The Seattle-Lausanne-Kampala Clinical Trials Unit (SLK CTU) shares a common goal over the next seven years to work toward a world free of AIDS. The proposed CTU, administered through Fred Hutchinson Cancer Research Center (FHCRC), will consolidate three current high-performing CTUs and add one new experienced, high-capacity CRS in sub-Saharan Africa. The SLK CTU will harness the collective diverse expertise of six international HIV-1 leaders who have made significant contributions to improve HIV-1 vaccine development, prevention and care over the past 2-3 decades. The four integrated Clinical Research Sites (CRSs) will address four NIAID HIV network leadership agendas: Seattle VMP (vaccine, microbicide, and prevention), UW ACTU in Seattle (adult therapeutic), Lausanne VIC (Centre Hospitaller Universitaire Vaudois) (vaccine), and Kasangati-lnfectious Diseases Institute (IDI) in Kampala (prevention and adult therapeutic). To accomplish the CTU's common goal and the networks'agendas, clinical research studies and activities will be directed toward the following four specific aims:
Specific Aim 1 : Contribute leadership and expertise to address current and new scientific priorities related to HIV-1 vaccination, prevention, microbicides and therapeutics.
Specific Aim 2 : Provide centralized administrative oversight through consolidation of the current infrastructure and operations of our existing CTUs and clinical trials programs, to integrate and expand the CRS activities within the four networks.
Specific Aim 3 : Conduct phase 1-3 clinical trials under the direction of the four NIAID- sponsored HIV networks and provide the trial support necessary to ensure the highest quality standards of clinical research.
Specific Aim 4 : Continue and extend partnerships with the CRS communities and stakeholders to enlist their support and guarantee successful enrollment and participation of relevant study populations that are impacted by the HIV epidemic. Our CTU recognizes the challenges moving forward. Inherent characteristics of our structure, expertise, and ability to leverage related activities in our rich environment offer innovation to te clinical trials networks. COMPONENT 1: CTU OVERVIEW The RESUME AND SUMMARY OF DISCUSSION section summarizes the final opinion of the committee after the discussion and is the basis for the assigned Impact/Priority score for Component 1. This discussion was taken into consideration by the review committee in assigning an Overall Impact/Priority score for the CTU application. Component 1 provides an overview of the research program for the CTU. Multiple strengths are identified in Component 1. Significance is high because the proposed CTU is anticipated to support four NIAID Leadership Networks in addressing international HIV prevention and treatment research priorities. The SLK CTU indicates a commitment to identify the most high impact strategies that will lead directly to an end of AIDS and the HIV-1 epidemic. The application provides an innovative and cost-cutting strategy for the CTU to merge and build upon three existing CTUs. More specifically, the Fred Hutchinson Cancer Research Center HVTU (Seattle, WA) will continue as the Seattle HIV Vaccine, Microbicide, and Prevention (VMP) CRS that is described in Component 10A. This site will become a pluripotent CRS based upon its diverse expertise and ability to support trials on microbicide, prevention, and vaccine studies. The University of Washington (UW) ACTU and HPTU (Seattle, WA) will continue as the UW AIDS Clinical Trials Unit (UW ACTU) CRS that is described in Component 10B. Based upon the extensive experience of the UW ACTU CRS in performing therapeutics research (e.g., a collective total of 211 years with the HIV-1 therapeutic network), this site is well-suited to focus on the HIV Adult Therapeutic Network. The Centre Hospitalier Universitaire Vaudois (CHUV) Vaccine and Immuotherapy Center (VIC) HVTU (Lausanne, Switzerland) will continue as the Lausanne Vaccine and Immunotherapy Center (Lausanne VIC) CRS that is described in Component 10C, and the site's strong expertise in vaccine trials will enable it to focus on the HIV Vaccine Trials Network. A new fourth site will be added, the Kasangati Prevention and Therapeutic CRS (Kampala, Uganda) that is described in Component 10D. The addition of this CRS will enable the CTU to use its years of experience and excellence in research to further develop an already strong and productive site in Kampala, and allow the CTU to perform critical trials for the HIV Prevention Trials Network and the Adult Therapeutics Network in high prevalence areas of Uganda and sub-Saharan Africa region. A clear organizational structure is presented with management plans that contain appropriate and delineated lines of authority. Reviewers express enthusiasm for the key personnel who will lead the SLK CTU based upon their exceptional qualifications, experience, levels of commitment, and ability to support and conduct CTU activities. The SLK CTU will be led by Dr. McElrath as Principal Investigator (PI) with co-Investigators Drs. Celum, Collier, Pantaleo, Marrazzo and Katabira who will form a Scientific Leadership Team. Dr. McElrath brings an exceptional HIV-1 research portfolio with more than 20 years of investigation and 10 years of leadership in the HIV Vaccine Trials Network, and extensive, effective administrative leadership experience in academic, multidisciplinary translational and multicenter clinical research programs. The other members of the CTU Leadership Team provide broad HIV-1 clinical research expertise;each member has devoted over 30 years to HIV-1 care and clinical research. Moreover, Drs. McElrath, Celum, Collier, Katabira, Marrazzo, and Pantaleo have international recognition for landmark investigations that have provided insights into HIV-1 prevention through vaccines, biomedical