A year ago, decentralized clinical trials were just another shiny new tool. By the end of 2021, all that changed. CenterWatch was now anticipating a new trajectory for the future of clinical trials: “[The] industry is approaching a watershed moment, with sponsors and CROs planning for the first time to conduct more hybrid trials than traditional site-based trials.” Clinical Trials Arena was making similar projections: In 2022, a record number of approximately 1,300 trials would be initiated with a decentralized or virtual component.

In fact, WRG figures put the number of 2021 trials with decentralized components at 2,642, and the adoption of DCTs continues to accelerate in 2022, burgeoned by new strategies for transitioning to digital studies. DCT teams, once ring-fenced, are now being integrated into sponsor and CRO organizations to disseminate their expertise across core businesses. What once was a side show has now become the main act. The explosion of telehealth is an important contributor to the increase in DCT acceptance as well. The adoption of telehealth platforms has skyrocketed: 76% of patients reported using telehealth to replace canceled healthcare visits in 2020—a massive increase from the 11% reported in the previous year.

But “decentralization” is not just about telehealth. CROs are increasingly incorporating decentralized components and services into many aspects of the trials they run.

Initiated worldwide drug trials identified as involving virtual/decentralized components

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With all this buzz, a comprehensive deep dive into the emerging—and increasingly normalized—field of DCTs is in order.

In this post, we will provide a definition of “decentralized clinical trials,” give a sliding scale for clinical study decentralization, highlight the benefits of incorporating DCTs, as well as the challenges associated with DCTs, provide 9 principles to keep in mind when planning and deploying a successful decentralized or hybrid trial, and, finally, call out specific use cases for DCTs in both ongoing and completed clinical trials.

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Decentralized Clinical Trials Definition

We will begin by answering the essential question: What is a decentralized clinical trial?
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According to the FDA, decentralized clinical trials (DCTs) are defined by "the decentralization of clinical trial operations where technology is used to communicate with study participants and collect data."

The CTTI further fleshes out this definition by addressing means of communication, highlighting the use of technology to connect patients with clinicians and underscoring the increased participant accessibility made possible through technology.

The term "decentralization" infers that activities which previously took place at sites can now be done remotely, most often in people’s homes but also at local pharmacies, labs, and other proximate options. Technology sits at the heart of this paradigm shift, enabling a level of participant convenience that would otherwise be impossible. As a result, the industry has stopped asking the question, “Can a trial be decentralized?” and is now asking, “How decentralized can a trial be?”
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How Decentralized Can You Go: The Sliding Scale of Decentralization

Clinical trial sponsors frequently ask which kinds of studies can be done virtually. Put simply: The greater the need for HCP intervention, the less likely it is that a fully remote decentralized clinical trial will be the solution. However, recent advances in telehealth, remote monitoring, and device integration have blurred these lines by enabling clinical trial support systems to operate from a decentralized clinical trial platform rather than a brick-and-mortar site. Clinical trial sponsors can now draw upon a broad spectrum of options that range from traditional to fully decentralized and everything in between.

Data collection, for example, is an essential and immense component of clinical trials that has been forever changed by decentralization. There are many types of data (physiological, behavioral, and perceptual) where technology can be substituted, either partially or entirely, for face-to-face collection. Data can be captured via digital questionnaires, journals, or remote devices, and test results (stools, blood, etc.) can be reported and transmitted via technology. Access to these digital tools has opened a world of possibilities for conducting trials more efficiently.

Determining whether and how much decentralization is possible and identifying the virtual components that make sense for a specific study will depend on therapeutic area, patient population, and study goals. The vast majority of trials will remain hybrid, with both traditional elements and virtual or decentralized components.
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The Sliding Scale of Decentralization

Recruitment

Site-Based Recruitment

Site-based recruitment and prescreening via TV, radio, newspaper, physician-to-physician referrals, recruitment agencies

Virtual Recruitment

Targeted digital recruitment and prescreening through social media  

Enrollment and Onboarding

Site-Based Enrollment and Onboarding

• Face-to-face consent
• Screening and site-based assessments at scheduled appointments
• In-person training at scheduled appointments

Virtual Enrollment and Onboarding

• Accompanied electronic consent (eConsent)
• Access to live chat and clinical study team
• Multifactor identity verification
• On-demand virtual training

Product Distribution and Administration

Site-Based Production and Administration

• Study staff dispensation, collection, and performance
• Accountability at sites during scheduled appointments

