The COVID-19 pandemic accelerated the development of decentralized clinical trials (DCT). DCT’s are an important and pragmatic method for assessing health outcomes yet comprise only a minority of clinical trials, and few published methodologies exist. In this report, we detail the operational components of COVID-OUT, a decentralized, multicenter, quadruple-blinded, randomized trial that rapidly delivered study drugs nation-wide. The trial examined three medications (metformin, ivermectin, and fluvoxamine) as outpatient treatment of SARS-CoV-2 for their effectiveness in preventing severe or long COVID-19. Decentralized strategies included HIPAA-compliant electronic screening and consenting, prepacking investigational product to accelerate delivery after randomization, and remotely confirming participant-reported outcomes. Of the 1417 individuals with the intention-to-treat sample, the remote nature of the study caused an additional 94 participants to not take any doses of study drug. Therefore, 1323 participants were in the modified intention-to-treat sample, which was the a priori primary study sample. Only 1.4% of participants were lost to follow-up. Decentralized strategies facilitated the successful completion of the COVID-OUT trial without any in-person contact by expediting intervention delivery, expanding trial access geographically, limiting contagion exposure, and making it easy for participants to complete follow-up visits. Remotely completed consent and follow-up facilitated enrollment.

Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized trials with outcomes assessed using RWD to fully observational studies. Yet, many proposals for generating RWE lack sufficient detail, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to prespecify study design and analysis plans; it addresses a wide range of guidance within a single framework. By supporting the transparent evaluation of causal assumptions and facilitating objective comparisons of design and analysis choices based on prespecified criteria, the Roadmap can help investigators to evaluate the quality of evidence that a given study is likely to produce, specify a study to generate high-quality RWE, and communicate effectively with regulatory agencies and other stakeholders. This paper aims to disseminate and extend the Causal Roadmap framework for use by clinical and translational researchers; three companion papers demonstrate applications of the Causal Roadmap for specific use cases.

Clinical trial processes are unnecessarily inefficient and costly, slowing the translation of medical discoveries into treatments for people living with disease. To reduce redundancies and inefficiencies, a group of clinical trial experts developed a framework for clinical trial site readiness based on existing trial site qualifications from sponsors. The site readiness practices are encompassed within six domains: research team, infrastructure, study management, data collection and management, quality oversight, and ethics and safety. Implementation of this framework for clinical trial sites would reduce inefficiencies in trial conduct and help prepare new sites to enter the clinical trials enterprise, with the potential to improve the reach of clinical trials to underserved communities. Moreover, the framework holds benefits for trial sponsors, contract research organizations, trade associations, trial participants, and the public. For novice sites considering future trials, we provide a framework for site preparation and the engagement of stakeholders. For experienced sites, the framework can be used to assess current practices and inform and engage sponsors, staff, and participants. Details in the supplementary materials provide easy access to key regulatory documents and resources. Invited perspective articles provide greater depth from a systems, DEIA (diversity, equity, inclusion, and accessibility) and decentralized trials perspective.

Long-term sequelae of severe acute respiratory coronavirus-2 (SARS-CoV-2) infection may include increased incidence of diabetes. Here we describe the temporal relationship between new type 2 diabetes and SARS-CoV-2 infection in a nationwide database. We found that while the proportion of newly diagnosed type 2 diabetes increased during the acute period of SARS-CoV-2 infection, the mean proportion of new diabetes cases in the 6 months post-infection was about 83% lower than the 6 months preinfection. These results underscore the need for further investigation to understand the timing of new diabetes after COVID-19, etiology, screening, and treatment strategies.

The 2020 COVID-19 pandemic has had a profound impact on the clinical research enterprises at the 60 Clinical and Translational Science Award (CTSA) Hubs throughout the nation. There was simultaneously a need to expand research to obtain crucial data about disease prognosis and therapy and enormous limitations on conducting research as localities and institutions limited travel and person-to-person contact. These imperatives resulted in major changes in the way research was conducted, including expediting Institutional Review Board review, shifting to remote interactions with participants, centralizing decision-making in prioritizing research protocols, establishing biobanks, adopting novel informatics platforms, and distributing study drugs in unconventional ways. National CTSA Steering Committee meetings provided an opportunity to share best practices and develop the idea of capturing the CTSA program experiences in a series of papers. Here we bring together the recommendations from those papers in a list of specific actions that research sites can take to strengthen operations and prepare for similar future public health emergencies. Most importantly, creative innovations developed in response to the COVID-19 pandemic deserve serious consideration for adoption as new standards, thus converting the painful trauma of the pandemic into “post-traumatic growth” that makes the clinical research enterprise stronger, more resilient, and more effective.

