NIH/NIAID – HIV/AIDS Clinical Trials Networks Laboratory Centers (UM1 Clinical Trial Required)

The purpose of this Funding Opportunity Announcement (FOA) is to solicit applications for Laboratory Centers (LCs) for the HIV/AIDS Clinical Trials Networks.  The main objective of an LC is to provide scientific expertise and a framework for laboratory leadership, management and oversight that contribute to the development of the research agenda of the network that an LC will support, and to execute the laboratory element of the network’s clinical research.

Background

The National Institute of Allergy and Infectious Diseases (NIAID) and its IC partners currently support five HIV/AIDS clinical trials networks: the AIDS Clinical Trials Group (ACTG), the HIV Prevention Trials Network (HPTN), the HIV Vaccine Trials Network (HVTN), the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT), and the Microbicide Trials Network (MTN). NIAID is soliciting applications for FY21 award consideration for the following four HIV/AIDS Clinical Trials Networks: HIV Prevention Clinical Trials Network, HIV Vaccines Clinical Trials Network, HIV/AIDS Adult Therapeutics Clinical Trials Network, HIV/AIDS Maternal, Adolescent and Pediatric Therapeutics Clinical Trials Network.

Since the beginning of the HIV/AIDS pandemic, the National Institutes of Health (NIH) has advanced understanding of disease mechanisms and used basic science to create opportunities for the discovery, development, and clinical evaluation of novel prevention and treatment strategies. With this approach, the scientific community has created an array of effective tools to treat and prevent HIV infection. Over the last 35 years, these interventions have been made safer and more effective. However, according to the latest Joint United Nations Programme on HIV/AIDS (UNAIDS) Global summary of the AIDS epidemic, there are approximately 36.9 million people living with HIV, 25.7 million of whom are living in sub-Saharan Africa, with 1.8 million new infections per year across the world. Significant challenges remain in delivering treatments and methods of prevention to the people who need them most. Although rates of death due to HIV/AIDS and rates of new HIV infections are declining in many areas of the world, these declines vary by region and in many places are slower than anticipated in reaching 2020 goals. In many parts of the world with generalized HIV/AIDS epidemics, new HIV infections far outpace access to effective antiretroviral treatment (ART).  Even in the U.S. and other industrialized nations, where the HIV epidemic continues unabated particularly in most at-risk populations, a large portion of individuals who meet treatment guidelines do not have access to ART.

Network Laboratory Centers (LC) have overseen and coordinated all clinical and specialized laboratory testing leading to the successful execution of protocols, providing the critical data for publications and regulatory submissions.  Numerous accomplishments and publications by the LC have contributed to licensure of several anti-HIV drugs in adult and pediatric populations, advances in the treatment guidelines, and options for prevention including the use of antiretrovirals to prevent transmission of HIV-1 in serodiscordant couples.  Other notable accomplishments include the development, validation and qualification of immunological assays that have enabled direct comparisons of different vaccine platforms and informed decision-making about which candidates to advance to large-scale testing.  Progress has been made on innate immune profiling across different vaccine platforms and sophisticated diagnostic algorithms to distinguish vaccine-induced sero-reactivity from HIV-infection have been devised.  For therapeutics research, the validation and standardization of HIV viral load and drug resistance assays; combined with phylogenetic analysis to determine genetic linkage of index-partner infections has led to the understanding of the potency of ART to establish durable virologic control and that if a patient viral load is undetectable, patients do not transmit HIV.  Standardized assays to measure HIV reservoirs in antiretroviral-suppressed adult trial participants have been deployed and have been adapted to smaller sample volumes for mucosal specimens and pediatric participants.  As the prevention and treatment fields explore the use of broadly neutralizing antibodies, technologies and standard operating procedures (SOPs) to measure infused human anti-HIV monoclonal antibodies in blood and mucosal tissues as well as methods to demonstrate that the antibody remains biologically active once in circulation are now in place.  Lastly, SOPs for a range of TB tests have been created and implemented in network-supported TB laboratories.

Clinical Trials Networks to be Supported by LCs

NIAID is soliciting applications for FY21 award consideration for the following HIV/AIDS Clinical Trials Networks:

  • HIV Prevention Clinical Trials Network
  • HIV Vaccines Clinical Trials Network
  • HIV/AIDS Adult Therapeutics Clinical Trials Network
  • HIV/AIDS Maternal, Adolescent and Pediatric Therapeutics Clinical Trials Network

Research Priority Areas for each of the HIV/AIDS Clinical Trials Networks can be found on the NIAID website here.