Virtual Production and Administration

Shipped directly to patient

Data Collection

Site-Based Data Collection

• Take-home paper diaries
• Face-to-face data collection at sites during scheduled appointments

Virtual Data Collection

• Electronic patient-reported outcomes (ePRO), including image, audio, and video capture
• Remote patient monitoring via digital instruments (wearables, medical devices)
• Event-based notifications and reminders

Assessment

Site-Based Assessment

• Face-to-face clinical trial outcome assessment by HCPs at sites
• Electronic clinical outcome assessment (eCOA) by HCPs at sites

Virtual Assessment

• Electronic clinical outcome assessment (eCOA) via telehealth
• Mobile HCP visits
• Centralized expert raters

The Benefits of Decentralized Clinical Trial Solutions

Any clinical trial can benefit from some decentralizing, which is why DCT technology is here to stay. Below, we outline 9 benefits of integrating virtual components into a trial.

1. Reduced burden for participants
2. Improved compliance and retention rates
3. Improved accuracy for a more robust evidence package
4. Speed of trial delivery
5. Reduced cost of data collection
6. Increased patient and researcher access
7. Participant safety
8. Long-term follow-up
9. Better decision making
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1. Reduced burden for participants

COVID-19 shifted the status quo for many industries, and the clinical trial space is no exception. The demand for analogous but less strenuous alternatives for trial patients is only growing. Participants are refusing to shoulder the large burdens of logistics and costs that characterize traditional clinical trials—especially because decentralized solutions offer them a reprieve.

• Fewer site visits: The ability for participants to report using an app and to collect data remotely via device reduces or eliminates the need to travel to sites. In the event that visits are needed, participants can also be given the option to visit local labs or pharmacies or choose to have home visits with a nurse.
• Reminders and notifications: Alerts are sent directly to patients’ smartphones to remind participants to take their medication and/or complete their study tasks.
• Multi-media training: Training videos provide potential participants and their caregivers with a clearer idea of their responsibilities while also offering more precise guidance on how to complete their tasks.
• Sensors and devices: Integrated sensors and devices often eliminate the need for the detailed patient reporting of vitals or other measurements.
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2. Improved compliance and retention for sponsors

Because a DCT program can make patient reporting easier, participants are more likely to see decentralized trials through to the end and complete their tasks throughout.

• Easier participant tracking: Increased visibility of participants who are missing tasks enables a patient insights team to reach out to participants who may need greater support before they become noncompliant.
• More informed and engaged participants: DCTs can also improve engagement through a feedback loop that gives participants access to their own data. This helps them to feel more actively involved in their trial. Increasingly, this information can be gamified, encouraging participants to maintain or increase their compliance levels versus previous days or weeks or compared to other study participants.
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3. Improved accuracy for a more robust evidence package

One of the critical limitations of on-site reporting is the reliance upon participants to diligently fill in their diaries. This leads to parking lot syndrome, where questionnaires are filled in just before a site visit, resulting in mistakes and the inaccurate capture of events.

• More and better data: Giving patients the ability to download an app on their own mobile devices and to report symptoms at the moment they occur is a superior method for capturing experiences and perceptions. Decentralized clinical trials also give sponsors the ability to collect more complex and real-time data via remote monitoring and to combine this with other clinical trial data—all integrated into a single EDC system. By expanding the number and nature of datapoints, DCT studies can generate a complete picture of the patient experience. This approach can be particularly useful when seeking insights into quality-of-life indicators alongside evidence-based efficacy measurements.
• Less missing data: Improved adherence to clinical trial protocols, along with a reduction of human error factors resulting from automated reporting tools like digital instruments, reduces the risk of missing or incorrect data entry.
• More contemporaneous data: The closer we get to the time of the event, the more likely the data is to be accurate. Pain ePRO is an example of situations in which patients might struggle to report the duration and intensity of an event as time passes. Real-time data collection allows participants to report when events are still sharp in their memories.
• Continuous and/or more frequent data collection: In some studies, the continuous capture of data can be important. Rather than asking participants to, for example, take a heart rate measurement several times a day, wearables can capture this data continuously. Averages and outliers can be recorded, providing a richer data set for analysis.  
• Real-life data: Reporting from home tends to be more accurate because it reflects the behavior of people as they live their real lives. The “white coat” influence is reduced, enabling participants to tell it like it actually is.
• Reduced patient subjectivity: The increased use of devices to record participant data also reduces subjectivity. For example, rather than asking caregivers to score their babies’ stools, rashes, or coughs, patient-friendly apps can simply guide participants to take and upload photos, videos, or audio recordings directly from their devices. These media outcomes can then be scored by expert raters, which radically reduces the risk of bias.
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4. Speed of trial delivery

