HIV PREVENTION TRIAL UNITS Release Date: June 18, 1999 RFA: AI-99-010 National Institute of Allergy and Infectious Diseases National Institute of Child Health and Human Development National Institute of Mental Health National Institute on Drug Abuse Letter of Intent Receipt Date: August 2, 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 Prevention Trial Units (HPTUs), which will be integral parts of an HIV Prevention Trials Network (HPTN) designed to carry out a comprehensive scientific agenda on HIV prevention strategies. This initiative is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Child Health and Human Development (NICHD), the National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH), herein referred to collectively as NIH. The HPTN will conduct domestic and international research on promising biomedical and behavioral strategies for the prevention of HIV transmission among adult, pediatric and adolescent populations. Modalities of interventions may include, but are not limited to: (1) antiretroviral drugs, (2) microbicides, (3) behavioral approaches, (4) barrier and other contraceptive/STD prevention methods, (5) vaccines (in perinatal settings), (6) chemoprophylaxis, (7) treatment of sexually transmitted diseases, and (8) combined approaches. The HPTN will have: o The HIV Prevention Leadership Group (PLG). A single leadership group (PLG) 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. See RFA # AI-98-015 at grants.nih.gov/grants/guide/rfa-files/RFA- AI-98-015.html. o HIV Prevention Trial Units (HPTUs) being solicited by this RFA. The HPTUs will: (1) contribute to the HPTN research agenda, (2) conduct/participate in Phase I, II, and/or III prevention intervention clinical trials domestically and/or internationally, and (3) expand for multiple prevention efficacy trials. 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 HPTN, the NIAID is supporting the creation of the HIV Vaccine Trials Network (HVTN) to perform Phase I, II and expand to Phase III clinical trials of HIV vaccines (AI-98-014 available at grants.nih.gov/grants/guide/rfa-files/RFA-AI-98-014.html, released October 23, 1998) Clinical trials of vaccines focused on questions around maternal-infant transmission will be conducted within the HPTN and may be in collaboration with the HVTN and, when desired, the Pediatric AIDS Clinical Trials Network. It should be noted that sites funded under the HPTN may also serve as effective venues for implementation of larger HIV vaccine trials; therefore linkages between HPTN, HVTN, and 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 Prevention 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 HPTU application, and/or a single application encompassing one or more scientific areas or approaches. An HPTU 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 NIH scientific and programmatic involvement is anticipated during performance of the activity. Under the cooperative agreement, the NIH'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 $15 million total costs will be available for the first year of support. NIH anticipates 10 to 15 awards. The usual PHS policies governing grants administration and management will apply. Although this program is provided for in the financial plans of the NIH, 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 and availability of funds for this purpose. DEFINITIONS Central Laboratory (CL). The CL will implement state-of-the-art assays and technologies that are essential for the completion of the prevention research agenda, as defined in the HPTN PLG Application. In addition to the performance of these assays for the HPTN, 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 HPTN PLG and will provide support for protocol-related studies only. Coordinating and Operations Center (CORE). The CORE consists of the PLG leadership (PI) and Operations Office. The CORE coordinates all aspects of the HPTN and has oversight for the CL and SDMC. 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 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. The Executive Committee, established and chaired by the PI of the PLG, represents the main governing body of the HPTN. This committee will be responsible for the conduct and overall activities of the HPTN. 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 Trial Units (HPTUs). The HPTUs will: (1) contribute to the HPTN research agenda, (2) conduct and participate in Phase I, II, and/or III prevention intervention clinical trials domestically and/or internationally, and (3) expand for multiple prevention efficacy trials. 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 main clinical site or a main site and several subunits under the leadership of a Principal Investigator, or Co-Principal Investigators. 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; these three will be the core of the Executive Committee. The Executive Committee will lead the HPTN. Members of the Executive Committee will be designated by HPTN policies and procedures. Statistical and Data Management Center (SDMC). The SDMC is the component of the HPTN that is responsible to the PLG leadership for the statistical aspects of study design and analysis and management of the HPTN database. Subunit. A subunit is an institution supported by subcontract within an HPTU. 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. The Executive Committee will lead the HVTN. Members of the Executive Committee will be designated by HVTN policies and procedures 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 HIV epidemic continues to grow worldwide despite major advances in understanding the pathogenesis of HIV infection and in our ability to treat the disease. HIV disease is now the leading cause of death among young men and women in the United States (U.S.) and worldwide. The World Health Organization estimates that by the year 2000, approximately 40,000,000 adults and children worldwide will have been infected with HIV, by sexual transmission, mother to infant transmission around the time of birth or through breast feeding, by the transfusion of HIV infected blood or blood products, or by injection drug use. This translates into 16,000 new HIV infections worldwide each day mostly among young adults, and with 1,600 new infant infections daily. Control of the epidemic requires identification of improved affordable