Clinical trial site readiness for decentralized trials – fitting trials into today’s world

Post-pandemic, decentralized clinical trials (DCTs) have emerged as a viable new way to efficiently conduct research. Originally piloted over 15 years ago, adoption of decentralized research methods during the COVID-19 pandemic was necessary to keep critical clinical trials running. As we emerge from the pandemic, regulators are clarifying their expectations in recommendation papers [1] and national guidance documents [2–4].

The Food and Drug Omnibus Reform Act (FDORA), signed into law in December 2022, defines a “decentralized clinical study” as a “clinical study in which some or all of the study-related activities occur at a location separate from the investigator’s location [5].” The main feature of a decentralized study is being centered around the participant and what may be most suitable for the participant’s access and experience. This may include engagement, recruitment, consent, study procedures, access to investigational product, and follow-up with a variety of data collections using active or passive methods.

Importantly, DCTs use a spectrum of methods that can be completely remote or partially decentralized with hybrid approaches (Table 1). Hybrid trials are typically defined as those that support some visits to be conducted on site, while other visits or assessments can be performed at a participant’s home or other preferred and accessible location. Fully remote trials have no required site visits, relying instead on all visits to take place using decentralized methods. Not every trial can be decentralized in the exact same way. Decentralized elements will need to be considered for every clinical trial in a fit for purpose fashion based on the condition under study, phase of the research, trial population, and procedures required in the protocol schedule of events. Any of these will determine which decentralized methods are best to be deployed. For example, complex study treatments like gene therapies in advanced stage disease trials may not be best suited for a telemedicine consent process, but might be better conducted in person [1], whereas trials for persons with decreased mobility may benefit from some trial visits conducted by telemedicine or some visits conducted by local healthcare providers. DCT methods could include but are not limited to electronic informed consent (eConsent), electronic clinical outcome assessment (eCOA), connected sensors, televisits, at-home shipments of investigational product, and other local elements such as the use of home health providers, local labs, local providers, mobile research sites, or retail pharmacies.

Table 1. Examples of clinical trials using decentralized elements

^a See FDA package insert at https://www.fda.gov/media/151707/download.

^b See ClinicalTrial.gov study record at https://clinicaltrials.gov/study/NCT05232929.

Historically, clinical trials have done a poor job of recruiting participants that are representative of the population living with the condition studied due to multiple factors, including access to clinical trials, distance to the trial site, and the time commitment of traveling to the trial site [6]. Decentralized methods have the potential to make trials more accessible to a larger population, make them easier to incorporate into daily life, and have the potential to collect more meaningful data on how the investigational medical product affects how trial participants feel and function. By improving trial access, decentralized trials may complement other equity initiatives and support goals for inclusion of more diverse and representative trial participants. Care has to be taken that the technology itself does not become a barrier and that digital access issues are addressed with options such as provisioned devices and paid data plans by trial sponsors. Decentralized methods can also make trials more resilient in supporting business continuity should participants be unable to reach sites for any reason, while also helping to support environmental and social responsibility objectives on the path toward more environmentally sustainable research.

As research models continue to expand the number and variety of locations to improve access, these approaches will challenge the definition of the “site” as a brick-and-mortar building and the foundational element for clinical trial readiness practices. A “building” does not conduct research—research is performed by a qualified investigator supported by people, processes, and technology surrounding a qualified investigator. Similarly, the term “investigator” may not need to be an individual but rather an organization. As we move toward more decentralized trial models leveraging the potential for systems of care or broader organizational approaches to reach people and conduct clinical trials, an organization may be more appropriate to be recognized as the “investigator.” For example, organizations routinely serve as sponsors and hold the IND with the commensurate responsibilities. Similarly, authorized officials are responsible for NIH grants or clinical care systems. So, if a system of care is being used for a clinical trial, then an investigator (the organization) is using the systems, units, personnel, and controls responsible for the trial conduct and can manage the appropriate master delegation of responsibilities. As the trial participants whom principal investigators enroll, are responsible for, and provide oversight of increase in numbers from 10s to 100s to 1000s and even more; and participation expands from local to regional to national, new models and supporting tools will need to evolve for operationalization. Select collaborative groups are working on exploring these issues and solutions, and best practices specific to oversight and responsibility should be created. Practices that promote clinical trial site readiness can be agnostic to location by modernizing our definition of a site or shifting the focus to the investigator and their supporting infrastructure.

Using the site readiness practices framework for decentralized trials requires additional considerations related to roles and responsibilities, technology access, medical licensing, and oversight (Table 2). Site readiness practices, originally described in a companion article [7], when adapted for decentralized trials provide regulators, ethics committees, and investigators and sponsors greater confidence to leverage decentralized methods to make research more accessible and more resilient. These practices help to guide investigators in the training and processes needed to support decentralized trials, while guiding study teams toward selecting the best possible investigators and sites for the needs of each study. Additionally, site readiness practices adapted for DCTs can help sites prioritize what additional skills and resources may be needed for training and other investment. Use of site readiness practices can also improve sponsor’s and CRO’s identification of appropriate sites for studies with decentralized elements.

Table 2. Considerations for site readiness in the context of decentralized clinical trials

Recent surveys have indicated sites are facing challenges with adoption of decentralized elements. A survey released by the Association of Clinical Research Professionals reveals that sites lack the training and budget to implement DCTs and that the technologies do not always take site user experience into consideration, for example, the lack of Single Sign On was mentioned as a barrier [8]. Additionally, the top-cited reason sites declined participation in decentralized trials in another site-based survey was hesitancy to adopt these methods without a sufficient budget to cover additional training or the integration of new technologies [9]. This points to the need for robust support of sites for training and adoption including the need for technology providers to take site users' experience and needs into consideration when developing new clinical trial technologies. Investigators have also raised concerns regarding oversight in decentralized research, in particular with connected devices streaming data or third parties being contracted to support some visit procedures. Regulatory recommendations and guidance have called for processes and tools to be included during study planning to address these concerns and support existing investigator obligations to safety and integrity [1,4]. Site readiness to deploy decentralized approaches needs to be ensured with specific training programs, intuitive easy to use software and applications, and sufficient budgets. The site readiness practices and the related adaptations for DCTs should help alleviate some of the challenges encountered by sites.