NIH programs. 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 final protocol must be approved by the Associate Director, VPRP. The DAIDS Prevention Sciences Review Committee (PSRC) (PSRC is a DAIDS committee created to provide scientific support and assistance during protocol development, and overall evaluation of research plans; in the context of relevance to NIAID HIV/AIDS research and on the basis of sound methodology, reasonable feasibility and safe, ethical standards) will evaluate the initial trial concept as well as a near final protocol 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. If significant safety or regulatory concerns exist and the 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. DAIDS will have the option to file an IND on investigational agents evaluated in HVTN studies. Appropriate DAIDS staff will advise the HVTU investigators on specific regulatory requirements for IND sponsorship. In situations where DAIDS is the IND sponsor, DAIDS 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) - Pharmaceutical collaborators providing investigational agents to DAIDS will negotiate a CTA with DAIDS describing respective responsibilities and rights. The agreement will include, but is not limited to, IND sponsorship, safety and data monitoring, publications, and access to data. Generally, terms in the CTA covering data access and sharing will conform to policies developed jointly by the HVTN and DAIDS. Pharmaceutical collaborators generally request that patentable inventions discovered in the studies be brought to their attention, and subsequently the company will have right of first refusal, provided that the collaborator has rights to the background patent. The awardee must provide a Letter of Understanding to DAIDS acknowledging these rights. 5. DAIDS Role during Study Conduct. DAIDS will provide Regulatory Training at an annual meeting held in the Washington, D.C. area. DAIDS will also provide ongoing and start-up training to domestic and international collaborators or for vaccine studies being conducted in domestic and 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 organization or company, monitoring activities will be the responsibility of 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 and/or reviewing other relevant information, 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. DAIDS has an external Clinical Site Monitoring Contract to evaluate GCP, regulatory compliance, accurate protocol implementation, internal quality assurance, and test agent accountability. The monitoring contractor will visit the awardee periodically to review selected protocols, provide training on general protocol conduct, review internal Quality Assurance/Quality Control (QA/QC) plans, audit pharmacies, and document error resolution. 9. Review of Performance. The performance of all sites will be reviewed at least annually by the Associate Director, VPRP, other VPRP staff, and the HVTN Executive Committee using the comprehensive annual progress report, clinical site evaluations developed by the HVTN Executive Committee, and site monitoring reports provided to DAIDS by its contractor. DAIDS staff will assist the HVTN 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. C. Collaborative Responsibilities 1. Group Governance. The VLG will establish an Executive Committee as the central decision-making body for the HVTN that will include the PI's of the three VLG components: the Core, Statistical Center, CL, as well as representative HVTU PIs. The PI of the Core will serve as the chairperson. The Committee will also include the Associate Director, VPRP, or designee, as a voting member. Additional membership and any change in the chairperson will be accomplished as defined in the HVTN Bylaws. 2. Performance. The leadership of the HVTN will establish procedures for evaluating the performance of all HVTUs. This mechanism will include a procedure for making recommendations to DAIDS regarding adjustment of institutional funds based on level of contribution and performance. D. 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 https://grants.nih.gov/grants/guide/notice-files/not94-100.html 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: https://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 August 18, 1999, a letter of intent that includes a descriptive title of the overall proposed research, the name, address, telephone number, and email address of the Principal Investigator, and the number and title of this RFA. Please note that 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 Potential applicants may refer to the following web site for further information on this initiative: http://www.niaid.nih.gov/daids/vtn-ptn/ Each competing HVTU will submit an application that addresses the RESEARCH OBJECTIVES AND SCOPE and Awardee Rights and Responsibilities (in TERMS AND CONDITIONS OF AWARD) stated above. Applicants should be aware that the Vaccine Leadership Group (VLG) award will not have been made at the time applications are due in response to this HVTU RFA. It is also possible that the research agenda of the VLG awardee will be modified as a result of the peer review process prior to award. It is the intent of NIAID to aid applicants responding to this RFA; see under INQUIRIES for how to contact Dr. Jorge Flores for further information. In addition, HVTU applicants may have the opportunity to submit a brief addendum to their application prior to review for the purpose of clarifying or addressing issues raised by the NIAID after review of the VLG research agenda. Further guidance from NIAID on vaccine research needs, can be found in the HVLG RFA. Applications must be submitted on the standard research grant application form PHS 398 (rev. 4/98). 