NIAID plans to fund one LC award for each network. Each application in response to this FOA must address only the research priority areas of ONE HIV/AIDS Clinical Trials Network. Applications addressing the research priority areas of more than one HIV/AIDS Clinical Trials Network will be considered non-responsive and will not be reviewed.

Structure of the Network

Each HIV/AIDS Clinical Trials Network is composed collectively of a Leadership and Operations Center (LOC), a Laboratory Center (LC), a Statistical and Data Management Center (SDMC) and affiliated Clinical Trials Units (CTUs) and Clinical Research Sites (CRSs).  Each will be funded via an independently-solicited FOA and each will contribute specific essential functions necessary to support a large-scale, complex clinical research program.  While the emphasis of each network is on clinical trials, clinical research studies that aren’t NIH-defined clinical trials are also in scope when undertaken to support the program. For the purpose of this FOA, the term “clinical study” refers to both clinical trials and clinical research studies, and “clinical trial” is used to refer to clinical trials only.

The LOC will manage the network’s scientific priorities and the corresponding alignment of clinical studies with those priorities.  The LOC has primary responsibility for the prioritization, selection and development of clinical protocols and project management of the full spectrum of activities needed to plan and conduct clinical trials including the coordination of efforts by the LC and SDMC, and clinical sites.  The LOC has responsibility to assure that the research is conducted according to principles of Good Clinical Practice (GCP).

The LC will lead the development, implementation and evaluation of the laboratory activities that are required to carry out the network research agenda. The LC will ensure that there are relevant state-of-the-art expertise and technologies to provide clinically useful study data and enable sound product development decisions. The LC will oversee laboratory operations that allow for consistent and reproducible laboratory results that can support study reconstruction.

The SDMC will provide comprehensive data management and data analyses for network clinical studies in compliance with regulatory standards.  The SDMC will provide leadership and services for biostatistics, study design, analysis, interpretation and publication of results, including innovative statistical methods, along with state-of-the-art clinical trial management systems and laboratory information management systems to ensure complete, high-quality data.

The CTUs will provide scientific and administrative expertise as well as the infrastructure to conduct clinical studies within the network.  A CTU is composed of at least one, but no more than eight, Clinical Research Site(s) (CRSs) that can contribute to at least two HIV/AIDS Clinical Trials Networks.

Each Clinical Trials Network will have an Executive Management Committee (EMC) to coordinate the activities of the Network’s LOC, LC and SDMC. The EMC will include the PDs/PIs from the LOC, LC and SDMC and will be chaired by the PDs/PIs from the LOC.

Additional Resources provided by NIAID:
  • Division of AIDS (DAIDS) Clinical Laboratory Oversight Team (DCLOT) helps develop, evaluate, coordinate, communicate, and oversee, the implementation of harmonized DAIDS clinical lab-related guidelines, standards, and requirements.  DCLOT members serve as points-of-contact to the LCs, as well as oversee DAIDS-funded contractual laboratory quality assurance resources. These contract resources ensure that network laboratories demonstrate assay proficiency and perform laboratory operations according to good clinical laboratory practices (GCLP).  These contracts include:
  • Clinical Research Support Services (CRSS),
  • Clinical Pharmacology Quality Assurance Program,
  • External Quality Assurance Program Oversight Laboratory (EQAPOL),
  • Immunology Quality Assurance (IQA) Program,
  • Mycobacterium tuberculosis (Mtb) Quality Assessment Program (TBQA),
  • Patient Safety Monitoring in International Laboratories (SMILE), and
  • Virology Quality Assurance (VQA) Program
  • Safety Oversight Committees: NIAID oversees the safety of all participants in clinical trials funded by NIAID.  Generally, NIAID DAIDS will provide NIAID-convened Data and Safety Monitoring Boards (DSMBs) to monitor Phase II, Phase III and Phase IV multicenter, randomized clinical trials.
  • Other Support Services: NIAID will provide additional support services for network trials that must be conducted under an Investigational New Drug (IND) or Investigational Device Exemption (IDE).  These services may include domestic and international regulatory sponsorship, management of clinical study products, and clinical site monitoring.  A detailed description of these NIAID contract resources can be found at the website here.
Laboratory Center Specific Responsibilities

