DCT and DHT Implementation during COVID-19

In March 2020, FDA released a guidance document regarding the conduct of clinical trials during the COVID-19 Public Health Emergency (Turner, 2020; U.S. FDA Conduct, 2021). This document provides practical advice for ensuring participants' safety, maintaining data integrity, and accounting for pandemic-related variability in trial protocols. It advocates for remote and decentralized trial methods, offering detailed considerations and recommendations for their implementation and integration into the study when appropriate. An expert on vaccine development pointed out that strong guidance documents from FDA early in the pandemic (Turner, 2020; U.S. FDA Conduct, 2021) helped many trials finish during COVID-19 pandemic and observed that some that did not follow recommendations struggled.

Two experts spoke of the challenges of referring to decentralized trials as a "separate category" of trials, instead emphasizing that decentralized elements and DHTs can be incorporated into a multitude of trials and trial designs to drive efficiencies and patient centricity. For example, even a fully inpatient trial might achieve more efficient and more patient-centric enrollment by designing an electronic informed consent (eIC) process that incorporates educational videos and interactive elements. Using these strategies to reduce on-site visits also benefits sponsors because of their high costs for clinical staff and significantly higher time burdens for participants.

Over the course of the COVID-19 pandemic, DCTs and DHTs saw effective use during various stages of the clinical trial. The implementation of these tools is described by trial stage below.

Trial recruitment, enrollment, and informed consent: Digital tools have long allowed patients to complete pre-screening, consultation, and informed consent through video-meetings or virtual platforms, but these approaches were leveraged more frequently during the COVID-19 pandemic. Although many non-COVID-related trials faced disruptions and delays in recruitment, those that had incorporated digital and decentralized strategies from the beginning were able to proceed and sometimes even benefit from the situation. For example, the "Intuition" study (ClinicalTrials.gov identifier: NCT05058950), an observational study using multimodal sensors to measure cognitive health in adults and detect mild cognitive impairment launched in January 2021, was designed to be remote and managed to recruit thousands of participants within the first three months. The surge in enrollment could be attributed, in part, to the COVID-19 pandemic because people who might have otherwise been involved in different studies opted to join the INSIGHT study. Other strategies to meet the patients where they are included the engagement of retail pharmacies, such as Pfizer's partnership with Walgreens to allow patients to conveniently enroll in the Paxlovid trial (ClinicalTrials.gov identifier: NCT05576662) while picking up their prescriptions (Grabenstein, 2022). These examples further underscore the importance of a patient-centric approach in increasing clinical trial participation.

Sponsors facilitated eIC through online portals, mobile apps, secured emails, or text messaging (Josan et al., 2021; Lee et al., 2021; U.S. FDA Conduct, 2021). These approaches were used to not only reach patients at their homes but also drive enrollment of intensive care unit patients, as non-clinical staff were frequently barred from entering patients' rooms or hospitals. The COVID-19 experience also highlighted the importance of a well-designed—often multimodal—eIC process, in which standard consent forms and language are enhanced by infographics, videos, links to learn more, Slack support groups, and multiple language options to improve patients' experience and comprehension. Independent experts cited better retention of information and higher patient satisfaction with the enhanced versions of consent procedures compared with the standard approach to decentralized/remote patient consenting of a 20-minute phone call. More importantly, enhanced forms of informed consent processes have been shown to empower people who were historically underrepresented in clinical studies, as witnessed in the All of Us study, which uses such approaches to enroll a group of participants that "reflects the diversity of the United States" (All of Us, 2020).

Treatment and monitoring: To minimize barriers to patient recruitment and participation, several experts highlighted the importance of patient-centric data collection; this includes accommodating participants by facilitating remote data collection outside the clinical setting. The experts saw this as a vital approach under all circumstances but particularly imperative during the COVID-19 pandemic, when patients could not or did not want to travel to clinical sites. The logistical challenges of conducting clinical trials amid a pandemic led to the adoption of several decentralized trial elements for clinical trial operations, often enhanced by DHTs. These include the following:

