During the recent pandemic, as with many facets of life and business, the design and conduct of clinical trials adapted to limit physical contact between individuals—in this case, those conducting and participating in clinical studies. Many companies opted to use a format that has been around for some time but not frequently used: the Decentralized Clinical Trial, or DCT.

As the name implies, a DCT does not involve a central facility but makes use of technologies such as telemedicine and mobile apps to allow participation from virtually anywhere. While not new, a lack of experience with this approach has proven challenging for companies seeking to conduct remote trials.

[Related: For more GCP insights from the author, view the recording of the webinar, “FDA GCP Inspection Trends Identified Using AI.”]

At the Society of Quality Assurance 2022 Annual Meeting in Palm Springs, Calif., FDA Office of Regulatory Affairs Bioresearch Monitoring Division I Director Anne Johnson provided FDA’s perspective on DCTs in a presentation titled, “Sponsor Oversight of Decentralized Clinical Trials.”

She noted that the agency has “experienced a rapid surge in pivoting to decentralized designs by necessity during the pandemic.” She reported that the use of DCTs has “sped up the adoption of technology and leveraged services that are closer geographically, available or open to patients and child participants.”

In her presentation, Johnson provided the agency’s perspective on DCTs, including the regulation framework, elements of the decentralized trials, and responsibilities of sponsors for oversight.

This report on her talk will be divided into three parts, as follows:

Part I

Background and an overview of the applicable regulations
Elements of DCTs, including the design, benefits, and challenges

Part II

Sponsor oversight responsibilities for DCTs regarding:

Electronic informed consent
Remote visits
Electronic data considerations

Part III

Risk-based monitoring
FDA guidance that directly impacts DCTs
Points to consider

Part I: Background, Benefits, and Challenges of DCTs

Johnson clarified that FDA regulations do not specify the type of trial a sponsor must conduct, and that sponsor requirements remain the same whether the clinical trial is traditional, decentralized, or a hybrid of the two. Regulations covering trials can be found in 21 CFR 312.50 for drugs and biologics and in 21 CFR 812.40 for medical devices.

What may change with DCTs, she said, is an increase in the use of electronic systems or digital health technologies, making 21 CFR Part 11 on electronic records and signatures applicable.

“The focus of FDA continues to be, and will remain, the protection of the rights of human subjects in trials and the quality and integrity of the data,” Johnson emphasized.

As a preface for her discussion, the regulator made what she termed “an important distinction” in terminology between the terms virtual and decentralized.

Virtual trials are preclinical trials that are conducted by means of computer modeling or computerized simulation (in silico) or by some other type of model.

DCTs, on the other hand, refer to remote interactions with real participants, i.e., clinical trials executed through the use of telemedicine visits or telehealth, mobile and local healthcare providers, and digital health mobile technologies.

Elements of DCTs

DCTs may comprise several terms and elements, Johnson said (Figure 1).

Figure 1 DCTs May Incorporate the Following

Annotating Figure 1, Johnson explained that DCTs can:

Incorporate remote study data collection via telemedicine or telehealth
Use or incorporate local healthcare providers for investigational product (IP) administration or exams, or lab specimen collections
Use and incorporate electronic informed consent and the use of digital health technologies, including electronic systems or components that can be off the shelf or customized
Be owned or managed by sponsors or be outsourced and owned and managed by vendors
Incorporate various aspects such as patient-reported outcomes or electronic clinical outcome assessments
Incorporate direct-to-subject investigational product shipments

Design of DCTs

The design of DCTs the agency has been seeing comprise a convergence in using many of the factors noted in Figure 1 and integrating them into a clinical investigation. Johnson discussed these factors and gave her perspective on aspects of the design of DCTs.

She suggested sponsors consider that the processes and the procedures must be provided, not just to the staff, but to the site and to the subjects as well, being especially mindful of the electronic interfaces.

It is important to note that in addition to regulatory considerations, there are legal aspects of telehealth and telemedicine to consider as well as trial participants’ expectations of privacy and confidentiality. Validation of the smart tools and computer security along with security threats posed to those electronic systems that are used are also important considerations.