The LC provides a framework for laboratory leadership, structure and activities that contribute to the development of the network’s research agenda, and leads the development, implementation and evaluation of the laboratory research and capacity essential to the successful execution of that research agenda. A research agenda is the broad strategic plan to address the stated research priority areas of the network. The LOC, in collaboration with the LC and SDMC, articulates the network’s scientific agenda, establishes a framework for the initial studies, and plans for future studies. The LC is expected to increase efficiency and promote resource-sharing through coordination of critical activities among LCs and with other research partners.  The LC is expected to work closely with the Leadership and Operations Center (LOC) to contribute to the design, development and execution of study protocols; coordinate selection of appropriate testing laboratories with Clinical Trials Units (CTU) / Clinical Research Sites (CRS); and coordinate with the Statistical Data Management Centers (SDMCs) to achieve reliable laboratory data capture and export as well as specimen tracking from acquisition, testing, storage and shipping.  In accordance with Good Clinical and Laboratory Practices, a LC will use various types of laboratories, both domestic and international, with a spectrum of capabilities, including some with specialized expertise to; oversee and monitor the reliability and integrity of protocol-specified laboratory testing; ensure reliable chain of custody for a variety of biological samples, including local and centralized sample storage; ensure use of appropriate data capturing and tracking systems; implement an approach to select, determine readiness and approve laboratories to participate in study protocols; and support the evaluation and performance of state-of-the-art technologies and assays for implementation in study protocols.

Each LC will provide leadership and staff with appropriate credentials and expertise (e.g., clinical pathologists, medical technologists, regulatory experts), and a management and operation unit to provide oversight of all LC activities.  The LC will provide relevant scientific expertise (e.g., immunology, microbiology, virology, pharmacology, systems biology), to contribute to the development, design and execution of study protocols, with particular emphasis on choice of laboratory assays, testing laboratory capabilities, relevant interval and types of specimens to collect and evaluate, and assessment of impact on resources (e.g., long-term storage of samples, training needs).  The LC will ensure the flexibility and timely acquisition of external specialized laboratory expertise to support study protocols and also shows flexibility to terminate assays and specimen analyses when redundant or of minimal value.  The LC will support the development, optimization and evaluation of existing and novel laboratory assays to implement in network studies so that those assays provide clinically useful information.  The LC will foster intellectual and material collaborations among clinical and basic scientists, as well as promote mentorship, training and involvement of early stage investigators and the next generation of leaders in clinical laboratory science, particularly investigators from resource-limited settings.

The LC accomplishes its objectives by using clinic-based laboratories associated with CRSs for local specimen processing and testing (e.g., HIV rapid tests, urine hCG), CRS-affiliated clinical laboratories and/or commercial laboratories for routine clinical testing (e.g., safety tests) and centralized, specialized laboratory testing (e.g., immunology, microbiology, virology, pharmacology, TB).  Specifically:

  • In coordination with CTU/CRS PIs, NIAID and NIAID-funded laboratory QA resources (e.g., VQA, SMILE), the LC selects laboratories with testing capabilities and capacity required for study-specified testing.  Laboratories must demonstrate initial and on-going compliance with sponsor and DAIDS requirements to ensure the reliability and integrity of protocol-mandated laboratory testing and standards of laboratory operations to allow for the approval of registrational studies by U.S. and non-U.S. regulatory entities as appropriate. Laboratories also participate in External Quality Assurance schemes to assess ability to perform tests correctly, meet CLIA certification when applicable, and/or compliance with good clinical laboratory practice standards (e.g., CAP, ISO, DAIDS GCLP).
  • In coordination with CTU/CRS PIs, the LOC, SDMC, and DCLOT, the LC must ensure the reliability, integrity and timeliness of all aspects of managing specimens obtained from study participants, including specimen acquisition/collection, specimen transport that complies with local and international shipping regulations from point of collection to point of testing and/or storage, as well as use validated and verifiable systems to track all aspects/stages of specimen management.
  • The LC will implement reliable and cost-effective local and centralized short-and long-term storage of study samples and will collaborate with the network LOC and SDMC to promote access to stored specimens for future research by the broader scientific community.
  • In coordination with the SDMC, the LC must ensure the implementation of a validated and verifiable laboratory data management system that maintains accurate specimen inventory and tracking records and provides timely capture and export of laboratory test results according to regulatory standards.
  • The LC will promote mentorship and involvement of early-stage investigators and the next generation of leaders in adult and pediatric clinical laboratory science, particularly investigators from resource-limited settings.