• Telemedicine, the remote delivery of health care services, played a crucial role in substituting in-person visits and ensuring the continuity of clinical trials during the pandemic. It encompassed various trial aspects, including virtual clinician visits, patient monitoring, symptom reporting, and virtual pill-taking (medication adherence monitoring through home delivery coupled with video conferencing software).
  Although telemedicine existed in the United States before COVID-19, its use was significantly constrained in clinical care delivery and research. These constraints included limited reimbursements, underdeveloped digital infrastructure, ambiguities in IRB jurisdiction (for some federally funded research), other regulatory variations across states, and restrictions on cross-state health professional licensing (Apostolaros et al., 2020; Lee et al., 2021).
  To ease these barriers during the COVID-19 pandemic, the Centers for Medicare & Medicaid Services issued waivers to grant payment parity between telehealth and in-person care, and the Office for Civil Rights exercised enforcement discretion (and effectively halted the use of penalties) for use of technologies that did not comply with the Health Insurance Portability and Accountability Act (HIPAA) (e.g., Zoom, Skype, and FaceTime) to provide telehealth services (Baumann, MacArthur and Michalski, 2020; Shachar, Engel and Elwyn, 2020; De et al., 2021; Schofield, 2021; HHS HIPAA, 2022). In addition, some states provided emergency licensing waivers, which alleviated the burden of cross-state licensure requirements (Federation of State Medical Boards, no date). Although these policies were not universally adopted across the United States, they expanded the deployment of telemedicine in clinical practice as well as in clinical trials—not only for research and care associated with COVID-19 but also for other diseases (Freedberg et al., 2020; Hatcher-Martin et al., 2020; HHS, 2020; De et al., 2021; Josan et al., 2021; Greenough et al., 2022; Kaizer et al., 2023).
  All the interviewed experts agreed that the COVID-19 pandemic demonstrated that many aspects of clinical trials can be effectively performed remotely—a belief long held by the DCT community but previously not widely adopted. The experts also agreed that, to harness the benefits of telemedicine for clinical trials outside of emergency situations, greater reimbursement parity and changes in cross-state licensing regulations are necessary, especially because many COVID-19 pandemic policies (at local, state, and national levels) have been reversed since the end of the federal public health emergency in May 2023.
• Self-monitoring and at-home measurements: During the COVID-19 pandemic, many sponsors opted to send measuring devices, such as blood pressure monitors, spirometry tools, or glucose monitoring devices, directly to patients' homes for self-monitoring to substitute for (some) in-person clinical site visits. Their use during the COVID-19 pandemic revealed that patients were capable of effectively using these at-home measuring devices. One expert referred to a PROGRESS study in which patients were offered an option of at-home visits or self-guided at-home testing to perform glucose monitoring. The vast majority (>90%) of the participants chose self-guided at-home testing, allowing the trial's leaders to shift some study coordinators' time to other work. The possibility of reducing at-home visits also creates potential for cost reduction and resource optimization. This trial includes a patient-centric approach that acknowledges the diverse range of patient preferences and comfort levels, fostering inclusivity regardless of participants' technological literacy.
  Certainly, activities such as neurological evaluation, neurocognitive or joint mobility assessment, and radiology scans require nuanced clinical judgment and expertise that patient-reported outcomes or at-home measurements cannot easily capture in the absence of a clinician. Moreover, concerns about the discrepancies between at-home and ambulatory clinic measurements remain. Still, it’s possible some at-home measurements might capture data in the context of a patient’s daily routines and natural behaviors, providing more true-to-life evidence on disease progression, symptoms, and side effects. Some discrepancies could be potentially reduced through telemedicine to supervise patients during the measurements. Others will inevitably remain, and ongoing research is necessary to validate at-home measurement tools and the measures they collect.
  Interviewed experts agreed that despite these uncertainties, there remains significant value in leveraging at-home measurements tools and that such approaches can and should be leveraged on an ongoing basis to substitute for select in-patient visits. A combination of ambulatory clinic and at-home measurements could be what one expert called the "goldilocks" solution, offering greater flexibility to patients and better accounting for real-world evidence (RWE) and maintaining oversight and the broad integrity of the trial's findings.
• DHTs were used for remote patient monitoring and data collection during the COVID-19 pandemic. For example, to monitor COVID-19 patient recovery or cardiac safety signals, some patients were allowed to use wearable devices and mattress sensors to track their vital signs such as heart rate, respiratory function, body temperature, sleep patterns, and movement. This continuous monitoring resulted in data reflecting the patient’s everyday status and could alert health care professionals of new side effects and symptoms (Seltzer et al., 2022; Von Preyss-Friedman et al., 2022). Trials also employed custom mobile applications, such as a medication adherence app that reminded patients to take their medication, specified the dosage, tracked missed doses, and provided refill notifications (Dockendorf et al., 2021; Volpi et al., 2021). Other digital tools included symptom tracking apps and eJournals that recorded symptoms and patients' experiences in real time, as opposed to the retrospective reporting normally collected in person during hospital visits (Drury and O'Connor, 2021; Houhamdi and Fournier, 2022; Pandit et al., 2022). Although DHTs hold promise for clinical research, trials using DHTs must ensure that patients have prior training or digital proficiency when reporting their symptoms and validate their methods so that they can maintain the integrity of these measurements (Hashem et al., 2020; Inan et al., 2020).
• Trials leveraged local medical centers and mobile units for interventions unsuitable for virtual conduct. In many trials, mobile units (e.g., phlebotomists) collected biological samples directly at patients' homes. For instance, the Healthy-Lung trial (ClinicalTrials.gov identifier: NCT04798664) accomplished two-thirds of its sample collections through mobile units, offering safer alternatives to on-site visits during the COVID-19 pandemic. An expert specializing in DCTs emphasized that despite the higher costs involved, the use of mobile units significantly simplifies patient participation in the trials and provides an additional tool to augment the diversity of participants.
  Clinical trial activities that required medical site visits, such as radiotherapy and imaging, were often conducted in collaboration with local medical centers (Izmailova, Ellis and Benko, 2020; Ali et al., 2021; Anderson, 2021; Boughey et al., 2021; De et al., 2021; Park et al., 2022). As with all multisite trials, this collaboration necessitated substantial harmonization of practices to address the variability in medical devices and protocols used across the health centers. Another innovation incorporated during the pandemic was allowing community pharmacists and local health centers to administer medications or delivering medication direct to patients (National Cancer Institute, 2020; Waterhouse et al., 2020; McDermott and Newman, 2021; Sami et al., 2021; Van Norman, 2021; Mohamed Ibrahim et al., 2022; Pantasri, 2022; Kaizer et al., 2023). Handling of medication outside of a centralized trial site requires additional oversight, detailed protocols, and close monitoring to ensure participants' compliance and drug stability and appropriate storage (e.g., temperature tracking). Precautionary measures also had to be implemented to prevent unauthorized medication access and to ensure timely refills to prevent study interruptions (National Cancer Institute, 2020; Van Norman, 2021). Beyond emergency conditions, involvement of local health centers and direct-to-patient delivery could serve to improve accessibility to clinical trials, benefiting patients from rural areas or those with limited travel possibilities.

