Digital health technologies (DHT) can collect objective, multi-dimensional data passively and remotely with a limited burden for clinical trial participants, providing a way to capture previously inaccessible insights to support drug development and commercialization. However, DHTs have not yet realized their full potential in drug development. Adoption is growing but has been hampered by uncertainties in the regulatory framework overseeing DHT deployment in clinical development. That's why the impact of the DHT guidance from the FDA cannot be overstated. It provides a clear framework for sponsors to assess and implement DHTs in their trials and for vendors to develop safe and high-performing DHTs. 

The FDA released the final draft of the guidance, “Digital Health Technologies for Remote Data Acquisition in Clinical Investigations,” in December 2023. And after some time working with this new guidance, we were excited to bring together key stakeholders from the industry to join us for the September 2024 Digital Health Monthly Webinar session to discuss how the DHT guidance fits into the regulatory landscape, practical advice, and resources for DHT integration, and the future outlook of DHT use in clinical trials.

Our panelists included: 

• Annie Saha, Associate Director for Strategic Initiatives, Digital Health Center of Excellence at FDA 
• Carrie Northcott, Head of Digital Sciences; Biomeasures, Endpoints and Study Technologies, Pfizer 
• Nicholas Fountoulakis, RAC, Manager, North America Regulatory Scientist Global Regulatory Affairs, Immunology, Janssen Research & Development 
• Bert Hartog, Chief Impact & Innovation Officer, Digital Medicine Society 
• Sylvain Zorman, PhD, Director of Digital Health Sciences, Moderator, ActiGraph
  

Opportunities to Advance Clinical Investigations with DHTs 

In addition to giving an overview of the key points in the guidance (review the slides here), Annie provided more context around the intention of the FDA DHT guidance and its impact on clinical investigations and drug development. The guidance is intended to accelerate efficient medical product development by helping to bring innovations and advances to patients. It supports the idea of decentralized elements of clinical trials and promotes health equity by enabling more frequent or continuous monitoring, better longitudinal views of health status, and improving patient recruitment and retention by meeting patients where they are.  

By leveraging these technologies in clinical investigations, drug developers can capture more accurate and comprehensive data. For example, DHTs offer the potential to develop novel clinical endpoints that are more reflective of the patient experience. Gathering new types of data allows technology providers and pharmaceutical sponsors to create endpoints that are complementary to existing forms of data used in regulatory submissions and provide a more detailed picture of patients' experiences and the effect of a treatment. 

Real-world data capture from DHTs could better track infrequent clinical events that might be missed through traditional data capture methods. The use of DHTs can also facilitate the direct collection of information from participants who are unable to adequately report their experiences, such as pediatric or cognitively impaired participants. This is particularly important in enhancing diversity in recruitment by facilitating the enrolment of those with limited access to healthcare. 

Overall, the potential benefits of using DHTs in clinical trials include fewer study visits, novel insights into participant health status and quality of life, and more sensitive study outcomes. By leveraging these technologies, sponsors can advance health equity and improve understanding of patients' experiences. 

Meaningful Measures for Patients 

One of the important opportunities DHTs bring to clinical investigations is the ability to capture objective data to support clinical endpoints that measure aspects of health that are meaningful to patients. For example, patients with cancer suffering from cachexia report that muscle weakness and fatigue significantly disrupt daily activities that are important to them, such as household chores, self-care, and participating in recreational activities such as walking their dog or playing with their grandchildren. The meaningful aspect of health that is impacted in patients’ lives is movement, i.e., physical activity.  

While measuring movement sounds straightforward, defining a concept of interest that can be measured is not quite as simple as it sounds. Patient diaries and clinical assessments can help capture subjective information about how much fatigue a patient is feeling or how far they can walk during a laboratory test. However, these measures are not capturing how much activity a patient actually does in the real world. DHTs can provide accurate and objective measure(s) of physical activity in a quantifiable manner to better characterize how a treatment impacts an aspect of health that is meaningful to patients.  

