Leveraging the Expertise of the CTSA Program to Increase the Impact and Efficiency of Clinical Trials.

Importance: Multicenter clinical trials play a critical role in the translational processes that enable new treatments to reach all people and improve public health. However, conducting multicenter randomized clinical trials (mRCT) presents challenges. The Trial Innovation Network (TIN), established in 2016 to partner with the Clinical and Translational Science Award (CTSA) Consortium of academic medical institutions in the implementation of mRCTs, consists of 3 Trial Innovation Centers (TICs) and 1 Recruitment Innovation Center (RIC). This unique partnership has aimed to address critical roadblocks that impede the design and conduct of mRCTs, in expectation of accelerating the translation of novel interventions to clinical practice. The TIN's challenges and achievements are described in this article, along with examples of innovative resources and processes that may serve as useful models for other clinical trial networks providing operational and recruitment support. Observations: The TIN has successfully integrated more than 60 CTSA institution program hubs into a functional network for mRCT implementation and optimization. A unique support system for investigators has been created that includes the development and deployment of novel tools, operational and recruitment services, consultation models, and rapid communication pathways designed to reduce delays in trial start-up, enhance recruitment, improve engagement of diverse research participants and communities, and streamline processes that improve the quality, efficiency, and conduct of mRCTs. These resources and processes span the clinical trial spectrum and enable the TICs and RIC to serve as coordinating centers, data centers, and recruitment specialists to assist trials across the National Institutes of Health and other agencies. The TIN's impact has been demonstrated through its response to both historical operational challenges and emerging public health emergencies, including the national opioid public health crisis and the COVID-19 pandemic. Conclusions and Relevance: The TIN has worked to reduce barriers to implementing mRCTs and to improve mRCT processes and operations by providing needed clinical trial infrastructure and resources to CTSA investigators. These resources have been instrumental in more quickly and efficiently translating research discoveries into beneficial patient treatments.

Decentralized clinical trials in the trial innovation network: Value, strategies, and lessons learned.

New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by facilitating participation outside of traditional clinical settings and taking studies directly to participants. The Trial Innovation Network, established in 2016 by the National Center for Advancing Clinical and Translational Science to address critical roadblocks in clinical research and accelerate the translational research process, has consulted on over 400 research study proposals to date. Its recommendations for decentralized approaches have included eConsent, participant-informed study design, remote intervention, study task reminders, social media recruitment, and return of results for participants. Some clinical trial elements have worked well when decentralized, while others, including remote recruitment and patient monitoring, need further refinement and assessment to determine their value. Partially decentralized, or "hybrid" trials, offer a first step to optimizing remote methods. Decentralized processes demonstrate potential to improve urban-rural diversity, but their impact on inclusion of racially and ethnically marginalized populations requires further study. To optimize inclusive participation in decentralized clinical trials, efforts must be made to build trust among marginalized communities, and to ensure access to remote technology.

Using gamification to enhance clinical trial start-up activities.

Background: The Trial Innovation Network (TIN) is a collaborative initiative within the National Center for Advancing Translational Science (NCATS) Clinical and Translational Science Awards (CTSA) Program. To improve and innovate the conduct of clinical trials, it is exploring the uses of gamification to better engage the trial workforce and improve the efficiencies of trial activities. The gamification structures described in this article are part of a TIN website gamification toolkit, available online to the clinical trial scientific community. Methods: The game designers used existing electronic trial platforms to gamify the tasks required to meet trial start-up timelines to create friendly competitions. Key indicators and familiar metrics were mapped to scoreboards. Webinars were organized to share and applaud trial and game performance. Results: Game scores were significantly associated with an increase in achieving start-up milestones in activation, institutional review board (IRB) submission, and IRB approval times, indicating the probability of completing site activation faster by using games. Overall game enjoyment and feelings that the game did not apply too much pressure appeared to be an important moderator of performance in one trial but had little effect on performance in a second. Conclusion: This retrospective examination of available data from gaming experiences may be a first-of-kind use in clinical trials. There are signals that gaming may accelerate performance and increase enjoyment during the start-up phase of a trial. Isolating the effect of gamification on trial outcomes will depend on a larger sampling from future trials, using well-defined, hypothesis-driven statistical analysis plans.

