Interagency Collaboration for Patient-Centered Antibacterial Drug Development

Abstract

This manuscript presents key advances of the Antibacterial Resistance Leadership Group (ARLG) Innovations Task Force, a collaboration focused on improving endpoints for registrational trials of antibacterial drugs, including health-related quality-of-life measures, for common acute infections. This group includes members from the United States Food and Drug Administration, National Institutes of Health, academia, industry, and patient representatives to amplify patient voices and ensure that the endpoints are meaningful to how patients feel, function, and survive.

Members from academia, the United States Food and Drug Administration, the National Institutes of Health, patient advocacy groups, and industry have formed a collaboration to develop innovative antibacterial registrational trial endpoints and measures of health-related quality of life.

Antimicrobial resistance (AMR) poses a threat to modern healthcare in that effective antibacterial support is needed for most surgeries, cancer chemotherapy, organ transplantation, care of critically ill patients, premature infants, and other life-saving procedures. A study in 2019 showed that an estimated 1.27 million deaths globally were caused by AMR and that AMR played a role in nearly 5 million deaths [1]. AMR now kills more people than malaria or AIDS.

Despite the urgent need for novel antibiotics to treat infections caused by resistant organisms, the current pipeline has <50 antibacterial therapeutics in clinical development worldwide, and only a handful target the most threatening gram-negative pathogens [2]. We need novel solutions and trial designs to revitalize and sustain antibacterial innovation and availability. This need is most critical for patients with multidrug-resistant organisms, but the importance of developing patient-centered endpoints can and should be applied to trials and antibiotics targeting susceptible pathogens as well. Here, we highlight completed and ongoing work from the Antibacterial Resistance Leadership Group (ARLG) aimed at creating innovative endpoints for antibacterial trials that better capture the patient voice.

ARLG 2.0

The ARLG, a multi-investigator group of >100 scientists, was initially formed in 2013 with funding from the National Institutes of Health (NIH). The team works collaboratively to combat AMR and improve patient care with a scientific agenda that prioritizes both the diagnosis and treatment of infections caused by resistant pathogens [3]. This work is well-aligned with the Combating Antibiotic-Resistant Bacteria (CARB) National Action Plan (NAP), especially Goal 3 (“Advance Development and Use of Rapid and Innovative Diagnostic Tests for Identification and Characterization of Resistant Bacteria”) and Goal 4 (“Accelerate Basic and Applied Research and Development for New Antibiotics, Other Therapeutics, and Vaccines”) [4].

In December 2019, the Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases, NIH, awarded the ARLG funding for a second 7-year cycle, supporting a clinical research network focused on AMR. The ARLG actively engages with researchers and AMR communities within and outside the network to establish and refine research priorities and to provide training opportunities for early-stage investigators. Central to this work are innovations in the design of clinical trials with a focus on improving the measurement of endpoints that directly capture how patients feel, function, and survive.

ARLG INNOVATIONS TASK FORCE

The ARLG Innovations Task Force is uniquely comprised of members from academia, including trainees; the NIH; the United States (US) Food and Drug Administration (FDA); patient representatives; and the pharmaceutical industry with expertise in clinical trial design, drug development, and statistical analyses. The ARLG Task Force was formed as a public–private partnership to advance the science of clinical trials of new antibacterials for infections caused by resistant pathogens. Importantly, the team recognized the need to elevate the patient voice in diagnostic and antibacterial therapy trials and included a patient advocate member from inception. The inclusion of patient representatives ensures that every project and all deliberations consider important patient factors. The interagency collaborations included in this task force align with Goal 4 of the 2020 CARB NAP, which calls for collaboration between governmental agencies and other partners. The Innovations Task Force aimed to create and/or validate health-related quality-of-life (HRQoL) measures and patient-centered endpoints that can be analyzed using desirability of outcome ranking (DOOR) for 4 common initial licensing indications in infectious disease syndromes, including complicated urinary tract infection (cUTI), complicated intrabdominal infection (cIAI), hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP), and acute bacterial skin and skin structure infection (ABSSSI). This work builds on and is informed by our prior experience developing an HRQoL measure for patients with bloodstream infections [5]. Ultimately, we hope to provide standardized and validated endpoints for use by drug sponsors and academic investigators within registrational trials of novel antibacterial agents, which will ideally be meaningful to understand how patients feel, function, and survive with resistant infections.