This concept was recently demonstrated in results from a Pfizer Phase II trial (NCT05546476) in patients with cancer-related cachexia, which demonstrated a meaningful change in physical activity following treatment using data captured by wearable DHTs. Together with improvements in weight gain, QoL assessments, and body composition measures, this data supported the new treatment as a promising option for further evaluation. 

Fit-for-Purpose: Why it’s Important and Generating Required Evidence 

If a clinical outcome assessment or biomarker that a study team would like to include in a clinical investigation can be best measured using DHT, the FDA will require that you explain why you’ve chosen to measure it digitally and provide evidence the DHT is fit-for-purpose, meaning that the level of validation associated with the DHT is sufficient to support the use, including the interpretability of its data, in the clinical investigation. 

The FDA DHT guidance outlines the evidence needed to support a DHT is fit-for-purpose, including design and technical characteristics, the data provided to the sponsor and investigator, how the DHT measures the clinical event and characteristics of interest, the features that impact usability, data security and privacy, access control methods, interoperability, and data management. 

We won’t go through the details of establishing an evidentiary dossier in this post, but the panel discussed resources that have helped them navigate this process. Bert, Chief Impact & Innovation Officer at the Digital Medicine Society, shared multiple freely accessible resources, including -  

• The Digital Health Measurement Collaborative Community (DATAcc) by the Digital Medicine Society (DiMe) has developed the V3 and  V3+ Framework plus associated resources to guide you through evaluating evidence for technical verification, usability validation, analytical validation, and clinical validation. 

• The Playbook, maintained by DiMe, is an industry guide for developing and deploying digital clinical measures and remote monitoring that is free to access and includes multiple checklists, toolkits, and case studies. 

Additionally, a white paper from ActiGraph guides clinical trial sponsors through what regulators expect in a submission, selecting the right fit-for-purpose DHT, operationalizing DHTs, and considerations to evaluate clinical endpoints from DHT data. 

One point actively discussed by the panel was the decision whether to use consumer-grade or medical-grade wearable devices in clinical trials. When it comes to incorporating consumer-grade wearables into research studies, there are pros and cons to consider. While consumer-grade wearables can be user-friendly and accessible, they may not meet the standards of accuracy, sensitivity, and specificity required for specific contexts of use in clinical investigations. Moreover, proprietary algorithms used to process data from consumer devices are often updated frequently, which could impact study outcomes if not properly controlled or if access to raw data is not available. Finally, the lack of documentation on the design, manufacturing, and testing of the product makes it difficult for the sponsors to establish evidence to support fit-for-purpose.  

The panel commented on how quickly technology advances for both consumer and medical grade solutions, requiring a proactive evaluation process to identify potential factors that could impact DHT device performance.

This is a particular challenge in drug development, where typical development (phase 1 to phase 3) takes 10 years. The panel discussed how a focus on the measure rather than the technology could mitigate the out-of-sync innovations between drug development and DHTs. Indeed, the measure can remain the same across study phases while the technology used could evolve from one phase to the other. The value of the raw data (high-frequency data) that enables the retrospective process was also identified as a critical asset.  

Finally, to appropriately manage DHT integration in clinical investigations and ensure their effectiveness, it's essential to take a risk-based approach by defining key specifications that drive desired outputs, assessing potential risks, and developing a comprehensive data management plan. This approach allows for informed decision-making and efficient maintenance of DHT solutions throughout their lifecycle, ensuring they continue to deliver meaningful results. 

Navigating the Regulatory Landscape 

Nick, Manager of Regulatory Affairs at Janssen Research & Development, pointed out that the regulatory landscape is often navigated by relying on precedence. Given that the DHT regulatory environment is at a “new to moderately mature stage”, there isn’t a lot of precedence put into place, with the exception of the EMA’s qualification of the wearable-derived measure of stride velocity 95th centile as a clinical endpoint. However, the panel agreed that regulators have been open and receptive to engagement on this topic as the landscape matures.  In terms of developing a digital clinical outcome assessment, the DHT guidance is meant to be used in conjunction with the Patient-Focused Drug Development guidance series.

