Anesthesiology Clinical Trial Networks in the United States: A Report from the Anesthesia Research Council

The Need for Large-scale Patient-centered Outcomes Research in Anesthesiology Patient-centered outcomes research aims to generate knowledge to improve outcomes that are meaningful, valuable, and helpful to patients and their families.1 For research comparing 2 or more treatment alternatives, this is often best achieved through the conduct of large-scale multicenter clinical trials. This approach provides a more accurate estimate of treatment effects than observational studies due to the use of randomization, allows for sufficient power when sample sizes are sufficiently large to detect small but clinically meaningful differences between treatment groups and effects in smaller subpopulations that may be more likely to benefit, and can create generalizable evidence when trials enroll diverse populations recruited from different care settings and environments. In addition to the potential benefit for patients, high-quality clinical research engages and educates clinicians in impactful science and contributes to the learning and professional development within the medical specialty overall. Within the United States, there is a significant need to establish high-functioning clinical research networks that facilitate the design, performance, and completion of such trials. In 2016, the American Society of Anesthesiologists (ASA), the International Anesthesia Research Society (IARS), and the Foundation for Anesthesia Education and Research (FAER) created the Anesthesia Research Council (ARC).1 The ARC’s mission is to provide “independent, trustworthy synthesis and advice to address complex challenges by mobilizing expertise, practice, and knowledge in science, engineering, and medicine.”2 The present report represents the work of the ARC Year 2 Working Group. This group was charged with: (1) summarizing the current state and future prospects of collaborative patient-centered outcomes research in anesthesiology in the United States; (2) identifying facilitators and barriers to establishing 1 or more collaborative, U.S.-based patient-centered outcomes research networks in anesthesiology; and (3) recommending specific actions that key stakeholders should undertake to transform the landscape of patient-centered outcomes research in anesthesiology in the United States over the next 5 to 10 years. Existing Clinical Trial Networks and Resources in Anesthesiology In working group discussions, we identified current U.S. and international patient-centered outcomes research networks in anesthesiology and other medical specialties that could serve as models for future U.S.-based anesthesia multicenter research networks. We then conducted informal interviews with leaders of these organizations and drew on the experiences of working group members within these organizations to learn more about the successes and challenges within these trial network groups. Interview notes were shared and discussed in working group meetings to identify barriers and facilitators to trial network function and operations, and generate potential recommendations. While the working group considered multiple networks within and outside of anesthesiology, here we focus on 3 established anesthesia trial networks and 1 quality improvement collaborative that has built the infrastructure to support trials within the United States. Australian and New Zealand College of Anaesthetists Clinical Trials Network, Australia and New Zealand The Australian and New Zealand College of Anaesthetists (ANZCA) is the specialist medical college accredited to train anesthesiologists and support their continuing professional development. In 2003, after the successful collaborations of the Multicentre Australian Study of Epidural Anaesthesia (MASTER)3 and the Bispectral index monitoring to prevent awareness during anesthesia (B-Aware)4 Trial, investigators and the College established the ANZCA Clinical Trials Network (CTN). ANZCA CTN now has more than 70 participating sites across Australia and New Zealand. This CTN offers pilot grants and programs to support emerging researchers and maintains staff to support CTN operations, CTN-endorsed trials, and the network of ANZCA sites, investigators, and research coordinators. Strengths of the CTN include that it is embedded within ANZCA—with the college providing administrative support (ie, event planning, communications) as well as ongoing financial support. This ensures some sustainability and a high degree of ownership and pride among the Australian and New Zealand anesthesia research community. The network has grown to be a world leader in clinical trial methodology and delivery, completing numerous, large, international, multicenter trials within budget, at over 130 sites worldwide.5–7 Perioperative Anesthesia Clinical Trials (PACT), Canada Within Canada, investigator-initiated studies led by academic centers (eg, PeriOperative ISchemic Evaluation [POISE-1] trial,8 PeriOperative ISchemic Evaluation-2 [POISE-2] trial,9,10 PeriOperative ISchemic Evaluation-3 [POISE-3] trial,11 Blood Conservation Using Antifibrinolytics in a Randomized Trial [BART] trial,12 Measurement of Exercise Tolerance before Surgery [METS] cohort study,13 and Functional Improvement Trajectories After Surgery [FIT After Surgery] cohort study14) have helped build informal networks, and in 2010, the Perioperative Anesthesia Clinical Trials (PACT) Group was established as a formal collaborative network for multicenter studies in anesthesiology and perioperative medicine with support from the Association of Canadian University Departments of Anesthesiology (ACUDA).15 PACT serves as a forum to foster collegial collaboration, refine study designs and grant proposals, identify partners for multicenter collaborations, and deliver educational content for researchers. Since its inception, the PACT group has steadily grown in membership, meeting attendance, and research success (as measured by publications and grants),16 and has mentored and supported a new generation of physician-scientists within the Canadian anesthesiology community. The formal and informal mentorship provided by the group, along with opportunities to extend collaborative networks, has allowed early-career and midcareer investigators across different academic centers to achieve success in highly competitive peer-reviewed funding competitions. Outcomes Research Consortium, Worldwide The Outcomes Research Consortium is an academic research organization consisting of over 200 investigators at 50 different institutions in 25 countries across the world, headquartered now at the University of Texas, Houston.17 Since its inception in 1990, the Consortium has published more than 2000 scientific papers and editorials, and has been involved in numerous clinical studies, including large international multicenter perioperative outcome trials.18,19 The administrative hub provides protocol design review; project management, including investigator and site identification, site monitoring, and help with regulatory documentation; and biostatistics and data management services. Members are expected to actively collaborate (which is the only criteria for membership) and help complete studies. While members of the Consortium have successfully competed for federal funding, many studies have been sponsored by