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Landscape analysis: A look at the regulation of decentralized trials and what’s coming soon

In the past few years, regulators and researchers have shown increased interest in leveraging decentralized trial methods – especially following the pandemic. In this article, AgencyIQ explores the current regulatory state of decentralized trials and what’s likely coming next.

BY LAURA DIANGELO, MPH | APR 10, 2024 5:44 PM CDT

Background: What are decentralized trials?

  • Decentralized clinical trials (DCTs) employ technologies to remotely communicate with study participants and collect clinical data. Study participants may complete some trial activities from sites other than those located at a traditional, centralized trial site model – for example, from their homes or with their community-based providers. Trials can be fully decentralized, in which all trial activities are conducted outside of the centralized trial site, or may be decentralized components in a hybrid approach, in which some activities will still require visits to the trial site. Decentralized trials may also include the use of digital health technologies (DHTs) to interact with patients.
  • Decentralized clinical trials became somewhat of a necessity during the coronavirus pandemic. Travel restrictions and clinical trial site closures during the COVID-19 public health emergency required many clinical trials to implement decentralized approaches to reduce person-to-person interactions between trial participants and staff. These efforts allowed many trials to retain existing trial enrollees, though it did often require modifications to be made to trial protocols at the urging of both the FDA and European Medicines Agency.
  • The more regular use of DCTs may have some potential advantages, such as reducing the need for potentially sick patients to travel to trial sites and increasing participant diversity. According to a white paper from the Association of Clinical Research Organization (ACRO), the ability to design studies to be more patient-centric is a top potential advantage of DCTs, including through “making trial participation more convenient” – with the research from ACRO finding that “the average one-way distance between patient and trial site [is] 25 miles (40 kilometers).” These types of study structures may functionally exclude people who rely on public transportation, do not have reliable caregivers for children or dependent adults, or have limited flexibility in their work schedules. In addition, trial sites tend to be concentrated in highly specialized clinical sites and hospital networks, so rural populations and those who receive their health care from community health centers or networks will also have limited opportunities to participate in clinical trials under more traditional models.
  • From a study perspective, DCTs can present opportunities for novel data collection, or for researchers to tap into data sources that were not previously available to them. These include options for data captured remotely via DHTs that can provide more regular (and, potentially, continuous) monitoring data or the types of assessments that can be captured from wearable devices that are more difficult in in-person settings (e.g., sleep). ACRO’s white paper also highlights the potential for “enhanced efficiency, long-term cost savings, and faster collection of data” through risk-based monitoring and other data collection efficiencies.
  • Decentralized trials are currently regulated under a patchwork of regulatory approaches, of which some remain under development. In early 2023, AgencyIQ conducted a landscape analysis of DCT policy in the U.S. and E.U. However, after a busy year of active and expected policymaking, this updated landscape analysis outlines what’s changed, what’s new, what we’re still waiting on and what’s next.

First up: The ICH E6(R3) Guideline on Good Clinical Practice and its ongoing “full rewrite” and new Annex