Feasibility of Core Antimicrobial Stewardship Interventions in Community Hospitals.

Importance: The feasibility of core Infectious Diseases Society of America-recommended antimicrobial stewardship interventions in community hospitals is unknown. Objective: To determine the feasibility and results of implementing 2 core stewardship intervention strategies in community hospitals. Design, Setting, and Participants: Three-stage, multicenter, prospective nonrandomized clinical trial with crossover design. The setting was 4 community hospitals in North Carolina (median bed size, 305; range, 102-425). Participants were all patients receiving targeted study antibacterial agents or alternative, nonstudy antibacterial agents. The study dates were October 2014 through October 2015. All statistical analyses were completed as of October 2016. Interventions: Two antimicrobial stewardship strategies targeted vancomycin hydrochloride, piperacillin-tazobactam, and the antipseudomonal carbapenems on formulary at the study hospitals: (1) modified preauthorization (PA), in which the prescriber had to receive pharmacist approval for continued use of the antibiotic after the first dose, and (2) postprescription audit and review (PPR), in which the pharmacist would engage the prescriber about antibiotic appropriateness after 72 hours of therapy. Two hospitals performed modified PA for 6 months, then PPR for 6 months after a 1-month washout. The other 2 hospitals performed the reverse. Main Outcomes and Measures: The primary outcome was the feasibility of implementing the interventions, determined by (1) approval by hospital administration and committees at each study hospital; (2) completion of pharmacist training; (3) initiation and implementation as determined by number, type, and outcomes of interventions performed; and (4) time required for interventions. Secondary outcomes included antimicrobial use (days of therapy) compared with matched historical periods and length of hospitalization. Results: A total of 2692 patients (median age, 65 years; interquartile range, 53-76 years) underwent a study intervention; 1413 (52.5%) were female, 1323 (49.1%) were white, and 1047 (38.9%) were African American. Intervention approvals took a median of 95 days (range, 56-119 days); during these discussions, strict PA was deemed not feasible. Instead, the modified PA intervention was used throughout the study. Pharmacists performed 1456 modified PA interventions (median per hospital, 350 [range, 129-628]) and 1236 PPR interventions (median per hospital, 298 [range, 273-366]). Study antimicrobials were determined to be inappropriate 2 times as often during the PPR period (41.0% [435 of 1060] vs 20.4% [253 of 1243]; P < .001). Pharmacists recommended dose change more often during the modified PA intervention (15.9% [232 of 1456] vs 9.6% [119 of 1236]; P < .001) and de-escalation during PPR (29.1% [360 of 1236] vs 13.0% [190 of 1456]; P < .001). The median time dedicated to the stewardship interventions varied by hospital (range of median hours per week, 5-19). Overall antibiotic use decreased during PPR compared with historical controls (mean [SD] days of therapy per 1000 patient-days, 925.2 [109.8] vs 965.3 [109.4]; mean difference, -40.1; 95% CI, -71.7 to -8.6), but not during modified PA (mean [SD] days of therapy per 1000 patient-days, 931.0 [102.0] vs 926.6 [89.7]; mean difference, 4.4; 95% CI, -55.8 to 64.7). Conclusions and Relevance: Strict PA was not feasible in the study hospitals. In contrast, PPR was a feasible and effective strategy for antimicrobial stewardship in settings with limited resources and expertise. Trial Registration: ClinicalTrials.gov identifier: NCT02212808.

Fundamentals and Catalytic Innovation: The Statistical and Data Management Center of the Antibacterial Resistance Leadership Group.

The Statistical and Data Management Center (SDMC) provides the Antibacterial Resistance Leadership Group (ARLG) with statistical and data management expertise to advance the ARLG research agenda. The SDMC is active at all stages of a study, including design; data collection and monitoring; data analyses and archival; and publication of study results. The SDMC enhances the scientific integrity of ARLG studies through the development and implementation of innovative and practical statistical methodologies and by educating research colleagues regarding the application of clinical trial fundamentals. This article summarizes the challenges and roles, as well as the innovative contributions in the design, monitoring, and analyses of clinical trials and diagnostic studies, of the ARLG SDMC.