By ConcertAI

The pharmaceutical research industry has seen an explosion of meetings and publications focused on decentralized and digital clinical trials in the past year. Fueled by the global pandemic, almost every company involved in clinical research has joined the discussion. There is a conference almost every week on the topic, where methods and technologies are discussed around bringing research out of the clinic and closer to the patients.

This transition has resulted in the growing use of many terms and tools to describe this shift. There has been a trend to use the terms “decentralized” and “digital” to describe technologies and methods associated with virtual visits. If you search the terms “decentralized vs digital clinical trials” all the results will be related to decentralized studies, to the point where the two words have become synonymous in many areas. However, is a “decentralized” trial the same as a “digital” trial?

The answer is no. Decentralized and digital clinical trials are two very different things. Although digital trials can be decentralized (and decentralized trials use digital tools), they describe different concepts. Unfortunately, both are often abbreviated as “DCT” which has also contributed to the confusion. Let’s look at the differences:

Decentralized Clinical Trials

A decentralized trial is, by definition, one that is done away from a central research facility. Patients complete their clinical trial visit at a remote location, either through virtual tools (such as video calls and patient reported electronic assessments), or by face-to-face interactions at a remote location. For a clinical trial to be decentralized, the relevant feature is the location of the patient interaction.

While digital tools are often used in a decentralized trial, use of digital technology is not the defining feature of a decentralized clinical trial. For example, a decentralized trial can be performed using paper forms exchanged by mail or through a remote healthcare visit to the patient’s home.

Digital Clinical Trials

A digital trial is defined by the method used to capture the clinical trial data. A true digital clinical trial is one where all data are captured without the use of any paper forms during the conduct of the study. The defining feature is the data capture method of the study.

Any study can be digital regardless of the location where the clinical visits are performed. Data integrity is a primary consideration for digital trials, including the use of regulatory compliant systems with complete audit trails back to source records (such as electronic medical records, patient reports, and lab results).

The Overlap of Decentralized and Digital for Clinical Trials

While decentralized and digital trials may not be the same, they do share features. This overlap is the likely source of the confusion between the terms as an efficient decentralized trial should use digitals where possible. Often a decentralized trial will depend on the use of digital systems, including:

• Video Visits
• Electronic Consent (eConsent)
• Electronic Patient Reported Outcome assessments (ePRO)
• Digital Sensors and Monitoring Devices

While these digital solutions are recommended for efficient decentralized trial execution, they are not required. In fact, a decentralized trial can be conducted without the use of dedicated digital tools using telephones, remote/home visits, and paper forms. In practice, this is rarely the case. Today, when someone mentions a decentralized trial, the use of digital solutions is implied. However, the value of digital solutions goes well beyond their use in decentralized clinical trials.

For oncology studies, a combined visit model using both clinic and decentralized visits is common. This occurs as many oncology treatments and tests cannot be performed in a decentralized setting. However, there are interim assessments which can be performed by the patient at home. In this case, consistent data collection procedures should be used for comparability between assessments. Ideally, digital tools should be used in both cases to avoid the known problems of paper assessments.

What makes a Clinical Trial “Digital”?

Now that we have made the distinction between decentralized and digital clinical trials, we can turn our attention to what is needed to make a clinical trial “digital”. The short answer is the complete elimination of any paper documentation or data capture methods during the conduct of the study. The target is to eliminate non-digital systems during the study, though there may be paper forms associated with the patient prior to study initiation that contain relevant study data. These forms would be digitized and curated as part of the study conduct, though the source document would remain the pre-study paper record.