  • Quick background: ICH and its E6 Good Clinical Practice (GCP) guideline. GCPs are intended to protect the welfare of trial participants and ensure that trials are run to appropriate standards with respect to trial design, trial conduct and the collection of data. While there are various ethical standards, laws and frameworks in place to protect study participants, among the most widely used is the International Council for Harmonisation (ICH) E6 guideline on GCP, which was first introduced in 1997. The GCP guidelines seek to protect the rights, safety and welfare of clinical trial subjects through the adoption of a series of “principles,” such as that the “rights, safety and well-being of subjects prevails over the interest of science.” The E6 guideline has been updated twice, including a major revision in 2016 that added significant content.
  • ICH is working on an update to E6 that would better apply the GCP principles to novel methods like DCTs. In 2019, ICH announced a final concept paper proposing “a full rewrite and reorganization” of its E6(R3) Guideline on Good Clinical Practice, noting at the time that the intent of the update would include a focus on “increasingly diverse trial types” including DCTs [Read AgencyIQ’s analysis of the Public Workshop on the ICH E6 renovation here]. In 2021, the ICH followed this up with a draft principles document on the E6 update.
  • In 2023, however, the ICH offered a slightly different plan for addressing DCTs in E6(R3): Annex 2. In March 2023, ICH announced a forthcoming addendum to the still-under-development new E6(R3) document, Annex 2. Per the concept paper, “When complete, E6(R3) will be composed of an overarching principles document, Annex 1 (considerations for interventional clinical trials), and Annex 2 (additional considerations for interventional clinical trials)” – with Annex 2 focusing on more granular recommendations sought by industry and researchers. In effect, as part of the work to update ICH E6(R3), the guideline is getting a new chapter, Annex 2, which will go beyond the “best practices” and general recommendations for trials in Annex 1 to further discuss operational guidance on the conduct of trials, including those with more novel methods and operational structures.
  • The goals for Annex 2 are focused, in part, on DCT issues. In its concept paper describing the plan for developing the document, ICH acknowledged the limitations of even the planned E6(R3) rewrite, noting that “while E6(R2) provided a great deal of details, it did not address many aspects of modern clinical trials.” These “modern” aspects include “advances in technologies” that “serv[e] as a new vehicle for data exchange among multiple stakeholders in the clinical trial enterprise.”
  • In particular, according to the ICH there are three “issues to be resolved” in Annex 2: Decentralized elements; pragmatic elements; and real-world data (RWD) sources. Notably, all three of these “issues” are closely linked. Decentralized elements to be addressed in Annex 2 are consideration or “when some or all trial-related activities occur at locations other than traditional clinical trial sites, such as patient homes, mobile trial units, or local clinics, and data collection may occur remotely.” The pragmatic elements, then, are “trials that closely resemble routine clinical practice” – and may, for example, be taking place at the kinds of clinics or sites references as “decentralised elements.” Annex 2 content will also focus on RWD sources including “the use of registries, electronic health records (EHRs), hospital data, pharmacy and medical claims data or wearables,” with both hospital and wearable data considered a key opportunity in decentralized data collection methods.
  • The first draft version of the new Good Clinical Practice E6(R3) guideline was endorsed in May 2023 – but does not yet include Annex 2 content [read AgencyIQ’s full analysis here]. The bulk of the document is still content in Annex 1 (best practices and general guidelines). However, the revisions to the guideline do have some relevancy to DCT issues, particularly in an enhanced focus on the expectations for investigator responsibilities and trial oversight – key aspects of regulatory consideration under decentralized trials, in which there are more (and more diverse) data sources and personnel involved – as well as additional information on electronic record keeping (the use of computerized systems).
  • Responses to the draft guideline highlighted DCT issues. The draft E6(R3) guideline was submitted for public consultation – while many commenters signaled approval of the expanded scope of the document, considerations about DCT-related issues were high on their list of priorities as well. In particular, the expectations about the roles and responsibilities of the study sponsor, investigators and delegated tasks was a key point of concern for several industry commenters. Further, several commenters cited ongoing discrepancies or a lack of concrete guidance on the nuts and bolts of clinical trial conduct, particularly for those more complex designs (including DCTs) and harmonization across jurisdictions.
  • When are we expecting a draft Annex 2? The final Concept Paper from ICH states that it “expect[s] approximately 12-18 months are needed to develop a draft that will be subject to public consultation” – so, under that timeline, between March and September 2024.
  • Notably, even without dedicated content under the to-be-issued Annex 2 yet available, the best practices described in the current E6(R3) guideline continue to be applicable for sponsors and researchers working on studies with decentralized components. At a February 2024 joint workshop with the U.S. FDA, U.K. MHRA and Health Canada, regulators from those agencies highlighted several case studies where study sponsors and investigators had run into challenges applying the regular regulatory framework to studies with decentralized components. For now, the key recommendation from regulators was to ensure appropriate documentation at every step, which can be challenging with new organizational structures or novel technologies and/or data sources involved. Further, regulators urged study sponsors to ensure appropriate risk assessments in the case of decentralized components, which require additional context for less-traditional methods.