methods and strategies for preventing HIV infection. In pursuit of this goal, the Vaccine and Prevention Research Program (VPRP), DAIDS, NIAID, and the other co-sponsoring Institutes foster basic and applied research leading to the development of safe and effective HIV prevention modalities. Through the HIV Network for Prevention Trials (HIVNET) begun in 1993, NIH has supported domestic and international studies to evaluate prevention trial preparedness and the safety and efficacy of promising interventions to prevent sexual, parenteral, and perinatal transmission using HIV seroincidence as the primary trial endpoint. The interventions evaluated encompass topical microbicides, sexually transmitted disease (STD) treatment, prophylaxis to prevent mother- to-child transmission, and behavioral risk reduction strategies. HIVNET studies have been carried out in close coordination and collaboration with other agencies that are involved in prevention research. The HPTN will be a coordinated group of clinical and laboratory researchers that will have the capability and capacity to carry out a comprehensive HIV prevention research agenda focused on the clinical evaluation of promising HIV prevention interventions, and addressing key scientific questions related to prevention research and development. The HPTN will transition ongoing studies from the HIVNET and initiate new studies according to the network's scientific agenda and priorities. In addition to the HPTN, the NIAID is supporting the creation of the HIV Vaccine Trials Network (HVTN) to perform Phase I, II and expand to Phase III clinical trials of HIV vaccines (RFA-98-014 available at grants.nih.gov/grants/guide/rfa-files/RFA-AI-98-014.html, released October 23, 1998.) Clinical trials of vaccines focused on questions around maternal- infant transmission will be conducted within the HPTN and may be in collaboration with the HVTN and, when desired, the Pediatric AIDS Clinical Trials Network. It should be noted that sites funded under the HPTN may also serve as effective venues for implementation of larger HIV vaccine trials; therefore linkages between HPTN, HVTN, and other scientific organizations, are strongly encouraged. SCOPE The objective of this RFA is to solicit clinical field sites (HPTUs) that will implement the scientific agenda of the HPTN and contribute to updating and expanding 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 HPTN research agenda, (2) capability and clinical expertise of a site to conduct Phase I, II, and/or III prevention intervention clinical trials domestically and/or internationally, and (3) ability to expand for multiple prevention efficacy trials. 1. Ability to contribute to HPTN research agenda. Applicants should describe their expertise, experience, and capacity to conduct prevention research in the U.S. and/or a foreign country for specific technical areas (e.g., microbicides, perinatal interventions, behavioral interventions, hormonal contraceptive use, and HIV, etc.) as it relates to the HPTN scientific agenda. Applicants should describe their ability to lead, contribute to, and prioritize prevention research activities, including their scientific contributions to the design and conduct of HIV prevention trials, such as addressing basic research questions utilizing prevention trial specimens. 2. HPTU capabilities. The ability to implement and manage prevention research in the U.S. and/or a foreign country should be described as outlined in the PLG scientific agenda (see APPLICATION PROCEDURES for information regarding how to receive copies of available PLG scientific agendas). Expertise of key staff should be described. Applications should describe the applicant's clinical research organization and include plans, information and documentation that describe the capability to accomplish the work successfully. Requirements of sites are outlined in Awardee Rights and Responsibilities in TERMS and CONDITIONS OF AWARD, below. 3. Plans for expansion for multiple efficacy trials. Applications should contain a plan for expansion for additional populations for prevention trials, as outlined in the PLG scientific agenda. The plan must specify the additional resources, including facilities and personnel, required to expand recruitment, enrollment, short-term and long-term follow-up, consistent with the requirements of the HPTN 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 HPTUs. Specific tasks and activities in carrying out the activity will be shared among the awardees, NIH staff and its contractors. A. Awardee Rights and Responsibilities Awardees will have the primary 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 agrees to accept and abide by the Bylaws of the awarded HPTN, the research priorities of the HPTN scientific agenda, and accept the performance standards established by the HPTN. 2. The awardee will follow the International Conference on Harmonization's (ICH) Guideline for Good Clinical Practice. In addition, each HPTU will have experienced physician/doctoral level investigators associated with the project who have demonstrated expertise in multi-center prevention clinical trials. Plans for adequate staffing should be included, such as the required nursing, pharmacy, data management and outreach personnel needed to recruit and screen potential participants, implement clinical research protocols, perform protocol required assessments, dispense investigational agents (if applicable) and appropriately document clinical data, to meet all data reporting requirements of the HPTN 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. Applicants proposing sub-sites to a main site, or a consortia of sites, should provide plans 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 of the HPTU. 3. The awardee will develop and implement strategies for recruitment, retention and long-term follow up of study participants appropriate to conduct Phase I, II, and/or III clinical trials, both domestically and in foreign countries in the specified technical areas. The awardee will make every effort to recruit volunteers for domestic or international trials who are representative of the populations within their geographical region, paying particular attention to gender and members of minority groups (e.g., in the U.S. should include African-Americans, Latinos/Latinas, Asians and Pacific Islanders, and Native Americans). 