HEALTH-RELATED QUALITY OF LIFE

Within the ARLG Innovations Task Force, the HRQoL Working Group aims to elevate the patient voice in registrational trials of interventions targeting common infectious disease syndromes. This includes employing novel approaches to understand and improve current gaps in the patient experience in infectious diseases [6].

Informed by the Wilson and Cleary HRQoL conceptual model, we include both patient-reported functional status as well as symptom status in our work around HRQoL [7]. The goal of the HRQoL Working Group is to incorporate endpoints into antibacterial clinical trials that reflect how patients feel and function as measured by patient-reported HRQoL. Specific work includes a review of the literature to understand existing evidence for measurement of HRQoL in common bacterial syndromes, studies to understand HRQoL in patients with bacterial infections, assessment of whether existing measures are “fit-for-purpose” to measure HRQoL in common bacterial syndromes, and ultimately, to have valid measures for HRQoL in common bacterial syndromes to be used in clinical trials and clinical care.

Initial work focused on studying HRQoL in patients with Staphylococcus aureus or gram-negative bloodstream infections. Semi-structured interviews (concept elicitation) were conducted and revealed that bloodstream infections impacted multiple aspects of HRQoL, particularly physical and functional domains [5]. Informed by these results, cognitive interviews were conducted with a different group of patients with S. aureus or gram-negative bloodstream infections to develop and refine an HRQoL survey using measures (ie, short forms) and items from the Patient-Reported Outcomes Measurement Information System (PROMIS). This survey, tailored for bloodstream infections, is now currently in use as part of the Dalbavancin as an Option for Treatment of S. aureus bacteremia (DOTS) trial [8].

In this supplement, we present this group's work toward adapting the process for measuring HRQoL in patients with bloodstream infections for deployment in trials of antibacterial drugs for cUTI, cIAI, HABP/VABP, and ABSSSI. Building upon the work presented here, the HRQoL Working Group and partners are also currently working on an innovative study to specifically compare clinician and patient perceptions of HRQoL in cUTI [9]. This study will help advance a long-term goal of ARLG, which is to understand how we can use DOOR to analyze HRQoL in combination with other clinical outcomes as effectively and parsimoniously as possible for registrational drug trials.

DESIRABILITY OF OUTCOME RANKING

The DOOR method of analysis was developed to allow an assessment of the overall global impact of an intervention, with the ability to include both the possible benefits and harms, on an individual patient in a single endpoint [10–12]. DOOR can be designed to be a patient-centered endpoint that helps evaluate a patient's entire clinical course during treatment of a specific infection and allows for a more comprehensive understanding of a novel therapeutic that can inform shared decision-making. Traditionally, the efficacy and safety of novel antibacterials have been separately analyzed in clinical trials. By combining efficacy and harms into a single endpoint, DOOR represents an innovation in clinical trial design that may better reflect associations among component outcomes and evaluate the cumulative impact of multiple clinical events. Furthermore, use of DOOR can demonstrate superiority of one treatment over another by including measures of importance to the patient [10].

Using a DOOR endpoint template originally developed from work in S. aureus bloodstream infections, the DOOR Working Group of the Innovations Task Force developed DOOR endpoints for cUTI, cIAI, HABP/VABP, and ABSSSI [12]. Progress to date includes work that assessed the utility of DOOR using retrospectively analyzed data from large cUTI, cIAI, and HABP/VABP randomized controlled trials [13–15]. The cIAI analysis was the first to derive a syndrome-specific DOOR endpoint and capitalized on a unique partnership with the FDA via the Oak Ridge Institute for Science and Education (ORISE) fellowship described in the next section. Studies are ongoing to assess the utility of DOOR in ABSSSI trials [16].

FDA PARTNERSHIP AND ORISE FELLOWSHIP

The FDA ORISE DOOR fellowship was inspired by collaboration in the ARLG Innovations Task Force. ORISE enables critical scientific research and facilitates access to large-scale, multidisciplinary research programs typically not available within universities or industry. The ORISE DOOR fellowship has provided the opportunity to leverage vast amounts of registrational trial data held by the FDA's Division of Anti-infectives (DAI) to critically inform and advance scientific enquiry, trial design, and endpoint development.