The key steps to keep in mind include identifying the desired measure, justifying your choice for that endpoint, and being transparent about the context of use, whether the measure is for safety or to support effectiveness, and the endpoint positioning (primary, secondary, exploratory, etc.). It’s only at this stage that various technologies can be assessed and selected. 

Annie, Associate Director for Strategic Initiatives at the FDA Digital Health Center of Excellence, explained that as an agency, they do talk with colleagues from other regulatory agencies around the world about DHT for learning and alignment. Of course, there will be differences in the way laws and regulation are written and applied, but they try to align as much as possible, especially on principles. 

Carrie, Head of Digital Sciences, Biomeasures, Endpoints and Study Technologies at Pfizer commented that while the guidances are similar, there are significant divergences. She and her colleagues would love to see more alignment on the terminology and concepts used, because it would streamline the application process across geographies. However, the overarching principles that were discussed during the webinar, including developing evidence for verification, validation, and meaningfulness, are consistent requests from regulators globally.  

Developing an Endpoint – “It's the Same Game with a New Name” 

One point the panel touched on throughout the discussion was that while DHTs are somewhat new, the method of generating an endpoint is not.  When using data from a DHT to inform an endpoint, sponsors should treat the DHT-derived endpoint like a conventional endpoint whose validity relies on information regarding its definition, justification, type (safety, effectiveness), and positioning (primary, secondary, etc.) and evidence supporting the context of use. At the end of the day, the level of evidence that clinical teams need is going to be the same whether the supporting technology is digital or not.  Nick pointed out that “It’s the same game with a new name.” 

The technology should neither be the focus nor the starting point for clinical teams. Having a valid measure should be, and the evidence the clinical team develops for a DHT-derived endpoint goes back to the context of use.

For primary endpoints, sponsors need to produce more evidence than an exploratory endpoint. Carrie mentioned that, in her experience, an exploratory endpoint in early development (Phase 1) can be an excellent way to start collecting data for elevation in a later phase. When sponsors want to use data captured with a DHT to support secondary or primary endpoint, they should start by including the measure as exploratory in earlier trial phases. This gives them the opportunity to collect and evaluate the data and improve operations, which could then be used to support deployment and regulatory engagement for follow-up studies.  

Annie commented on one unique aspect to using DHTs in the context of drug development – it's a multidisciplinary effort. Bringing together clinicians, technicians, patients, and data scientists at the beginning of the development process is important to effectively develop, validate, and operationalize DHTs for use in a clinical investigation. It’s not necessarily harder than conventional instruments, but it does require education and effective communication across the team.  

Challenges and Next Steps 

While DHTs bring many opportunities to clinical investigations, this new potential does not come without challenges to navigate as well. One way to accelerate the adoption and integration of DHT-derived measures could be to develop standard measures of concepts of interest in particular clinical populations. Bert mentioned that DiMe has initiated efforts to develop sets of core measures for aspects of health, such as sleep or physical activity, to harmonize the measures across the industry. These collaborative efforts with clinical trial sponsors and technology vendors are advancing the understanding of what is required and meaningful regarding core measures. This effort can help streamline analytical validation evidence collection, as well as possible reuse of certain aspects of the evidence package across different regulatory agencies, making DHT integration more feasible for study teams.  

Continuing to collaborate and learn from study teams that have deployed DHTs in their clinical trials will be important for realizing the full potential of these new tools. In a recent white paper, ActiGraph collected 4 real-world examples of clinical trials that incorporated DHTs. We assess the aspect of clinical trial design that DHTs had an impact on and the value this helped clinical trial sponsors realize in these specific use cases. 

Examples like these case studies as well as growing regulatory acceptance are cause for optimism when it comes to the expanded use of DHTs and their potential to transform clinical drug development.  

Read the full white paper and case studies, Crossing the Chasm: Real-World Value Realized from DHTs in Clinical Trials.