There is no doubt that the decentralization of clinical trials has accelerated trial timelines. Every step of the clinical trial journey has benefitted from digital enhancements:

• Faster recruitment and enrollment: DCT trial recruitment and enrollment is often 2- to 4-times faster than in traditional trials. Participants are exposed to digital advertising that solicits and holds their interest. When they click on the ad, participants are led to a landing page that explains the contours of the trial and, if interested, they can answer a few prescreening questions. If qualified, they can then download a mobile app and proceed through the enrollment process, including eConsent and training for the trial. This process takes minutes or hours rather than days or even weeks. At any point, if participants have questions or concerns, they can speak with members of a virtual support team.
• Faster data collection: As with all things digital, electronic patient reporting is easier and faster than paper. Automatic notifications and reminders help to increase compliance, which enables studies to be completed more quickly.
• Faster data analysis: Although decentralized clinical studies are not conducted in a single location, the data is in fact very much centralized. Cloud-based Electronic Data Capture, otherwise referred to as EDC systems, ensure that the data from patient reporting, devices, patient history, medical assessments, and other sources is centralized in a single system. Data can then be managed and cleaned in real time, allowing study teams to advance more quickly to the analysis phase.
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5. Reduced cost of data collection

Moving data collection from sites to homes has a positive impact on the cost of studies. Maintaining staff at multiple sites is expensive and inefficient. Virtualizing site support allows for one team to serve more patients across multiple regions. And, direct data entry by patients reduces the need for, and cost of, source data verification.
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6. Increased patient and researcher access

Clinical trial technology is changing the demographics of access to clinical trials. Patients who previously lived too far from a site or who were not able to take time for site visits are now able to participate from their homes. Digital media targeting also enables recruitment from populations who were previously unaware of trial opportunities while targeted ads deliver more relevant messaging to underserved populations, increasing cohort diversity. Additionally, decentralized and distributed trials are opening up opportunities for academic researchers to become principal investigators without the administrative burden or cost.
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7. Participant safety

Decentralized clinical trials facilitate real-time reporting, which in turn enables investigators to ensure safety surveillance as study teams track behaviors in real time. In traditional trials, adverse events (AEs) often go undetected until a scheduled site visit with an HCP—possibly days or weeks from when the event occurred. Real-time visibility means adverse events can be spotted quickly. Patients respond to a daily question to determine whether their medical status has changed. If affirmative, the system asks further questions to capture the scope of the issue. Alerts built into the system help study teams to quickly identify patients that require support or urgent follow-up. A virtual clinical study team then reaches out via email, phone call, or chat to determine whether an AE has occurred and create an electronic case report.
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8. Long-term follow-up

Most drug and device trials require long-term follow-up both to track effectiveness over time and to identify any safety issues that may not have surfaced during Phase III. Post-marketing observational studies requiring follow-ups are particularly inconvenient for patients and can lead to substantial drop-off. Virtual tools can mitigate the challenges facing long-term studies by reducing the burden on patients to promote higher retention. The easier we make it for the patient participation, the more likely people are to remain in the study.
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9. Better decision making

In the past, sponsors were not able to access their data until a formal interim analysis had been completed or the study came to an end. The improved speed and accuracy of DCTs, along with real-time dashboards, enables sponsors to obtain earlier insight into how their trials are proceeding. This greater visibility into the status of their studies allows them to react more quickly when hurdles arise. It also means that when a study delivers positive endpoints, sponsors can get to market more quickly.

As evidenced here, incorporating DCT solutions into any and all stages of the clinical trial journey presents a wealth of opportunities for improvement. But, despite the remarkable benefits of decentralization, DCTs can nonetheless pose challenges.
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4 Key Challenges Associated with Decentralized Clinical Trials

As with any innovation, there are learning curves associated with transitioning from legacy to new methods. Below, we elaborate on four of the most common issues to be confronted and how they might be resolved when planning a clinical trial with DCT components.