strategies and HIV-1 therapeutics. The CTU leaders also possess experience in managing of local and multicenter clinical research programs that will ensure success of each CRS and the entire SLK CTU. The Seattle HIV Vaccine, Microbicide, and Prevention (VMP) CRS will be led by Dr. McElrath, who has led the Seattle HVTU. Dr. McElrath's successful laboratory research program has focused on HIV immunology and vaccine development for over two decades and she is well suited to head and manage the Seattle VMP CRS's research efforts. Two strong and experienced co-leaders (i.e., Drs. Celum and Marrazzo) will assist the PI/CRS Leader. Dr. Janine Maenza, a former medical director of the Johns Hopkins ACTU, has been the Medical Director of the Seattle vaccine trials unit since 2008 and she will be the on-site supervisor for clinical research activities. The roste of support staff reflects little or no turnover in the most recent funding period, and personnel have several years'experience in their current roles. The investigators have provided several strong letters of support from the UW and FHCRC. The UW AIDS Clinical Trials Unit (UW ACTU) CRS will be directed by Dr. Ann Collier, who has a pioneering record in HIV vaccine trials. Dr. Collier has directed the UW ACTU since 1987 and she has held a number of leadership roles within the ACTG. Moreover, Dr. Collier has clearly documented the availability and appropriateness of the potential participant cohorts. The application provides evidence of the ability to recruit and retain research participants drawn from these populations based on standard procedures, and provides plans and mechanisms to protect clinical trial participants. The site Leader developed effective partnerships with the community, and plans to continue to incorporate community support and involvement in site activities, including decision-making about the scientific agenda. The staff of the UW ACTU CRS has excellent qualifications, appropriate availability and experience to recruit, screen, enroll, follow, retain, adequately manage and refer subjects for required clinical care. The Lausanne Vaccine and Immunotherapy Center CRS (VIC) CRS will be led by Dr. Giuseppe Pantaleo (Professor of Medicine and Head of Immunology and Allergy, University of Lausanne, Switzerland) who is a leader in the European HIV vaccine program. Dr. Pantaleo is well-funded as the current Principal Investigator of several large programs awarded by the Bill and Melinda Gates Foundation. The CRS team has excellent overall qualifications. The Kasangati Prevention and Therapeutic CRS will be led by Dr. Elly Katabira, who was the co-PI for the Development of Anti-Retroviral Therapy in Africa (DART) study, the CRS PI for the Partners PrEP study, and the CRS PI for the Partners in Prevention HSV/HIV Transmission Study. Dr. Celum (Professor of Medicine, UW, Seattle, WA), will serve as the CRS co-Leader. Dr. Celum was the PI for the Partners in Prevention Study, the Chair of the HPTN Integrated Strategies Working Group, and a member of the MTN Executive Committee. Innovative approaches are presented for efficient utilization and sharing of resources, and for cost containment measures that will support the proposed CTU. The application reveals an understanding of how to capitalize on the structure, expertise and environment of each of the involved institutions and CRSs in order to provide innovative research concepts and approaches to the clinical trials networks. The plan to consolidate the Seattle CTU pharmacy management structure is considered an innovative and cost-cutting strategy to increase efficiency and to avoid duplication of efforts. Discussions on shifting the paradigms of HIV-1 prevention are presented, including a shift from anti-retroviral therapies to integrated prevention strategies and to expand innovative home-based self-testing for HIV-1. The CTU also has been innovative by streamlining regulatory procedures (e.g., IRB). Reviewers express enthusiasm for the well-reasoned overall strategy and approach to accomplish the specific aims. The financial management structure, including the duties, responsibilities, experience, and time commitments of essential staff, is adequate with respect to the size and scope of the CTU. Appropriate fiscal management plans and processes are proposed to establish consortia agreements, to allocate resources/protocol funds in a transparent manner, and to provide financial reports to NIAID and the LOCs. Appropriate structures and processes are described for the ongoing evaluation and improvement of financial systems that ensure the ability to make quick decisions and adjustments in order to maintain efficient, high quality operations across the CTU components. Appropriate and feasible plans are proposed for effective communication between the CTU and clinical research networks, NIAID and other groups. Adequate plans also are provided for effective communication across all components of the CTU, including the performance sites. Appropriate and feasible procedures are proposed to measure and assess the performance, productivity and capacity of the CRSs. Appropriate and feasible procedures also are proposed to improve inadequate performance of the CTU component parts. An important aspect is recognition by the applicants that relationships are important in long-term clinical trial research in sensitive areas and their goal to form strong bonds with the involved communities. Each proposed CRSs has an established Community Advisory Board (CAB) with memberships reflective of the surrounding communities. There are strong connections between the researchers at each site with a full range of stakeholders and groups from which participants are recruited. The CTU proposes to build on existing relationships with the CRS CABs and broader communities in order to engage and enroll