The focus of FDA continues to be, and will remain, the protection of the rights of human subjects in trials

Regarding the data that is captured and stored, consideration must be given to access control points in the electronic system and short and long-term data storage requirements.

Johnson stressed that the education of the trial subject is crucial to the success of any clinical investigation and to accurate data capture. She advised that step-by-step videos and written how-to guides that the average individual will be able to understand and use are “very important to optimizing their experience in the trial and also ensuring that you are obtaining the best quality data possible.”

[Related: From 2007-2022 there were 173 primary 483 observations involving informed consent issued to clinical investigators. Contact us to learn how Redica can help you monitor enforcement actions involving your clinical investigators.]

Benefits of DCTs

In her discussion of the benefits and challenges of DCTs, Johnson pointed to work done by a public-private partnership—the Clinical Trials Transformation Initiative (CTTI)—that was published in 2019. The article is titled, “Legal, Regulatory, and Practical Issues to Consider When Adopting Decentralized Clinical Trials: Recommendations From the Clinical Trials Transformation Initiative.”

The benefits of conducting a DCT that CTTI cited include a more efficient clinical trial with lower costs, along with accelerated enrollment of study subjects and increased diversity. DCTs, the group said, have the option to include more participants by removing some of the barriers that are associated with geographic location and limited mobility.

DCTs also allow more convenient participation for people with disabilities, busy schedules, young children, or transportation issues.

The CTTI study concluded that the increase in diversity of the participants makes the trials more representative and that DCTs lessen the burdens of time and travel on the participants.

“It also gave the ability to gather more frequent measurements, more frequent information, and even continuous data in certain ways,” Johnson reported. “In addition, there are the more representative aspects of real-world administration post-approval, because you have a decentralized trial design with a more dispersed population that is participating in it.”

The use of DCTS for rare disease trials of limited, smaller populations that are geographically dispersed allows eligible participants a greater ability to join the trials.

Challenges of DCTs

Challenges encountered in DCTs include aspects of the use of electronic data and federal and local regulatory frameworks.

The robustness of the digital infrastructure is sometimes an issue, which can be compounded by limited experience with a digital, remote, decentralized approach by the study staff, the clinical investigator, and the study subjects.

DCTs also allow more convenient participation for people with disabilities, busy schedules, young children, or transportation issues

There are federal regulatory barriers, “some real and some perceived or anticipated,” Johnson said. She noted that FDA is “very open to considering and encouraging innovative trial designs that are enhanced to get more quality data and get more participants and greater diversity into the trials that are being conducted.”

Also challenging are detailed and highly variable state laws and regulations that include protection of patient information, confidentiality, and prescribing practices for investigational products. “Some of these are very real hurdles that have to be addressed,” Johnson explained.

The more decentralized a clinical investigation, the greater the challenge of ensuring consistency when executing the protocols. DCTs can also be challenging from the standpoint of how data is handled and stored, Johnson said. She recommended a close examination of the data generated—specifically focusing on data reliability and integrity.

Using Redica Systems for Due Diligence

An important part of designing and planning a clinical trial is conducting due diligence on clinical investigators (CIs), Institutional Review Boards (IRBs), and other potential partners to learn about and evaluate any compliance issues they may have had in the past.

In a six-year collection of FDA warning letters issued to CIs of human drug studies, the Redica Systems Expert Model for GCP confirms that “protocol compliance” is the most common category of observation involving “responsibilities of the investigator”—and “dosing issues” is the largest subcategory under “protocol compliance.”

Designed to unearth an actionable level of detail from Redica Systems’ vast collection of inspection documents, the Expert Model for GCP reveals compliance issues found in both FDA warning letters and a 20-year collection of 483s issued to CIs of human studies.

For a better understanding of the Redica System models and how they can help you find and evaluate compliance issues in warning letters and 483s, view a recording of the webinar, “FDA GCP Inspection Trends Identified Using AI.”

Part II examines sponsor oversight responsibilities for DCTs.