1. Regulatory hurdles
2. Systems integrations
3. Risk aversions in sponsors and sites  
4. User accessibility
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1. Regulatory hurdles

In the U.S., FDA guidance on decentralized clinical trials has been generally accepting of the digitization of many of the steps within a trial. Outside of the U.S., the reception is more reserved. EMA (European Medicines Agency), for example, released temporary guidance during the COVID-19 pandemic, permitting some DCT components such as direct-to-patient shipping, telemedicine, and remote monitoring, while guidance in other areas is less clear. In APAC and LATAM, where regulations can vary widely, deciphering DCT acceptance is more of a challenge, requiring careful conversations with ethics committees in each country. Read more on our decentralized clinical trials FDA post.
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2. Systems integration

As with any digital innovation, getting fit-for-purpose technology is essential. Initially, enthusiasm surrounding DCTs led companies to “shoehorn” DCT components into traditional trials without adapting them. As traditional sites tend to be firewalled with siloed data systems, integration has not gone as smoothly as promised. In many cases, patients need to interact with multiple systems or collect data through different sources (ePRO, devices, EHR records, etc.). This increased complexity can be vexing and dissuasive to trial completion. Lack of integration is also an issue for project managers. When systems are not designed to manage the exponential growth in data sources and streams, workflows can become unwieldy, leading to errors and prolonged timelines.
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3. Risk aversion of sponsors and sites

Today, one of the greatest hurdles to the successful deployment of clinical trials is behavioral. As is the case in other industries, the DCT revolution was kickstarted by innovative teams. But, when trials were handed off to the legacy clinical operations teams for implementation, the innovators came up against the forces of inertia and fear. Site staff are often anxious about transitioning to new ways of working. When the technology is not intuitive or the training is insufficient, a bad experience can result in even greater resistance to change. Fortunately, we have begun to see a greater willingness on the part of operational teams in large organizations to adopt new methods. But, they need to be reassured that the risks throughout the transition period will be carefully managed.
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4. User accessibility

It should not be assumed that geographic expansion translates automatically into access for all. There remain situations in which participant access to, and comfort with, digital tools may be hindered. While it is true that digital literacy has skyrocketed, and that recent data shows older users can deliver even higher ePRO compliance than their younger counterparts, there is often the need to adapt the tools to the target. Older users may need larger screen fonts or different types of training while users in some regions or socioeconomic situations may not have access to broadband and may need to be able to work offline.
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9 Principles for Planning and Deploying Successful DCTs

Having covered DCT definitions, benefits, and risks, the question remains: “How does one successfully plan and execute a decentralized clinical trial?” There may be no magic recipe for a flawless DCT, but we have complied a list of nine principles that can transition most clinical trials successfully into decentralization.

1. Ensure digital endpoints are validated
2. Technology must support and enable clinical professions—not replace them
3. Engage with regulators early and often
4. Build in risk mitigation strategies
5. Adapt participant training to a virtual context
6. Prioritize participant optionality
7. Recruit inclusively
8. Simplify study designs
9. Consider ways to encourage post-trial engagement
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1. Ensure digital endpoints are validated

Transitioning validated questionnaires—such as the Numerical Rating Scale (NRS) and the Visual Analog Scale (VAS)—from paper to digital formats can be trickier than you think—and it can lead to data inconsistencies. Even slight changes to the ways that traditional validated scales are displayed to participants can affect participant entries. As a result, it is necessary for the study and app designers to ensure that ePRO technologies adapt to different screen sizes to ensure that the presentation of information is consistent across participants and does not skew study results.
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2. Technology must support and enable clinical professionals—not replace them

It is incorrect to assume that the move to decentralized or virtual trials shifts the entire burden of delivery onto participants. The assumption is that, if sites are to be eliminated, there will no longer be a need for support teams. This is far from true. The fact that sites are virtual should make them no less accessible. Participants’ questions must be answered regardless of their physical location, and they must feel supported throughout the trial.
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3. Engage with regulators early and often

In the world of DCTs, regulation is all about collaboration. Because regulations in many countries are not always clear, it is best to engage with ethics committees and government agencies as early as possible. More often than not, regulatory bodies are open to protocols with DCT components.
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4. Build in risk mitigation strategies

There are inherent risks in running any clinical trial. In the case of DCTs, these risks can be different than those in a site-based trial and must be anticipated. If medications being shipped directly to patients require a cold chain, a temperature control and monitoring system must be built in. If subjects drop out mid-trial, patients must be prepared to taper their doses. If remote monitoring devices cease working, troubleshooting tech support and/or device replacement must be accessible. Proper mitigation planning requires a careful review of each step in the digital process.
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5. Adapt participant training to the virtual context