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. Applications are also available on the internet at https://grants.nih.gov/grants/forms.htm Each application requesting support as an HVTU is subject to the following page limitations: o 25 pages for the Research Plan for a single clinical site application as specified in the Form PHS 398. o 5 additional pages for each additional clinical site The RFA title (HIV Vaccine Trial Units) and number (AI-99-009) must be typed on line 2 of the face page of the application and the YES box must be marked. The RFA label and line 2 of the application should both indicate the RFA number. The RFA label must be affixed to the bottom of the face page. 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. Submit a signed, typewritten original of the application, including the checklist, and three signed exact photocopies (but no appendices) 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 five copies of appendices must 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 October 14, 1999. Applications received after this date will be considered non-responsive to this RFA and will be returned without review. In summary, applications in response to this RFA must include, but are not limited to, responses to the details set forth in the SCOPE section. Specifically: 1. Contribute to the HVTN research agenda. Applicants should describe their expertise, experience and capacity to conduct vaccine research in the U.S. and foreign countries, as it relates to the HVTN scientific agenda. Applicants should demonstrate their ability to lead, contribute to, and prioritize vaccine clinical research, including their scientific contributions to the design and conduct of HIV vaccine or related trials and the conduct of laboratory research ancillary to HIV vaccine trials, such as the development or applications of new assays, or addressing basic research questions utilizing vaccine trial specimens. 2. Phase I and II Vaccine Trials. The capability and experience to implement and manage a Phase I and/or II vaccine clinical trial based in the U.S. and/or a foreign country as it relates to the HVTN scientific agenda should be described. Applicants should assume that they will be participating in four to six domestic phase I trials and one phase II domestic trial at any time, and/or in one phase 1 or phase II trial at international sites, at any time. 3. Efficacy trials. Applications should describe a plan for transition from Phase I and II vaccine study activity to vaccine efficacy trial recruitment, enrollment, immunization, and short-term and long-term follow-up, consistent with the requirements of the HVTN research agenda. BUDGET INSTRUCTIONS Each individual application must contain a detailed budget for the first 12-month period and a budget for the entire proposed project period. Note that for AVEG or HIVNET sites conducting vaccine clinical trials, the HVTN leadership group will develop a plan for transition of these studies to the HVTN. Current AVEG or HIVNET awardees that apply for awards under this RFA should include in the budget the costs for completion of these current studies, and any new studies that may be implemented under the HVTN. Budgets should address at a minimum the following: o Scientific, medical, technical, recruiting/outreach and support staff o Local laboratory costs consistent with performance of the clinical laboratory tests required in a typical Phase I and II vaccine trial. The applicant should also include laboratory costs for screening potential volunteers. o Travel, communications, general recruiting and outreach costs (including volunteer reimbursement costs) o Support of a Community Advisory Board, including travel of CAB members to HVTN meetings o Costs for the Principal Investigator to attend two 2-day meetings annually o Necessary equipment and supplies PERSONNEL 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. REVIEW CONSIDERATIONS 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 will focus on the scientific merit of each applicant's proposed contributions to the cooperative group consistent with the HVTN's scientific agenda. 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. 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 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? - Scope and quality of the proposed scientific contributions of the applicant to the HVTN research agenda - Quality of the operational contribution to the HPVN research agenda - Evidence that the scientific contribution reflects a broad understanding of HIV vaccine research within the changing context of the HIV/AIDS epidemic and of the implications/consequences of prevention 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? - Availability of relevant populations for vaccine trials, particularly minority populations for U.S. sites and subsites (if applicable) - Strength and adequacy of plans and mechanisms for recruitment and retention of clinical trial participants from relevant populations - Strength and adequacy of the site's and subsites' (if applicable) management and communication plan, particularly for subsites/sites outside the U.S. - Appropriateness of arrangement and clearances with local and national authorities - Adequacy of plan to implement Phase II/III and III HIV vaccine trials including ability to expand - Adequacy of plans for CAB and community involvement at the site and subsites (if applicable) - Adequacy and feasibility of plans to foster participation of new investigators, especially