Antibacterial resistance (AR) is a growing, multifactorial, global public health threat that has recently garnered increased national attention as the subject of the United States (US) Government’s Combatting Antibiotic Resistant Bacteria (CARB) National Strategy, Action Plan, Task Force, and Presidential Advisory Council. Internationally, AR has recently been the focus of key meetings of the United Nations General Assembly, of the G7 and the G20, and has also received extensive attention from the World Health Organization (WHO). These national and international efforts have consistently recognized the need for sustained support for AR research and product development in general, and clinical research specifically. An integrated clinical research program that both explores ways to reduce the overall risk of antimicrobial resistance and tests new approaches to diagnose, prevent, and treat AR infections is a critical component of the response to the AR problem.
The Leadership Group for the Clinical Research Network on Antibacterial Resistance (LG) was initiated by the National Institute of Allergy and Infectious Diseases (NIAID) in 2013 in response to the growing public health threat of AR. Their charge was to design, prioritize, implement and manage an integrated, clinical research program targeting the most important clinical questions in AR. The objective of the current FOA is to continue support for a Clinical Research Network composed of an LG and affiliated clinical sites that will develop, implement, and manage a research agenda that can adjust and react to the evolving clinical priorities in AR. The LG is complementary to NIAID’s other preclinical and clinical AR activities, as well as AR programs at other government agencies.
Since its inception in 2013, the Antibacterial Resistance Leadership Group (ARLG)’s clinical research agenda has focused on studies to address gram-negative and where appropriate gram-positive infections, as well as studies to support the development and use of diagnostic tests and to inform antibiotic stewardship efforts. They have solicited studies from their network of expert clinician scientists, as well as from the external research community, industry, and NIAID. Key achievements include: expansion of an observational study of patients infected with gram-negative pathogens to collect data on patient characteristics, treatments, and outcomes, as well as the genotypes and phenotypes of their infecting organisms; clinical validation of a host gene expression-based diagnostic test that rapidly determines whether a patient’s respiratory symptoms are viral, bacterial or non-infectious in nature; a strategy trial to evaluate whether a short course of antibiotics is superior to the standard course in children with community-acquired pneumonia; a collaboration with multiple diagnostics companies to implement a master diagnostic protocol to allow for the evaluation of multiple diagnostic tests simultaneously using specimens from the same patients; mentoring the next generation of clinician-scientists focused on addressing AR; and statistical innovations, including novel tools for assessing strategy trials and diagnostic evaluation studies.
While progress has been made to further our understanding of and ability to manage AR infections, the AR problem continues to grow, and numerous significant clinical research gaps remain. These include the development of better therapeutic and prophylactic approaches for resistant infections, including non-antibiotic approaches like vaccines, monoclonal antibodies, microbial ecology approaches, and bacteriophage; strategy trials to study optimal treatment of bacterial infections using existing drugs; and the development and deployment of novel, rapid diagnostic strategies. This FOA places a priority on studies that address these gaps and that cannot be done by other NIH programs, government funders, or private industry.
Research Objectives and Scientific Scope:
The LG is designed to conduct clinical research studies and clinical trials that will impact the prevention, diagnosis and treatment of AR infections. The LG research agenda is expected to give the highest priority to the top AR threats identified by US and international expert bodies, such as the CDC and the WHO. Efforts should be generalizable to the US experience and could include, but are not limited to:
- Early clinical evaluation of new antibacterial therapeutic and prophylactic products, including small molecule antibiotics, monoclonal antibodies, applications of microbial ecology approaches, bacteriophage-based products, and vaccines.
- Comparative effectiveness trials.
- Strategy trials to optimize currently licensed antibacterials (e.g. dose, duration, clinical algorithms, need for drug, combinations) to reduce the risk of resistance.
- Validation studies of new diagnostic tests using clinical isolates or specimens, including to support regulatory submissions.
- Clinical utility studies of diagnostic tests to determine the impact of approved tests on patient- and facilities-level outcomes and prescribing behavior.
- Molecular epidemiological studies to provide data on the associations between patient characteristics, clinical outcomes, and resistant genotypes/phenotypes, and to inform future interventional trials.
- Pharmacokinetic (PK) and pharmacodynamic (PD) studies.
- Strategies to better manage the consequences of broad spectrum antimicrobial use, e.g. Clostridium difficile infections.
- Collaborations with industry and academic groups as needed, both domestically and internationally, to guide optimal clinical trial designs, answer key questions that cannot be addressed alone, and strengthen a community of AR researchers that can contribute to the US government’s response to emerging resistant threats.
The following types of studies are beyond the scope of the FOA:
- Studies of infection control programs and broad antimicrobial stewardship interventions, which are supported by other government agencies. However, innovative statistical analyses of ongoing stewardship efforts are permitted.
- Studies focused on parasites, viruses, and mycobacteria, which are supported by other NIAID programs.
Leadership Group Structure
The LG is collectively comprised of a Scientific Leadership Center (SLC), Clinical Operations Center (COC), Laboratory Center (LC) and Statistics and Data Management Center (SDMC). The activities and synergies of these centers will support the large-scale, complex LG and carry out the essential functions necessary for achieving the network’s clinical research agenda.
Scientific Leadership Center (SLC)
The SLC will be responsible for overall administrative and scientific leadership for the network, as well as oversight and evaluation of all network activities, including developing and refining the research agenda, prioritizing research concepts, and ensuring timely publication and communication of results. The SLC is also responsible for the following:
- Governance. Integral to the success of the LG is establishing clear governance structures, including effective communication and decision-making plans, lines of authority, plans for coordinating and collaborating effectively with external collaborators and NIAID, and resource distribution policies. The SLC may establish committees to achieve the work of the LG.