The goal of the collaboration between the ARLG Innovations Task Force and DAI was to explore DOOR endpoints and, to date, this work has included analyzing data from recent registrational trials of treatments for cIAI and HABP/VABP [14]. This work provided an unprecedented opportunity to evaluate an a priori DOOR endpoint developed by expert opinion through the ARLG Innovations Task Force, in large patient-level datasets, and to allow the data to inform further modification of the endpoint. Data analyses were conducted by FDA staff with scientific input from ARLG investigators. Patient-level data were de-identified, and trials were anonymized. This retrospective, data-driven approach incorporated a much larger body of data than could be practically collected prospectively, allowed incorporation of elements that are commonly experienced by trial participants, and informed derivation of syndrome-specific endpoints. Additionally, by highlighting the limitations of current trial design, this method may improve prospective collection of efficacy and safety data in future trials. The results obtained through application of the DOOR endpoint to the datasets from cIAI and HABP/VABP clinical trials mirror those from FDA analyses of preapproval trial databases in New Drug Applications. However, the probability estimates for each DOOR component may provide a more consistent and reproducible methodology of assessing benefit and risk prospectively. The generalizability of DOOR across clinical trials may depend, in part, on utilization of a common syndrome-specific DOOR endpoint in trials for each condition [14]. Additionally, DOOR endpoints should be continually evaluated to ensure that they are measuring outcomes that matter most to patients, including HRQoL. The potential application of DOOR needs prospective evaluation as a secondary or exploratory endpoint in registrational clinical trials.

In addition to advancing trial design, this exciting FDA/ARLG collaboration is also helping to build a platform for scientific interaction among various partners engaged in combating AMR and allows for a productive interface among clinicians, statisticians, regulators, and patient advocates. Importantly, it is also well-aligned with Goal 4 of the 2020 CARB NAP, including a critical focus on building a workforce to combat AMR [4].

COMMUNICATION AND DISSEMINATION

Communication has been and will remain an important focus of the ARLG Innovations Task Force. In addition to disseminating academic presentations and publications, a critical goal of the task force is to engage with patients, healthcare consumers, and partners who design, conduct, and analyze registrational trials. To this end, the team developed plain-language infographics to communicate with patients, clinicians, researchers, and all members of the healthcare team (eg, https://arlg.org/wp-content/uploads/2022/08/arlg-door_infographic_social_01jun.png). Additionally, we have developed a web-based application to conduct DOOR analyses that can be used and adapted to fit different syndrome-specific DOOR endpoints and create relevant figures. In the future, the website will also contain a DOOR sample-size and power assessment tool, and our team is working to certify this as a regulatory science tool [17, 18].

CONCLUSIONS

In summary, the ARLG Innovations Task Force has built an interdisciplinary and interagency collaboration to elevate the patient voice and advance methods for measuring, analyzing, and communicating patient outcomes and HRQoL in antibacterial trials. Future work includes applying these methods to prospective studies, continuing the ORISE fellowship, and facilitating ongoing collaborations to further curb AMR and enable the development of novel antibiotics.

Notes

Author contributions. Concept and design: All authors. Drafting of the manuscript: J. H.-A. and H. W. B. Critical revision of the manuscript for important intellectual content: S. B. D., D. D., R. G., D. R., T. K., P. K., D. C., S. E. C., V. G. F., H. F. C., S. R. E., T. L. H., H. A. K., and H. W. B. All authors have seen and approved the manuscript and have contributed significantly to the work.

Acknowledgments. The authors acknowledge feedback and suggestions from members of the Antibacterial Research Leadership Group (ARLG). Brooke Walker, MS, Duke Clinical Research Institute, provided editorial review and submission of this manuscript. She did not receive compensation for her contributions, apart from her employment at the institution where this study was conducted.

Disclaimer. The content is solely the responsibility of the authors and does not necessarily represent the official views or policies of the National Institutes of Health (NIH), US Department of Veterans Affairs, US government, Duke University, or the US Food and Drug Administration (FDA).

Financial support. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH (award number UM1AI104681). H. A. K. is also supported by the Durham Center of Innovation to Accelerate Discovery and Practice Transformation (CIN 13-410) at the Durham VA Health Care System.

Supplement sponsorship. This article appears as part of the supplement “In Pursuit of Patient-Centered Antibacterial Trials: Listening to, Learning From, and Leveraging the Patient Perspective,” sponsored by the Antibacterial Resistance Leadership Group.