Next, the U.S. FDA’s work on DCTs and DHTs – and more

  • The FDA released its first, long-awaited draft guidance on conduct of DCTs in May 2023. While the agency had previously released a guidance on DHTs – digital health technologies, which may be used to facilitate decentralized elements of studies – in 2022, the May 2023 draft guidance was the first on the conduct of these studies themselves. As part of the 2023 Consolidated Appropriations Act (or “omnibus” bill to fund the federal government through 2023), Congress directed FDA to “issue or revise draft guidance” on decentralized clinical studies by December 2023, and particularly focus on information on how these trials should be operated, how they may increase diversity, and how sponsors should consider the incorporation of technologies like DHTs.
  • The draft DCT guidance from FDA lays out the key considerations for DCT conduct, including the investigator roles and responsibilities, delineating tasks and appropriate documentation, and offers key definitions and high-level regulatory parameters for DCTs. Much of the draft guidance document is focused on the expectations and documentation requirements for the different entities and partners engaged in a DCT, as involving decentralized elements into study designs mean an expansion of the research team (and operations that Investigators must oversee) and the types of activities that are considered to be part of a trial. The guidance provides an overview of the way that the agency would expect to see “delegation of trial-related activities” addressed and documented, specifying the types of information that fall under Investigators’ responsibilities and how these should be reflected in task logs, as well as considerations for using local health care providers and on the use of different clinical laboratories. The guidance touches on expectations for how safety monitoring plans address the decentralized elements, the flow of data from different entities contributing to the study.
  • Other key areas addressed: Inspections, and the kinds of decentralized elements and studies that the FDA is expecting. Up front, the agency noted in the draft guidance that DCTs may be less-well suited to non-inferiority studies, and goes on to specifically cite scenarios that might lend themselves well to being conducted in a decentralized basis. For example, the guidance discusses the types of activities that local non-trial providers might be best suited to conduct, as well as considerations for when a telehealth visit would be considered as an alternative to an in-person visit (and its expectation that the parameters for each visit type to be clearly defined in the study protocol). The guidance also offers preliminary recommendations on how the inspections systems will be applied to studies with DCTs – in particular, the agency noted that there needs to be a physical location with all trial-related records and for personnel interviews, which needs to be detailed in an FDA Form 1572 (for drugs) or investigational device exemption (IDE) application (for devices). Further, the guidance highlights some practical recommendations – for example, the agency indicates that drugs with a long shelf life and good stability profiles may be better suited to shipping directly to a patient home than those with specialized shipping, handling and storage considerations.
  • The guidance accompanies another document specifically on digital health technologies. As noted above, the FDA issued a draft guidance on the use of DHTs in 2021, which was finalized in December 2023. DHTs are defined by the FDA as “a system that uses computing platforms, connectivity, software, and/or sensors, for health care and related uses” – and are considered to include the types of digital tools that can enable decentralized elements, like wearables/sensors and participant reporting portals available by a phone or computer.
  • The guidance offers some best practices on leveraging DHTs from a regulatory perspective – but less so from a practical perspective. The final 2023 guidance discusses recommendations on how to describe a DHT in a regulatory submission, the verification and validation of a DHT in the context of a particular research program, and how to identify and manage risks with a DHT during an investigation, as well as regulatory expectations for retaining and protecting the data and the role of the investigator. While the final version does include some additional context about the role of the device regulations in the leveraging of DHTs (for example, a DHT may be a medical device, or contain a medical device component), it specifically does not address whether specific DHTs are medical devices. Further, it doesn’t address “approaches to selecting, modifying, developing, and validating clinical outcome assessments (COAS) to measure outcomes of importance to patients in clinical investigations” – in effect, it discusses what the agency would want to see documented, not best practices for deploying DHTs in research programs in a way that would lend regulatory confidence. Notably, that is likely because this field of research is still very much emerging.
  • As AgencyIQ noted at the time, there are still significant outstanding questions in this area, even with a final guidance. Practically, the DHT guidance does not provide advice on key areas in DHT deployment, such as how to account for changes over time and how to set the minimum performance and technical specifications for individual DHTs that would then serve as the baseline for verification and validation activities. As AgencyIQ has previously discussed, this is still an emerging area, with the FDA set to host a variety of workshops on the subject over the next few years under the user fee (PDUFA VII) commitments. Per the discussions at the first of those workshops, standardizing these specifications is still a work in progress. However, reliance on those baseline common specifications – rather than going one-by-one through specific DHTs – could help build regulatory confidence in an approach that’s research program-agnostic and also allow for more generalized measures to be captured using a variety of technologies, potentially supporting bring-your-own-device (BYOD) efforts.
  • This is still a work in progress – and there’s some action expected in 2024. The FDA announced the establishment of a DHT Advisory Committee in October 2023, with the announcement citing a remit for the committee that is effectively a laundry list of the most pressing topics in DHT policy development. For example, the committee will advise on “issues related to Digital Health Technologies (DHTs), and FDA policies and regulations about these technologies, providing relevant expertise and perspective to improve the FDA’s understanding of the benefits, risks, and clinical outcomes associated with use of DHTs, as well as identifying risks, barriers, or unintended consequences that could result from proposed or established FDA policy or regulation for topics related to DHTs. This also may include advice on the use of DHTs in clinical trials or post-market studies subject to the FDA’s regulation.” This broad description captures many of the outstanding questions that both regulators and researchers have been raising and which may help sponsors interpret or apply the recommendations in the new final guidance. While the committee has not yet been convened, AgencyIQ will be watching for potential meeting announcements in 2024.