4. The awardee will provide long-term follow-up for volunteers who become infected with HIV after trial enrollment. The awardee will refer an infected volunteer to a qualified physician or clinic for medical care after HIV infection is determined. In addition, HPTN clinical sites will submit information on the availability and locality 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 NIH must comply with all Federal regulations for investigational agents, and with DAIDS Standard Operating Procedures. Before clinical studies are initiated, the awardee 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 record, and operating procedures. These plans are subject to approval by the HPTN 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 Laboratories. The awardee shall follow the standards set forth by the HPTN for certification and specifications. 9. Participation of New Investigators, Women and Minorities. The awardee will establish procedures, 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 Boards (CABs). The awardee is required to establish a CAB 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 must comply 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 HPTN Executive Committee will establish policies for reporting requirements of the sites. 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. The awardee must follow all reporting policies set forth by the HPTN. 14. Publication of Data. The awardee must comply with the rules and regulations set forth by the HVTN leadership, DAIDS, and manufacturers, regarding presentation and publication in the 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. B. NIH Responsibilities The NIH will have substantial scientific and programmatic involvement during the conduct of this activity, through technical assistance, advice, and coordination. The role of the NIH staff, as described throughout these terms of cooperation, is to assist and facilitate, not to direct the research activities. Although communication primarily will be with the Executive Committee of the HPTN, substantial communication is anticipated with all members of the HPTN. The following are specific responsibilities of NIH staff in terms of interventional clinical research, and the NIAID's role as a drug sponsor as defined in 21 CFR Part 312. This project is a part of NIH's overall program of prevention research. 1. NIH Coordinating Committee. The Associate Director for VPRP, DAIDS, NIAID, will establish an NIH Coordinating Committee for the HPTN. Members will be selected from each of the sponsoring NIH components. The role of the committee will be to ensure that the awardees receive consistent advice and optimal assistance from the NIH. The VPRP Associate Director, or designee, will serve as chair of this committee. 2. Scientific Role in Sponsored Clinical Research. The Associate Director for VPRP, or designee will work closely with other members of the HPTN Executive Committee to assure that the research efforts are consistent with the NIH agenda for HIV clinical research. DAIDS will serve as a liaison/facilitator between pharmaceutical companies, the FDA, and HPTN investigators. NIH staff of sponsoring NIH components will serve as a resource, and will disseminate information regarding promising new agents, prevention strategies, or developments. DAIDS will also independently support a Data and Safety Monitoring Board (DSMB) that will oversee prevention trials. 3. 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 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 NIH research agenda and other 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, NIH will not provide investigational products or permit expenditure of NIH funds for the proposed investigation. 4. Involvement in Investigational New Drug Applications. DAIDS or other involved NIH organizations will have the option to file an IND on investigational agents evaluated in HPTN studies. Appropriate DAIDS staff will advise the HPTU 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. 5. 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 HPTN 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 intellectual property administrator for each primary trial site must provide a Letter of Understanding to DAIDS acknowledging these rights. 6. 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 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. 7. Role in Protocol Closure. The Associate Director, VPRP, or designee, and designees from co-sponsoring institutes, 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 HPTN Leadership. NIH co-sponsoring institutes, 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. 8. Access to Data. The Associate Director, VPRP, or designee, and designee's from co-sponsoring institutes, 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. Secondary data analysis may be undertaken by the NIH with the concurrence of the grantee. 9. 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 site 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. 10. Review of Performance. The performance of all sites will be reviewed at least annually by the Associate Director, VPRP, other VPRP staff, the co- sponsoring institutes, and the HPTN Executive Committee using a comprehensive annual progress report, clinical site evaluations developed by the HPTN Executive Committee, and site monitoring reports provided by the DAIDS contractor. DAIDS and co-sponsoring Institute staff will assist the HPTN 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 PLG will establish an Executive Committee as the central decision-making body for the HPTN and will include the PIs of the three PLG components: the Core, Statistical and Data Management Center, Central Laboratory, as well as representative HPTU PIs. The PI of the core will serve as the chairperson. The Committee also will include the Associate Director, VPRP, or designee, as a voting member, and representatives of co- sponsoring Institutes included as non-voting ad hoc members. Additional membership and any change in the chairperson will be accomplished as defined in the HPTN Bylaws. 2. Performance. The leadership of the HPTN will establish procedures for evaluating the performance of all awardees. This mechanism will include a procedure for making a recommendation to DAIDS regarding adjustment of institutional funds based on level of contribution and performance. 