Quality Management. The LC is expected to ensure the overall Clinical Quality Management (CQM) of all activities through Quality Assurance and Quality Control processes and procedures. The purpose of CQM is to ensure protocol regulatory compliance, ensure human subject protection and data integrity, and compliance with all applicable regulatory requirements.  The LC will also be responsible for enabling sponsor/client audits.

Network Meetings. Each network will hold at least one annual meeting to share recent findings and facilitate collaborations. All key personnel and NIAID program staff are expected to attend and participate. External Advisors may also attend the program update portion of the meeting.

External Interactions and Opportunities. The LC serves as an integral part of an HIV/AIDS Clinical Trials Network.  Further, each LC will be strongly encouraged to collaborate with other HIV/AIDS Clinical Trials Networks and other NIH-supported research groups (e.g., the Human Immunology Project Consortium, Centers for AIDS Research, the Martin Delaney Collaboratories), and other Federal and private sector clinical research programs, and to interact with government, non-government and community organizations (including the private and non-profit sector), as well as committees to achieve harmonization and centralization of specialized testing (e.g., pharmacokinetics and immunology).  Such collaborations and interactions are essential for the development and implementation of a comprehensive research agenda that utilizes the strengths, experience and expertise of the various collaborating organizations. The sharing of expertise, resources and procedures is expected in key areas, including: development of clinical infrastructure in resource-limited settings; harmonization of laboratory resources and specimen management; harmonization of common data elements and data entry interfaces. Examples of additional entities with which the LC will need to collaborate and/or communicate include but are not limited to: the NIAID Strategic Working Group (SWG), NIAID DAIDS Office of Clinical Site Oversight (OCSO), the DAIDS Clinical Laboratory Oversight Team (DCLOT) and the Office of HIV/AIDS Network Coordination (HANC).

Core and Protocol Funds

Funding to carry out the network’s research agenda falls into two categories:

Core Funds.  NIAID will provide core funds directly to the LOC, LC, SDMC and network-affiliated CTUs on an annual basis.  Core funding is the initial fixed-base funding and provides infrastructure and salary support that is not protocol-specific.  Examples include, but are not limited to:

  • Administrative and management support
  • Community education and engagement structures and activities
  • Clinical quality management activities
  • Maintenance and replacement of equipment
  • Travel to attend clinical trials network meetings
  • Mentoring and training of staff
  • Record retention to meet regulatory requirements

Protocol Funds (PF).  NIAID will provide PF to the LOC, LC and SDMC on an annual basis.  In addition, NIAID anticipates providing PF directly to network-affiliated CTUs on an annual basis.  PF provides support to conduct protocols, including protocol-specific infrastructure or other requirements needed to conduct protocols at a site.  PF varies annually, depending on costs of ongoing protocols and will be awarded to cover expenses attributable to protocol development, implementation or close-out of a clinical trial. Protocol funds include, but are not limited to, the following protocol-specific expenses:

  • Personnel salary (protocol-specific)
  • Good and Services Tax (GST) where required
  • Protocol required tests and evaluations
  • Travel for protocol-specific personnel, as required by network, to attend clinical trials network meetings
  • Travel to attend protocol-specific trainings
  • Equipment and supplies
  • Protocol specimen shipment and storage

NIAID expects that equipment and services funded via Core or PF will be made available, as appropriate, for other NIAID-funded network activities regardless of how funds were initially provided to purchase those items.

Based on communications with the LC, SDMC and CTUs/CRSs, the LOC will estimate protocol funding needs for the network (salary and non-salary PF) annually and submit a budget request to NIAID.  NIAID will then determine the amount of PF to be provided in the coming grant year.  Adjustments in PF allocation will be made at regular intervals during each budget period, based on both performance and availability of funds.

Deadline:  August 1, 2019 (letters of intent due 30 days prior to deadline)

URL:  https://grants.nih.gov/grants/guide/rfa-files/RFA-AI-19-001.html