Analysis and what’s next

  • Documents that are currently under construction are likely to be influential, including ICH E6(R3) Annex 2 and a potential final version of the FDA’s DCT guidance document. While a first draft of Annex 2 is expected at some time in 2024, the FDA’s policy making timeline on its final guidance specifically is uncertain. That said, the FDA is working in 2024 on several different initiatives related to identifying best practices for deploying remote data collection, including investigations into the types of measures that can be captured digitally/remotely and what that data collection and analysis looks like for regulatory purposes.
  • Regulatory policies on DCTs aren’t just about adjusting the existing expectations for trial conduct to account for decentralized methods, but rather also about considering the different mechanisms by which specific decentralized elements are enabled or supported. For example, the FDA’s DCT guidance also relies on content and context from the guidance and ongoing policy work around DHTs, as well as a recent draft guidance on electronic systems, records and signatures in clinical investigations, while ICH’s E6 update also includes enhanced content about digital records and electronic systems.
  • The interaction between DCTs and Real-World Data remains a challenge. As noted above, the policy considerations and documents on DCTs are closely linked to RWD policy issues, with the Annex 2 work focused on decentralized study elements, pragmatic elements and RWD. While RWD has traditionally been defined as data captured outside of the clinical trial infrastructure, relying on more pragmatic approaches or novel data sources like DHTs or regular clinical practice can blur the line between what is RWD in the traditional definition sense and what is data that is technically within the bounds of trial infrastructure but from a source that would have traditionally been associated with RWD. This same issue was highlighted in some of the comments to the European Medicines Agency (EMA) on ICH’s June 2023 reflection paper on standardizing RWD/real world evidence (RWE) terminology for regulatory purposes. Views submitted to EMA diverged, with the Association for Contract Research Organizations (ACRO) directly requesting clarification about whether RWD can be collected in research settings (e.g., from wearable devices), while the European Hematology Association (EHA) called specifically for definitions to distinguish between RWD and the types of data collected during clinical trials.

 

To contact the author of this item, please email Laura DiAngelo ( [email protected]).
To contact the editor of this item, please email Alexander Gaffney ( [email protected])

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