industry partnerships, which have provided a sustainable source of support for research activities. Multicenter Perioperative Outcomes Group (MPOG), United States The Multicenter Perioperative Outcomes Group (MPOG) is a collaborative of medical centers/hospitals, physicians, nurses, software developers, data scientists, statisticians, researchers, and administrators focused on promoting safe and evidence-based perioperative care through collaboration, research, education, and quality improvement. MPOG maintains a growing registry of over 23 million cases combining preoperative, intraoperative and postoperative outcome data contributed by over 70 participating hospitals. Primarily, MPOG data has contributed to observational studies.20,21 Now, MPOG has transitioned to also enable large, multicenter, pragmatic clinical trials given the robust electronic health record data collection platform and collaborative relationships. MPOG is now serving as the Data Coordinating Center for 3 distinct prospective clinical trials: Trajectories of Recovery after Intravenous Propofol versus inhaled VolatilE anesthesia (THRIVE),22 a Patient-Centered Outcomes Research Institute (PCORI)-funded pragmatic clinical trial of 12,500 patients across approximately 20 U.S. hospitals (NCT05991453), an Agency for Health care Research and Quality’s (AHRQ) funded cluster-randomized trial of precision feedback to anesthesia clinicians to improve clinical quality measurement performance (NCT05923463), and a multicenter cluster-randomized cluster-crossover trial of different intraoperative oxygenation strategies (IntraopOx) funded through the Initiative for Multicenter Pragmatic Anesthesiology Clinical Trials (IMPACT) award instrument. Lessons Learned and Potential Threats to a Successful U.S. Anesthesia Clinical Trials Network Several key factors to success emerged from examining existing trial networks and from discussions within the working group. Successful networks must (1) generate interest among stakeholders, (2) impact the field, (3) maximize efficiency, (4) create a culture of accountability, and (5) plan for growth. Networks can generate interest among a variety of stakeholders by targeting clinically important outcomes, testing compelling interventions, and producing generalizable evidence. Several nonanesthesia networks in the United States were started in partnership with funding agencies, which allowed these networks to begin with administrative support, a clear directive, accountability to a funding agency, and seed money for trials. Achieving early successes engenders and propagates buy-in from funders, and achieving early success should be considered when selecting initial studies to serve as demonstration projects or when selecting sites for participation. Buy-in from both academic and community clinicians is critical, as clinicians are responsible for patient recruitment and study implementation and are the “end-users” of research results; individual clinicians having a sense of ownership over the research and being motivated to contribute to research efforts was highlighted as a major facilitator to completing studies in the ANZCA CTN. Professional societies can also play an important role in supporting a burgeoning research network, as they have in Australia and Canada. Established national organizations are well-suited to provide organizational and administrative support; additionally, societies communicate regularly with member clinicians, and their support serves to publicize and endorse a network’s efforts. Completing impactful studies demonstrates success. Scientific impact is generated by answering clinically important practice-changing questions through the completion of well-powered trials and the publication of results in high-impact journals. However, networks also have specifically focused on mentoring early-career investigators to broaden their impact on future research and the specialty. Lastly, to maximize generalizability of research, attention must be paid to participant and site (eg, community practices) diversity and to the incorporation of implementation science that better facilitates the translation of the generated knowledge into clinical practice. Efficiency is a critical attribute for the success of a burgeoning trial network, as the efficient use of resources reduces incremental effort and financial requirements. While the United States lacks a formal trial network within anesthesiology, resources such as the Outcomes Research Consortium, MPOG, and existing networks from previously conducted or ongoing trials (eg, Regional versus General Anesthesia for Promoting Independence after Hip Fracture [REGAIN,]23 Postoperative Pulmonary Complications, Early Mortality, and Hospital Stay After Noncardiothoracic Surgery,24 and Prophylactic Acetaminophen to Prevent Postoperative Delirium in Older Cardiac Surgical Patients [PANDORA])25 may be leveraged or built on to maximize efficiency. To streamline the conduct of clinical trials, certain aspects of study conduct or data collection (eg, common data elements) should be standardized. Establishing a culture of accountability at the outset of any trial network is essential. Individual sites should be held accountable for the science being conducted by maintaining robust processes for participant screening, participant recruitment, participant follow-up, and study oversite. A successful network provides “mentoring” of lower-performing sites from high-performing sites. The network should also aim to set and meet predesignated metrics to measure its own success (eg, completion of a certain number of trials, use of the network for federally funded trials), demonstrate return on investment, and establish the value of the network to all its member sites, funding agencies, and patients. Although initial steps of any network will focus on establishing a footprint and sustainability, there is a need to plan for growth. The network and participating sites would ideally prepare to expand and create capacity to conduct different types of studies (eg, mechanistic, longitudinal, or translational studies) with different designs (eg, stepped wedge, cluster randomization, hybrid implementation, platform trials), as well as the creation of centralized shared resources, such as tools for data collection or training research personnel, research support services (eg, biostatistical consulting, institutional review board resources), and data repositories or biobanks. 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The Anesthesia Research Council is sponsored by the American Society of Anesthesiologists the International Anesthesia Research Society and the Foundation for Anesthesia Education and Research The and in this report are the of the and the of the or Research was provided from institutional funding from the U.S. of Health through grant funding from grant and has from and funding from grant funding from grant the Patient-Centered Outcomes Research Institute grant and Research from and serves as an for is also with the which is supported by funding from grants and from and from the of award a from the of Anesthesiology and at the University of and the and in Anesthesia Research at Hospital and the University of has also from for in and to the work and is a member of the scientific board of Surgical The other

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