women and racial/ethnic minorities 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 proposed scientific contribution to the HVTN incorporates innovative approaches to the development and clinical evaluation of HIV vaccines - Evidence that the proposed plans for recruiting and retaining target populations employ innovative methods, especially in studies recruiting populations at higher risk for acquisition of HIV - Evidence that the proposed plans for implementing Phase II/III vaccine trials utilize innovative approaches for expanding recruitment and ensuring adequate retention - Evidence that the proposed plans for community education for HIV preventive vaccine trials incorporate effective strategies 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 professional qualifications, research experience, and time commitment of the PI and key personnel, and previous experience with participation in a multi-center clinical trials network 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? - Evidence of the necessary expertise, experience and capacity of the site and subsites (if applicable) to carry out the aims of the HVTN research agenda - Strength and adequacy of the plan to ensure a synergistic environment for institutions that submit more than one site application Additional Specific Review Criteria 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, 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 applications in response to this RFA. Consideration will be given to the following factors in the final selection of applications to be funded: (1) inclusion of populations currently under-represented in clinical trials in the described research agenda; (2) cost-effectiveness of proposed studies; and (3) the ability of the applicant to contribute to the scientific agenda. SCHEDULE Letter of Intent Receipt Date: August 18, 1999 Application Receipt Date: October 14, 1999 Scientific Review Date: January 2000 Advisory Council Date: April 2000 Earliest Award Date: June 1, 2000 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: Jorge Flores M.D. Division of AIDS National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 2A11 Bethesda, MD 20892-7620 Bethesda, MD 20852 (for express/courier service) Telephone: (301) 435-3578 FAX: (301) 402-3684 Email: jf30t@nih.gov Direct inquiries regarding regulatory affairs and oversight information to: MaryAnne Luzar, Ph.D. Division of AIDS National Institute of Allergy and Infectious Diseases 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 Bethesda, MD 20852 (for express/courier service) Telephone: (301) 496-5601 FAX: (301) 480-3780 Email: ad22x@nih.gov 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. APPENDIX A Federal institutions are, in general, eligible to receive NIH grants, including research project grants and training grants. Federal institutions must also meet the eligibility requirements of the grant program from which support is sought. PHS organizational segments, other than PHS hospitals, may receive NIH grant support under exceptional circumstances only. Such circumstances may include situations where a project cannot be supported within the mission of the applicant PHS agency or organizational segment, the activity cannot be performed elsewhere, its non-pursuit would have an adverse or potentially important impact on the NIH mission, and a grant is determined to be the appropriate means of carrying out the activity. However, NIH may not award a grant to an NIH component. Although the performance site may be at a level lower than the agency or department level of the Federal institution, when an award is made to an eligible Federal institution, the Federal agency or department will be the designated grantee and must assume responsibility for the project. A Federal institution must also ensure that its own authorizing legislation will allow it to receive NIH grants and to be able to comply with the award terms and conditions. A document certifying both the assumption of responsibility and authority to receive a grant must accompany each new and competing continuation application. The certification must be signed by the head of the responsible Federal department or independent agency or a designee who reports directly to the department or agency head. (In the case of the Department of Defense, the Departments of the Army, Navy, and Air Force shall be considered the Federal department; and their Secretaries, the responsible Department head.) This certification is in addition to any certifications that are made by the authorized institutional official's signature on the face page of the application. The certification requirement does not apply to Department of Veterans Affairs' Medical Centers (VAMC), Bureau of Prisons' (Department of Justice) hospitals, PHS hospitals (including Indian Health Service hospitals), or other PHS organizational segments. Investigators with joint appointments at the Department of Veterans Affairs (VA) and an affiliated university must have a memorandum of understanding (MOU) that specifies the title of the PI's appointment, the responsibilities (at both the university and the VA) of the proposed PI, and the percentage of effort available for research. The MOU must be signed by the appropriate officials of the grantee organization and the VAMC and must be updated at least annually. Under this model, there is no involvement of a VA-affiliated non-profit research corporation (VANPC). The joint VA/university appointment of the investigator constitutes 100 percent of his or her total professional responsibilities.
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