OBJECTIVES/GOALS: The North Carolina Translational and Clinical Sciences Institute (NC TraCS) supports faculty and staff in carrying out clinical and translational research at UNC-Chapel Hill. To better understand customer satisfaction and impact, a survey was administered among NC TraCS users. METHODS/STUDY POPULATION: NC TraCS has 13 program areas that range from Biostatistics to Community and Stakeholder Engagement. These programs provide services to faculty, staff, students, and outside researchers in the area of clinical and translational science. A customer feedback survey was administered in Spring 2019 to anyone who had used at least one NC TraCS service between March 1st, 2017 and February 28th, 2019. A total of 856 survey invitations were sent. The survey included questions around users’ perception of the ease of access, helpfulness, outcome, and promptness of the services received using 6-point Likert scale. The survey also addressed career impact, communications, and suggestions for improvement. RESULTS/ANTICIPATED RESULTS: We received 268 responses, (31% response). Majority of respondents were satisfied with Overall Helpfulness (95%), Outcome of Service (96%), Ease of Access (93%), and Promptness of Service (90%). They also noted that their careers had at least slightly improved in the following areas: Mentorship (76%), Research Methods (75%), Skill Development (77%), Research Direction (71%) and Collaboration (80%). Furthermore, 96% responded positively to returning to TraCS. The feedback received was shared with service administrators and NC TraCS leadership to identify areas of improvement and further strengthen their services. Concerns, when present, were addressed by service directors or the overall PI’s. DISCUSSION/SIGNIFICANCE OF IMPACT: Need to communicate expectations to customers the expected turn-around time for help emerged as a clear take-away. In response, TraCS leadership is working to improve staffing and workflows for efficient service delivery including expectation management, especially among the most popular services.

OBJECTIVES/GOALS: The goals of this evaluation were 1) to describe the pilot grant application cycle and processes at NC TraCS, 2) to illustrate the impact of pilot grants on extramural grant funding, and 3) to provide a framework for other institutions to utilize for the evaluation of pilot grant programs. METHODS/STUDY POPULATION: From 2009-2019 the NC TraCS pilot program funded 925 projects, varying from $2,000 to $100,000. Pilot grants are available to any researcher affiliated with the university as well as partner institutions and community stakeholders. For this evaluation we analyzed data on pilot applicants (demographics, type of pilot, funding status, resubmissions, etc.) and outcomes (extramural funding, publications, etc.) yielded from funded pilots. In addition to summary statistics, we also calculated return on investment (ROI) for the program as a whole and by specific grant type. We will use bibliometric network analysis to assess productivity, citation impact, and scope of collaboration. RESULTS/ANTICIPATED RESULTS: There have been 2,777 submitted proposals with an acceptance rate of 33.3%. Unfunded proposals can resubmit, 61.8% of resubmitted applications are successfully funded, and 29.6% of funded applications are resubmissions. The $2,000 awards accounted for 43.4% of all grants awarded but only accounted for 6.4% of all pilot funds awarded. Success of proposals was proportional to the number of applications from each academic unit. 60.8% of funded applicants were affiliated with the School of Medicine and account for 65.3% of all funding awarded from 2009-2019. Additionally, we plan on analyzing return on investment rates to illustrate the impact of pilot awards on future research funding. DISCUSSION/SIGNIFICANCE OF IMPACT: Pilot grants can lead to subsequent extramural grants, publications, and successful translation of research into practice. This evaluation will assist our institution in understanding the impact of pilot grants and will provide a road map for other institutions evaluating their own programs.

Electronic health records (EHRs) provide great promise for identifying cohorts and enhancing research recruitment. Such approaches are sorely needed, but there are few descriptions in the literature of prevailing practices to guide their use. A multidisciplinary workgroup was formed to examine current practices in the use of EHRs in recruitment and to propose future directions. The group surveyed consortium members regarding current practices. Over 98% of the Clinical and Translational Science Award Consortium responded to the survey. Brokered and self-service data warehouse access are in early or full operation at 94% and 92% of institutions, respectively, whereas, EHR alerts to providers and to research teams are at 45% and 48%, respectively, and use of patient portals for research is at 20%. However, these percentages increase significantly to 88% and above if planning and exploratory work were considered cumulatively. For most approaches, implementation reflected perceived demand. Regulatory and workflow processes were similarly varied, and many respondents described substantive restrictions arising from logistical constraints and limitations on collaboration and data sharing. Survey results reflect wide variation in implementation and approach, and point to strong need for comparative research and development of best practices to protect patients and facilitate interinstitutional collaboration and multisite research.