- Research Agenda/Scientific Priorities. The LG research agenda articulates the network’s scientific priorities and establishes a framework for the initial project portfolio and future studies and trials envisioned. The SLC is expected to actively engage researchers and AR communities within and outside of the network in establishing and refining the research agenda.
- Innovation. The LG is encouraged to explore innovative types of countermeasures, study/trial designs, approaches to public-private partnerships, and statistical techniques that will have a broad impact on the overall field of AR clinical research.
- Mentoring. The LG should make every effort to provide clinical research training opportunities for early stage clinical investigators. This may take the form of small clinical research projects, classroom training in clinical research and statistical analysis, participation in network committees, participation as junior investigators on studies and trials, and exposure to other aspects of clinical research in AR.
- Collaborative Responsibilities. The LG is encouraged to collaborate with other NIH-supported networks and other Federal and private sector clinical research programs. 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. Sharing of expertise, resources and procedures is expected in key areas, including: harmonization of laboratory resources and specimen management and harmonization of common data elements and data entry interfaces.
Clinical Operations Center (COC)
The COC provides operational support, management, and oversight for the network’s clinical studies and trials. This requires close coordination with the SLC, LC, SDMC, network-affiliated clinical research sites, and NIAID’s Project Scientist and clinical research support programs. The COC provides leadership on protocol development and implementation and is responsible for protocol-specific site selection, qualification, and management. The COC is responsible for effective management and oversight of protocol teams and all LG center activities and must establish efficient systems for resource distribution and re-allocation in response to evolving priorities identified by the SLC. Finally, the COC is expected to provide specialized training for clinical trials, applicable laboratory procedures and data management for network and site staff in support of LG activities. The COC is also responsible for the following:
- Management. The COC is expected to employ strong project management practices for management, oversight and coordination of long-term and day-to-day activities associated with LG studies and trials, including: development of project plans that establish realistic milestones and timelines; ongoing evaluation and adjustments; and implementation of contingency plans. The COC should work synergistically and seamlessly with NIAID and the clinical research sites in driving protocols through to completion. Other responsibilities of the COC include development of policies, by-laws, standard operating procedures (SOPs), budgets, and communication plans.
- Clinical Research Sites. Due to the diverse nature of LG studies and required patient populations, it is expected that performance sites for implementation of the research agenda may be located at the applicants’ institutions, subcontracted to protocol-specific clinical research sites, or provided by other NIAID clinical sites. A major activity of the COC is establishing efficient processes for identifying, qualifying, and approving protocol-specific sites to address specific clinical research network needs.
Laboratory Center (LC)
The LC contributes to the development of the network’s research agenda, and leads the development, implementation and evaluation of the laboratory research that is essential to the successful execution of that research agenda. The LC manages and oversees relevant laboratory services, including any necessary PK services, bioanalysis, and network specimen characterization; laboratory quality management programs; the monitoring and evaluation of all specialized laboratories in the network; sharing of specimens outside the network, as necessary; and provides adequate storage facilities necessary to accomplish the network’s clinical research agenda. LC leadership fosters collaboration and harmonization of laboratory activities within the network, including clinical research site-affiliated laboratories.
Statistics and Data Management Center (SDMC)
The SDMC provides leadership and services for biostatistics, study design, analysis, interpretation and publication of results, including innovative statistical methods in the field of AR, along with state-of-the-art clinical and laboratory data management systems to ensure complete, high-quality data. The SDMC must ensure the integrity of study design and statistical analysis for all LG studies and trials, as well as training and education for protocol-specific site and laboratory staff on data management and specimen shipping/tracking systems. The SDMC will also provide comprehensive data management and data analyses for LG studies and trials not conducted under an Investigational New Drug or Device Exemption (IND/IDE). The SDMC has a central role in standardizing and harmonizing statistics and data management activities within the network and coordinating with other NIAID-sponsored programs, as necessary.
External Advisory Board (EAB)
An External Advisory Board (EAB) will be established by NIAID in collaboration with the awardees to review the progress in meeting the goals of the LG and NIAID and will make recommendations for the continuation or re-direction of all projects and activities of the LG on an ongoing basis. In addition, the EAB may make recommendations about areas needing intensified attention by the LG’s research agenda. The EAB is expected to consist of investigators who are not current collaborators of the funded programs.
Additional resources provided by NIAID:
- Safety Oversight Committees. NIAID oversees the safety of all participants in clinical trials funded by NIAID. NIAID monitors Phase II, Phase III and Phase IV multicenter, randomized clinical trials primarily through Data and Safety Monitoring Boards (DSMBs). NIAID monitors Phase I and small Phase II clinical trials primarily through Safety Monitoring Committees (SMCs) in conjunction with Independent Safety Monitors (ISMs). (https://www.niaid.nih.gov/research/safety-oversight-clinical-research).
- Other Support Services. NIAID will provide additional support services for LG trials that must be conducted under an Investigational New Drug (IND) or Investigational Device Exemption (IDE). These services may include domestic regulatory sponsorship, data management and statistical support, management of clinical agents and specimens, and clinical site monitoring. Each study will be evaluated for the need for an IND/IDE by NIAID and support services to be provided will be determined on an individual study basis. For clinical trials that do not require an IND/IDE, the LG should be prepared to provide all support services other than safety oversight. For clinical studies that do not meet the NIH definition of a clinical trial, the LG will need to provide all resources and expertise necessary for the conduct of the study.
Deadline: December 3, 2018 (letters of intent); January 3, 2019 (full proposals)
Filed Under: Funding Opportunities