On Sept. 18, 2024, the U.S. Food & Drug Administration (FDA) issued a final guidance document titled “Conducting Clinical Trials With Decentralized Elements, Guidance for Industry, Investigators, and Other Interested Parties”(CTDE guidance). The final guidance, which builds upon a prior draft guidance document issued in May 2023, provides valuable insight into a host of issues implicated by decentralized clinical trials (DCTs). It also reflects the FDA’s continued support for well designed and implemented DCTs and underscores the benefits that trials with decentralized elements can provide to trial participants, industry members and healthcare consumers. This article provides an overview of the guidance and discusses key takeaways for industry members, investors and other stakeholders.
Decentralized Clinical Trials
While DCTs are not new to drug and device research, they have a less robust history than their traditional counterpart. FDA defines a DCT as “a clinical trial that includes decentralized elements where trial-related activities occur at locations other than traditional clinical trial sites.” DCTs can be fully decentralized with all trial activity taking place remotely or at locations other than traditional trial sites, or partially decentralized — sometimes referred to as “hybrid” trials — where some but not all trial activity takes place at nontraditional sites. In either case, at least some DCT activity takes place at a location other than a traditional site, such as at a participant’s home or a local healthcare facility.
A DCT offers a more participant-centric approach to clinical research, in that it effectively brings the clinical trial, or some component of it, to the participant, whereas a site-based trial requires the participant to come to the trial. While not every trial will be amenable to decentralization, a properly designed and implemented DCT has the potential to enhance participant convenience; improve participant enrollment, diversity and retention; and generate more targeted data. DCTs can present challenges in terms of coordinating trial activities across multiple locations, overseeing remote trial activity and ensuring data integrity. The CTDE guidance seeks to balance these considerations by providing practical advice on DCT implementation while emphasizing key regulatory and compliance requirements.
DCT Design and Implementation
A DCT can achieve decentralization by using local healthcare providers (HCPs), local labs and other facilities to perform trial activities; conducting trial activities at participants’ homes or other nontraditional locations; and utilizing digital health technologies to gather and transmit participant data from remote locations. Because certain DCT elements could potentially introduce variability or bias into a trial, the guidance advises sponsors to implement these decentralized elements through specific protocol instructions. For example, a protocol should contain instructions identifying which visits will be conducted remotely and which visits, if any, will be performed at traditional clinical trial sites. A protocol should also contain specific instructions identifying the types of remote visits (telehealth, local HCP, etc.) that are permissible and the remote data collection activity that will be performed by study participants.
While addressing these elements in a protocol may take some discretion away from investigators and clinical trial sites, it also empowers sponsors to design trials creatively with many decentralized elements, so long as those elements are tethered to regulatory requirements and research needs. Sponsors may also be able to build flexibility into a protocol that would give investigators room to maneuver with specific decentralized elements (for example, by allowing investigators to use different visit options in response to individualized participant needs). Sponsors should consult with the relevant FDA review division, as appropriate, when planning a clinical trial with decentralized elements.
Use of Decentralized Elements to Increase Diversity and Generate Meaningful Data
Government and industry leaders have increasingly recognized the importance of improving inclusion and diversity in clinical research. The FDA has identified clinical trial diversity as a “key to advancing health equity” and has taken numerous steps to promote diversity in FDA-related research. The FDA has emphasized the important role that DCTs can play in improving clinical trial accessibility and diversity, as DCTs are capable of mitigating or eliminating geographic, logistic, economic and other barriers to clinical trial participation.
The guidance identifies several remote trial activities that can be used to promote broader and more diverse trial participation. For example, the guidance describes several visit options for trial participants, including fully remote telehealth visits, in-person visits where trial personnel are sent to the subject’s home and in-person visits conducted by HCPs who are located near the trial participant’s home or other preferred location. As to the latter option, the guidance explains that the “use of local HCPs close to potential participants’ homes may further improve engagement, recruitment and retention of a more representative participant population and reduce cultural or linguistic barriers to participation in clinical trials.”
The guidance also emphasizes the importance of digital health technologies (DHTs) — systems that use computer platforms, connectivity, software and/or sensors to gather and transmit subject data — to achieving broader clinical trial participation. Examples of DHTs include spirometers with smart connectivity, glucose monitoring devices, activity tracker bracelets and various mobile applications. DHTs have considerable utility in this space, as they can be used to transmit data from trial participants remotely and securely across geographic boundaries. Many DHTs can also collect data more frequently or continuously compared to intermittent in-person site visits and can facilitate more comprehensive data sets.
By broadening clinical trial participation, DCTs are also capable of generating more useful data. As the guidance explains: “[t]he clinical trial population should reflect the intended patient population for the medical product being studied, including with respect to race, ethnicity, age, sex, and geographic location, as applicable.” By enrolling subjects who better represent the patient population that would use the investigational product if it were to be approved, it may be possible to generate more relevant, useful and powerful data capable of successfully navigating the FDA approval process. More targeted data could also facilitate a better understanding of a product’s post-market safety profile and provide keener insight into a product’s utility within patient subpopulations.
Regulatory Considerations: FDA Oversight and Industry Responsibility
While DCTs offer significant benefits to stakeholders, they also raise regulatory challenges. The FDA explained that the regulatory requirements applicable to DCTs are the same as those applicable to traditional site-based clinical trials and detailed that it will conduct oversight through regulatory inspections of regulated entities and, when appropriate, remote regulatory assessments. What remains to be seen is how the FDA will apply certain existing regulatory requirements to parties operating in the DCT space. While the guidance does not plumb the depths of that question, it sheds light on issues that may be of greater consequence going forward.