3. National Meetings. The awardee's Principal Investigator will attend two 2-day national meetings/year. The HPTN is expected to hold at least one of the two national meetings in the Washington, D.C. metropolitan area. D. Arbitration Any disagreement that may arise on scientific or programmatic matters (within the scope of the award) between award recipients and the NIH 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 NIH, and a 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 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 16 years of age and older. The NIH has other programs for HIV clinical research in children under 16 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 Each competing HPTU 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 PLG will not have been awarded at the time applications are due in response to this HPTU RFA. It is also possible that the highest scoring PLG may 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 by making available the research agendas of those applicants who responded to the PLG RFA, when permission of the applicants has been granted. Requests for the available research agenda(s) must be made in writing to Dr. Rodney Hoff at the address that appears under the INQUIRIES section. Upon receipt of a written request, the research agenda(s) will be mailed (either hard copy, or electronically if possible). In addition, HPTU 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 PLG research agenda. Further guidance from NIAID on prevention needs, can be found in the HPLG 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 HPTU 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 Prevention Trial Units) and number (AI-99-010) 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 (without 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 any 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 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. Ability to contribute to HPTN research agenda. Applicants should describe their expertise, experience, and capacity to conduct prevention research in the U.S. and/or a foreign country for specific technical areas (e.g., microbicides, perinatal interventions, behavioral interventions, hormonal contraceptive use, and HIV, etc.) as it relates to the HPTN scientific agenda. Applicants should describe their ability to lead, contribute to, and prioritize prevention research activities, including their scientific contributions to the design and conduct of HIV prevention trials, such as addressing basic research questions utilizing prevention trial specimens. 2. HPTU capabilities. The ability to implement and manage prevention research in the U.S. and/or a foreign country should be described as outlined in the PLG scientific agenda (see APPLICATION PROCEDURES for information regarding how to receive copies of available PLG scientific agendas). Expertise of key staff should be described. Applications should describe the applicant's clinical research organization and include plans, information and documentation that describe the capability to accomplish the work successfully. Requirements of sites are outlined in Awardee Rights and Responsibilities in TERMS and CONDITIONS OF AWARD, below. 3. Plans for expansion for multiple efficacy trials. Applications should contain a plan for expansion for additional populations for prevention trials, as outlined in the PLG scientific agenda. The plan must specify the additional resources, including facilities and personnel, required to expand recruitment, enrollment, short-term and long-term follow-up, consistent with the requirements of the HPTN 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 for direct costs. Note that for HIVNET sites conducting prevention intervention clinical trials, the HPTN leadership group will develop a plan for transition of these studies to the HPTN. For this application, include in the budget the costs for completion of these current studies, and any new studies that may be implemented under the HPTN. If applicable, budgets should address participation in any ongoing HIVNET studies, and any new studies that may be implemented under the HPTN. 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 typical Phase I-III prevention intervention clinical trials. 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 HPTN'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. 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 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 contribution to the HPTN research agenda - Quality of the operational contribution to the HPTN research agenda - Evidence that the scientific contribution reflects a broad understanding of HIV prevention 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 HIV prevention interventions studies - Strength and adequacy of plans and mechanisms for recruitment and retention of clinical trial participants from relevant populations, particularly minority populations for U.S. sites and subsites (if applicable) - 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 plans for implementing multiple efficacy trials including ability to expand - Adequacy of the 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 HPTN incorporates innovative approaches to the development and clinical evaluation of prevention interventions - 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 multiple efficacy trials employ innovative approaches for expanding recruitment and ensuring adequate retention - Evidence that the proposed plans for community education regarding HIV preventive interventions trials incorporates 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 HPTN 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: Rodney Hoff, Sc.D., MPH Division of AIDS National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 2A12 Bethesda, MD 20892-7620 Bethesda, MD 20852 (for express/courier service) Telephone: (301) 496-6177 FAX: (301) 402-3684 Email: rh25v@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. Jane Unsworth Grants Management Branch National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4B25 Bethesda, MD 20892-7610 Bethesda, MD 20852 (for express/courier service) Telephone: (301) 402-6824 FAX: (301) 480-3780 Email: ju3a@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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