Decentralization of trials places a great onus on participants to complete their tasks without face-to-face support from clinicians. This is where subject training and education become essential. On-demand training modules can help participants to better understand their roles and responsibilities in a study. Multi-media formats (e.g., printed/video/interactive quizzes) can keep participants engaged. Study coordinators will want to make themselves accessible to respond to any questions or areas of confusion at the outset and throughout the study.
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6. Prioritize participant optionality

Maximize the ways you enable subjects to participate. For example, some participants may prefer televisits or even visits to the clinic over visiting nurses coming to their homes. Others may choose home health visits by an HCP as their preferred option, providing them with direct clinical contact while curtailing travel and wait times. It is important to get patients’ input—and, when appropriate, that of their families or caregivers—prior to finalizing study design to ensure a full understanding of patients’ needs and constraints.
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7. Recruit inclusively

DCTs tend to improve access to trials by removing geographic boundaries. But, digital studies requiring smartphone use, data, and/or reliable Wi-Fi connections run the risk of excluding cohorts from lower socioeconomic circumstances. Financial incentives should be built into studies to ensure that these populations can participate.
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8. Simplify study designs

Do not add tasks into the protocol that place an undue burden on participants, especially if the data collected is not essential for the study’s success. Simplify outcome measurement as much as possible. Design for higher compliance while also considering real-world constraints. Balance what is realistic for the patient with what is necessary for the protocol.
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9. Consider ways to encourage post-trial engagement

Participants have different motivations for joining a clinical trial. Some are in search of treatments while others have purely altruistic motivations. In both cases, if their trial experience is a smooth one, they may be receptive to sharing data or insights even after the trial is completed. This long-term patient insight can be of great value for post-market strategies and safety surveillance.
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Use Cases

Perhaps the most important part of learning about decentralized clinical trials is understanding how to successfully design and conduct them. There is no better way to appreciate the definitions, benefits, risks, and guidelines for DCTs than to see these concepts applied in actual clinical studies. The following use cases are practical, real-world instances of the above guidelines put into practice.
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Remotely assessing infant formula safety and tolerability

It is notoriously difficult to recruit infants for interventional clinical trials, making this patient population and therapeutic area ripe for decentralization. Below is a use case for a fully decentralized pediatric infant GI study.

For this innovative 7-week, randomized. placebo-controlled DCT, 215 healthy infants are being digitally recruited and enrolled to evaluate a pre- and probiotic infant formula. Infant health and stool observations will be recorded via an ePRO diary. Stool images will be captured and uploaded to a clinical rater portal for grading by two GI physicians. Periodic infant stool samples are also sent to labs for analysis.

Read Full Case Study
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Monitoring patients remotely  

A recently completed Phase 2 decentralized clinical trial on a COVID-19 treatment monitored symptomatic patients using a combination of remote digital devices. Home healthcare providers visited subjects at key moments in the study to take complementary tests and to validate device data. The digital devices included a 6-lead ECG, a pulse oximeter, and a thermometer. The vitals from these devices were automatically transmitted to a centralized database where they were monitored for adverse events.

Read Full Case Study
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When older DCT subjects are more compliant than their younger counterparts

ObvioHealth recently completed the first ever fully virtual urogynecology study to evaluate a medical digital intravaginal device for female stress urinary incontinence. In this randomized trial, pelvic floor muscle contractions were monitored while subjects were completing at-home Kegel exercises. The wand-like device collected data and wirelessly transferred it to a smartphone app downloaded at the start of the study. While there had been initial concerns that older participants might be intimidated by the technology, the results of the study showed that women aged 65 and older had higher rate of completion versus their younger counterparts.

Read Full Case Study
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Catching an AE in Real-Time

Even symptoms as seemingly harmless as headaches can indicate underlying complications to a patient’s health; a headache is considered an AE. A virtual trial on menopause had a participant report a slight headache via their daily e-diary. This information was immediately made available to the principal investigator, who then recommended a lower dosage of the study product. It was ultimately recommended that the patient receive testing through their HCP for worsening COPD.

Read Full Case Study
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Conclusion

For decentralized clinical trials, are we ready to make the leap? The answer is yes. And, in our opinion, the benefits of decentralized clinical trials far outweigh the challenges. It’s important to remember, the traditional way of conducting clinical trials is rife with issues. Recruitment in traditional trials is so slow that 80 percent of clinical trials fail to reach enrollment. In addition, on average, 30 percent of patients drop out. For years, patients in clinical trials have been over-burdened and underappreciated. It's time we make trials more accessible, easier, and safer for them, and, as a result, the industry as a whole will get more accurate, real-world data from more diverse populations on faster research timelines.  

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