In May 2023, the FDA released its long-anticipated draft guidance to the healthcare industry on decentralized clinical trials (DCTs) for drugs, biological products and devices. This document is a signal that the agency is putting its full support behind DCTs, while ensuring that hybrid or fully decentralized trials are conducted with the same level of rigor as traditional site-based trials.
The guidance, which builds on COVID-19 recommendations from 2020 and comes as the U.S. ends the COVID-19 public health emergency, acts as a best-practices checklist for conducting DCTs and creates a holistic document that incorporates previously published guidance. It indicates that the FDA is serious about supporting the transformation of clinical research through the use of technologies and systems that make trials available to broader populations by reducing the barriers to participation.
The recent increase in the number and percentage of decentralized or hybrid clinical research studies is not surprising when you consider that they solve a number of issues that have long plagued clinical trials. Historically, only a small percentage of eligible patients have participated in trials, but not due to a lack of interest. A study from the Center for Information and Study on Clinical Research Participation found that more than 75% of people would be willing to participate in a trial, yet other research shows that trial participants must travel an average of 67 miles each way to reach clinical research sites. DCTs reduce or eliminate travel burden and allow for a broader reach of patients, reducing the total time required for trial enrollment. DCTs also allow for faster and more complete data collection by permitting participants to provide answers to trial surveys and contribute device-sourced data through the course of the trial.
While the latest FDA guidance reiterates what might be called DCT best practices that have emerged within the healthcare industry, one key message from the document is that the logistical aspects of DCTs need to be planned, documented and discussed. Sponsors should bring their protocols to the agency for review, and these protocols must clearly detail the logistical plan. For example, protocols need to detail:
- Where labs will be performed (at trial sites, patients’ homes or other local facilities), how investigational products will be delivered and how safety monitoring will be performed.
- Which activities will require trained study personnel and which activities untrained personnel can do.
- How adverse events will be reported and managed.
The guidance also reinforces the need for a robust data management plan that describes how data from all sources must be managed and kept secure through the trial life cycle.
As part of the FDA’s risk-based approach journey that began with its risk-based management guidelines in 2013, the FDA continues to emphasize that upfront risk assessment and management are key to implementing a DCT successfully. The monitoring plan for a DCT, much like that of any other trial, should be based on the sponsor’s risk assessment.
While the FDA says that, in general, there are differences in the regulatory requirements for DCTs as compared with traditional site-based trials, the need for training, oversight and coordination grows substantially in the DCT world.
Proper coordination is mandatory for DCTs. While this is the responsibility of the sponsor, most sponsors do not have the means to ensure proper preparation, training and synchronization of digital health technologies, telehealth components and nontraditional sites such as retail pharmacies and local labs. It is often the role of outsourced research organizations to ensure that all of these components are aligned for success. Yet even the most experienced contract research organizations are not equipped to coordinate and manage necessary DCT elements. For example, it is essential to ensure that devices have been delivered to trial participants, that the participants understand how to use them correctly and that participants are using the devices as expected.
DCTs require a level of coordination that is not at all out of the box. To illustrate this point, CVS, one of the largest integrated healthcare organizations, shut down its nascent clinical trial unit, in large part because the level of coordination needed to deliver DCTs didn’t lead to a scalable business model.
While the FDA’s guidance will likely reinforce the role of DCTs in the industry, there are some notable issues that it does not address. Many investigators remain concerned about maintaining the robust consistency and quality of a trial when it involves clinicians for whom they do not have sufficient oversight. One example of this is the use of home health services, which are a frequent component to DCTs. While home health nurses may take vitals or samples in the home using standard equipment and while they may be trained by their agency, it is not clear if the oversight for their work is the responsibility of the investigator or the sponsor. And if it does fall to the investigator, how will the investigator ensure that procedures are maintained as defined per the protocol? These issues affect good clinical practice quality, and a lack of clear guidance on these issues will introduce new risk.
With this guidance, the FDA has opened the door to a much broader ecosystem of players to play a part in DCTs, including the use of local HCPs, retail pharmacies and local labs. The FDA guidance points out, however, that increased flexibility in where and how testing will be performed will likely lead to more variability and less precision in trials. For this reason, the FDA is recommending that it be consulted on the design of any non-inferiority trial with active comparators to ensure that these trials are powered correctly. While the FDA’s willingness to be consulted for such trial design is a welcome step, the lack of details on when, what and how such a consultation needs to happen during the design process may add additional burden for sponsors and CROs, leading to lower adoption of DCTs for these trials.
At ZS we generally applaud this FDA draft guidance on DCTs. Through the digitally enabled DCTs that we have managed, we know firsthand that participants and trial personnel need to be trained on all digital health technologies and that data sourced from software and digital technologies needs to be tested before deployment. We have seen that DCTs allow for greater inclusion and diversity. They give patients and clinicians who had never participated in clinical trials in the past the opportunity to do so now. And with the use of a coordinated framework of technologies, systems and trained personnel, we have seen that it’s possible to manage the operational burdens and complexities of DCTs effectively. As with any new, evolving approach to clinical trials, we recommend creating a role for a DCT risk management lead to provide better input and oversight of DCT modalities and vendors.
One silver lining of the COVID-19 pandemic was that it was, in a way, a dress rehearsal for the clinical trials of the future. Over the past few years, the industry has learned how to manage adverse event collection, safety monitoring, data management and remote patient engagement at a distance. Like others in the healthcare industry, we have paid special attention to the critical success factors when deploying digital health technologies in DCTs. With the different types of smartwatches and monitors available, it is not so much the technologies themselves that are at risk of failure, but it is the onboarding, deployment and ongoing use factors that add risk. What is needed is a vigilant control tower to ensure that core technologies are deployed, understood and used as expected.
We are at a pivotal moment in the design and operation of clinical trials. This latest FDA guidance will actuate a shift in how trials are delivered, bringing greater diversity, improved participant engagement, better retention and a greater ability to incorporate both digital endpoints and patient-sourced data. All in all, the FDA is pointing to a future where trials are more efficient and more generalizable in the real world.