With the conclusion of state public health emergency declarations beginning in 2021, and the federal public health emergency concluding in May 2023, certain regulatory waivers and flexibilities were reversed (Cox et al., 2023; U.S. FDA Staff, 2023). For instance, some states discontinued cross-state licensing waivers (Licensing across state lines, no date), and the use of HIPAA-compliant technologies became a requirement for virtual patient encounters (HHS HIPAA, 2022; Cox et al., 2023). Notably, certain platforms such as Zoom have updated their services to provide HIPAA-compliant solutions (Zoom, 2021; Alder, 2023). Significant aspects of telemedicine, such as payment parity, waiver of geographic and location requirements, and the in-person visit requirement for initiating tele-behavioral health services, were extended until December 31, 2024 (U.S. FDA Staff, 2023; HHS Fact Sheet, 2023).

Lessons Learned for decentralized clinical trials and digital health technologies

The accumulated expert interviews and literature outcomes of the use of DCTs and DHTs catalyzed by the COVID-19 pandemic underscore that DCTs and DHTs offer participant-centric approaches to clinical research and have the potential to reduce barriers to trial participation, enhance engagement, improve retention, and drive participants' satisfaction. These lessons apply to therapeutics, vaccines, and diagnostics in pandemic and non-pandemic (normal) contexts.

Telemedicine or virtual visits, in which therapy assessments and interventions are carried out online or at home, could reduce pandemic disruptions for many trials, not just pandemic product trials. Remote models can lower costs, focus on individual family needs, and support equal access to evidence-based quality. Achieving telemedicine advantages in non-pandemic settings will necessitate clarifications of and some updates to reimbursement and state-specific medical licensing regulations.

Decentralization supports the extension of trial participation to underserved populations, including rural, socioeconomically disadvantaged, and mobility-limited people, as well as patients with rare or severe diseases. At-home measurements can substitute for certain in-site visits, improving patient flexibility, generating RWE, and concurrently reducing costs and study coordination workload.

Fit-for-purpose uses of DCTs in "meeting people where they are" proved effective at various stages of a trial, ranging from recruiting, to consent, to data collection. Utilizing social media, pharmacist referrals, and/or community ambassador involvement are just some of the decentralized approaches that can support clinical trials. As such, DCTs and DHTs should be approached as tools to enhance the conduct of clinical trials, rather than distinct entities. For example, eIC processes, supplemented with visuals and videos, improves information retention and patient satisfaction, while also strictly adhering to the goals of informed consent processes for research.

With respect to any future clinical trials and for pandemic preparedness, it will be important to draw on experiences with the use of decentralized approaches and DHTs during the COVID-19 pandemic. These approaches and tools proved vital to keeping many trials going during the COVID-19 pandemic, but were widely viewed as "retrofits" and in many cases they were costly to incorporate into trial designs after-the-fact. Vitally, integration of situation-appropriate decentralized elements into clinical trials will result in building both the infrastructure and expertise needed for future pandemic resilience. As a corollary: solutions that "bolt on" DHTs and decentralized elements to existing trials will fail to take advantage of the full promise of these tools and learnings from the COVID-19 pandemic.