To conduct a digital trial, there are several required components:

A Digital Protocol

A digital study begins with a digital protocol. This does not mean that the protocol is simply written on a computer our converted into a PDF. Instead, it refers to translating the written protocol into a set of digital objects and specifications which are used to feed other digital systems. This includes:

• Inclusion/Exclusion Criteria
• Treatment Arms
• Assessments
• Visit Schedules
• Safety Thresholds

Once digitized, the protocol is now digitally accessible for feasibility studies, modeling, and optimization. Tools and systems are available to evaluate the protocol details, assess the impact of different eligibility criteria on enrollment, and identify ways to reduce patient burden by aligning clinical trials to standards of care.

Digital IRB Package

Prior to patient screening and enrollment, IRB approval is required. In a digital study, this can be facilitated by an electronic set of study documents for review and approval generated from the digitized protocol. Once a study has digital protocol, generating a digital IRB submission package is simplified as many of the required information and forms are electronically available.

eScreening System

Linked to the Electronic Medical Record (EMR) system at each research clinic, the eScreening application identifies potential study participants at each site based on the criteria from the digital protocol. These patient records are reviewed by the site research staff, and eligible patients are invited to participate.

A critical feature of an eScreening system is the digital link to the full patient history, which will include the EMR data as well as other electronic and paper documents from the patient’s medical file. The structured data in the EMR can be accessed using established data protocols (such as HL7 or FHIR). However, unstructured data (such as notes and nonstandard endpoints) as well as paper forms must be digitized and curated so they can be used for eScreening and verification of eligibility.

Converting paper and unstructured data into a usable digital format is one of the greatest challenges of creating a fully digital study. However, it can be done using document upload tools (from paper forms) combined with skilled curators to interpret and digitize the paper and unstructured data gathered from the patient file. Artificial intelligence tools can be used to aid the curation process, but they should only be used with trained human oversight. According to the recent FDA draft guidance on the use of RWD, when using AI, the FDA requires specifying the assumptions, validating the methods and documenting data quality.

eConsent System

Qualified participants are referred to an electronic consent (eConsent) system that digitally describes the study, presents the risks, benefits, and alternatives, and then captures patient consent using digitally documents approved by the IRB. This same system also allows for updates and reconsent procedures required due to any protocol changes. If needed, this system can also be used to implement post study surveillance assessments after protocol completion.

Additional Linked Systems

Every clinical trial uses an array of systems to manage both study conduct and data collection during the trial. For a digital trial, each of these systems produces clinical study data and associated case report forms that must be managed through an integration system. These systems include:

• Virtual Visit Systems
• Electronic Clinical Outcomes Assessments (eCOA)
• Medical Imaging Results
• Clinical Trial Management System (CTMS)
• Electronic Data Capture (EDC) system
• Adverse Event Reports
• Safety and Monitoring Systems

Developing digital integrations across the multitude of systems and technology vendors is a major challenge for any digital trial. It requires the use of compatible interfaces that can be integrated into a single reference system. Once built, these integrations can be used across sites and studies, but the initial development can be challenging.

Digital Case Report Forms (eCRFs)

The data captured from the study is used to electronically populate a set of digital case report forms. These are aligned to study protocol and consistent with the target EDC system, where they can be viewed and verified before finalization and approval. Once complete, the data from digital case report forms are stored in the target EDC system for the study, completing the digital path. From here, the digital data path can be fully traced back to each source system and document that is part of the digital clinical tria

The seamless audit trail is a critical regulatory feature of a digital trial, allowing for complete data monitoring and source data verification.

Advantages of Digital Trials

Digital trials provide advantages for patients, sites, and sponsors. The overarching benefit is improved identification of potential patients, efficient study site workflows, and simplified study monitoring enhanced by artificial intelligence. Timelines can be reduced, particularly for recruiting, site activation, and overall study duration. Ultimately, digital trials will benefit patients directly by increasing access to research studies and treatments – and providing a platform for lifelong engagements after study completion.

Building a digital trial requires an initial investment from sponsors, CROs, and study sites. Fortunately, much of the investment is for the development of systems and integrations, which can be used across multiple studies and programs. Once the foundational systems and workflows are in place, the return on this investment will continue for many years.