Sponsors. FDA regulations impose responsibility for many aspects of clinical trials on sponsors. Consistent with this paradigm, sponsors are responsible for ensuring that a DCT is properly monitored and conducted according to its protocol. The guidance explains that sponsors are responsible for ensuring proper coordination of the decentralized elements of a clinical trial as well. Because DCTs may involve many contracted services, such as local HCPs and third-party labs, it is the role of the sponsor to implement, coordinate and oversee these activities. Given that research may take place across a range of locations with many different recordkeepers and data sources, complying with these responsibilities may be more complex in the DCT setting.
The guidance also advises sponsors to implement certain plans and processes specifically addressing a trial’s decentralized elements. For example, sponsors should develop a monitoring plan that uses a risk-based approach to address “unique aspects related to the [trial’s] decentralized elements.” To account for multiple sources of data collection in a DCT, sponsors are advised to prepare a written data management plan that tracks data origin and flow from all sources, the methods and technologies used for remote data acquisition, and related information. Sponsors are also advised to implement a safety monitoring plan that “take[s] the decentralized nature of the clinical trial into account and ensure[s] that adverse events and medication errors are appropriately collected and adequately addressed.” It will be important for sponsors to effectively incorporate these new activities into their oversight roles and to document these activities thoroughly.
Contract Research Organizations. While the guidance does not expressly address contract research organizations (CROs), FDA regulations permit sponsors to transfer clinical trial responsibilities to CROs. Thus, as with site-based trials, sponsors may choose to transfer responsibility for many aspects of DCT implementation, oversight and monitoring to a CRO.
Because DCTs may have more complex operational structures than many traditional trials, they could benefit from the use of specialized resources to achieve management and oversight goals. CROs could add significant value here, as they can leverage their deep trial management expertise to provide greater efficiencies to sponsors burdened with complex oversight requirements. In such scenarios, the clinical trial agreement (CTA) between the sponsor and the CRO will be the key mechanism for identifying the decentralized elements over which the CRO has ownership. It will be critical to draft and evaluate these CTAs carefully with an eye towards the parties’ respective business interests as well as the FDA regulatory implications that flow from a CTA’s division of responsibilities.
Institutional Review Boards. An institutional review board (IRB) must review and approve site-based clinical research involving drugs, devices and biologics, and the same is true in the context of a DCT. The guidance recommends the use of a central IRB in the context of a DCT, as opposed to a local IRB, which would typically review studies that take place at a single institution. The guidance also flags the potentially difficult issue of obtaining informed consent from remote trial participants and notes that IRB oversight is required to ensure that the remote consent process is adequate and appropriate.
Investigators and Clinical Sites. As with site-based trials, investigators are responsible for the conduct of a DCT and for protecting the rights, safety and welfare of subjects under their care. Investigators also remain responsible for, among other things, completing and signing Form FDA 1572 in all new drug investigations, ensuring compliance with the protocol and maintaining accurate records of each subject’s case history.
One noteworthy area of responsibility for investigators relates to the use of local HCPs. The guidance explains that investigators have significant responsibility for the work of these HCPs. For example, investigators must ensure that trial-related activities delegated to local HCPs are conducted according to the protocol and applicable regulations. Investigators are also responsible for adequate supervision of HCPs and for reviewing their data to ensure quality.
This allocation of responsibility to investigators could raise interesting regulatory questions. Generally, local HCPs are not sub-investigators but rather are doctors and nurses who perform clinical services separate and apart from a trial’s core infrastructure. The HCPs would not be listed on a Form 1572 and would not fall within the same regulatory category as persons traditionally under an investigator’s authority. Indeed, in the usual course, the sponsor or CRO — not the investigator — would directly retain and compensate local HCPs, underscoring the independence of the HCP from the investigator and the clinical site. In the event of a worst-case scenario — such as one involving negligence or research misconduct on the part of an HCP — it is difficult to see how the existing oversight structure would facilitate discovery and remediation of such misconduct. While the devil may be in the details of the specific DCT, it is important for the interested parties to exercise care and diligence in the formation, oversight and documentation of working relationships with local HCPs.
Conclusion and Key Takeaways
The FDA continues to pay significant attention to clinical trial decentralization. The CTDE guidance provides helpful insight into the FDA’s current thinking on DCTs and more broadly reflects the momentum that DCTs continue to build within the research industry. While the incorporation of decentralized elements may pose certain regulatory challenges, all indications are that use of DCTs will continue to grow and provide significant benefit to stakeholders going forward.
Some key takeaways:
- Sponsors have significant discretion to incorporate appropriate decentralized elements into research, subject to coordination with FDA and adhering to regulatory requirements. Sponsors should consider the extent to which a protocol should provide investigators with greater or less discretion to implement DCT elements in response to individualized participant needs.
- Many stakeholders — ranging from clinical trial participants to CROs — stand to benefit from the increased use of decentralized elements in clinical trials. The movement toward greater decentralization can promote significant goals, including improving clinical trial diversity and generating probative research data.
- Certain regulatory issues generated by DCTs will be specific to one’s industry position (e.g., sponsors will face issues different from those faced by investigators). Some industry members may be able to transfer and delegate certain responsibilities to third parties, but any such transfer or delegation needs to be consistent with regulatory requirements, agreed upon by all interested parties, and carefully documented.
- While DCTs will generate new regulatory challenges, thoughtful consideration of a particular trial’s investigational product, investigative scope, participant population and data objectives will provide important context for identifying and addressing regulatory issues. Coordination with the appropriate FDA review division may be particularly useful when decentralized elements raise novel and nuanced regulatory issues.