representative populations into vaccine, prevention, microbicide, and treatment trials. CTU CABs composition will be a diverse group of volunteers who provide community input into participant safety, participant rights, informed consent and confidentiality, study design and local procedures. Each CRS will have a staff liaison to the CAB who will assist with CAB management, training, CRS information and fiscal coordination for meetings and travel. CRS CABs will have a budget to fund meetings and retreats, office supplies and material for meetings, and travel for certain CAB members to annual network conferences as needed. CRS CABs will determine the specific composition, mission, training needs and meeting frequency for their CAB based on requirements related to their target communities. Each of the CRSs will build upon a well-established pharmacy. The pharmacies have strong histories in implementing interventional clinical trials with evidence of past performance in high level research studies. Pharmacy staff at all sites is appropriately educated with seven to more than twenty years of clinical trials experience in their current positions. There is a comprehensive proactive Quality Management Plan for all sites with sufficient policies in place to efficiently and accurately manage the medication needs of the research studies and for participant counseling. The organization structure and plans of the CTU laboratories are sound. The three current CRSs (i.e., Seattle HVTU, Lausanne HVTU and University of Washington (UW) ACTU) have a full complement of highly functional laboratories that meet all network requirements for the HVTN and ACTG Laboratory Centers, and maintain the necessary quality standards and certifications. The laboratory in each site is well equipped for the CTU testing requirements. A major advantage of the proposed SLK CTU is the extensive collaboration that already exists among the investigators and laboratory members across all CRSs. Appropriate measures are presented for laboratory QA/QC, participation in external QA programs, adherence to GCLP, and regulatory guidelines. Most laboratory staff members are stable long term employees with adequate training, qualifications, experience, commitment, and availability. Evidence exists for strong past laboratory performance. A plan is presented to develop the new Kasangati CRS laboratory into the DAIDS-supported networks. Reviewers agree that the central regulatory organizational structure is strong and capable of addressing regulatory assurance. A clear process is described by which new protocols proceed from the regulatory process to implementation. Reasonable timelines for protocol start-up are delineated. The infrastructure is adequate to support the accuracy and integrity of the data. There is an integrated system that focuses on time and cost efficiencies, as well as novel approaches to monitoring and evaluating progress at each CRS. The CTU will have its central administrative base at the FHCRC, Seattle, WA, which is home to one of the world's largest HIV research program. The resources and scientific environment at the FHCRC is outstanding. Appropriate institutional support is available for CTU operations in terms of space and administrative assistance. The facilities at all sites are adequate to outstanding, with appropriate security, climate control, and back-up power to ensure the integrity of study products required for the range of proposed activities. Some weaknesses are identified in Component 1. Reviewers express a strong concern for the lack of investigators with expertise in behavioral adherence. Reviewers discuss that this type of expertise is becoming increasing critical for success in the fields of microbicides and biomedical prevention interventions, as well as in the use of condoms and the adherence to therapeutic agents. Although the application discusses some innovative approaches for the SLK CTU to mentor investigators, (e.g., including bidirectional communication and learning approaches at the scientific, operational and community levels), mentoring plans could be improved. For example, it is not clear whether any formal mentoring is planned or how the mentoring process will occur. Opportunities also exist in the application for an increased discussion regarding expanded dissemination, implementation and integration of protocols and data across sites and disciplines. For example, the application discusses an integrated scientific leadership but lacks an integrated communication and management plan among the CRSs. Information is lacking on how the sites will be coordinated and operate with a standardized set of procedures or core assays across locations that might operate under a common protocol (e.g., a vaccine trial that might be run at all four sites). It is not clear how the integrity of core approaches and assays wll be maintained across sites. Integration of the CRS CABs with a centralized SLK CTU CAB is lacking. Although the application discusses data quality and data merging, information is lacking on a general plan for a structured approach to conducting data analysis. Plans are lacking to follow subjects after the completion of the trials to observe any potential impact of adverse events or long-term outcomes on the health of these individuals. Based upon the evaluation of scientific and technical merit, Component 1 received an Overall Impact/Priority score of 20.
The progression of the HIV epidemic, as well as its international, political and economic toll, make a compelling case for effective vaccine, prevention, microbicide and treatment strategies. In order to reduce the spread of this global pandemic, we propose an innovative clinical trials unit with demonstrated productivity to effectively test candidate regimens to address these fields of study.
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