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Despite high potential of DHTs, regulatory picture remains unclear.
The well-recognized potential of sensor-based digital health technologies (DHTs) as drug development tools has not led to their widespread adoption by drug developers as originally anticipated.1 Part of the problem is the lack of consensus on regulatory terminology and the corresponding regulatory pathways that would enable the effective leveraging of these technologies in medical product development.2
FDA defines a DHT as “a system that uses computing platforms, connectivity, software, and/or sensors for healthcare and related uses. These technologies span a wide range of uses, from applications in general wellness to applications as a medical device. They include technologies intended for use as a medical product, in a medical product, or as an adjunct to other medical products (devices, drugs, and biologics). They may also be used to develop or study medical products.”3
Although the European Medicines Agency (EMA) does not provide a precise definition of DHT, its description of the digital technologies covered by its remit is virtually the same.4 Hence, the dizzyingly broad definition of DHTs encompasses a vast array of tools and applications, while the uses of the various DHTs in clinical investigations come with different implications and require different regulatory considerations.
The use of body-worn sensors, combined with data processing algorithms in drug development, is particularly challenging. The data generated can be a biomarker or a clinical outcome assessment (COA), but the distinction between the two is, at times, blurred by conflicting definitions. One area of confusion is when these sensors (e.g., accelerometers) are used to collect data on the wearer’s real-world behavior or activity. They can be COAs, but the passive nature of these measurements does not fit within the four types of COAs defined by FDA.5 These have been called “DHT-passive monitoring COAs” within FDA’s COA qualification program6 but remained undefined in FDA’s recent draft guidance titled “Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments.”7
As mentioned, wearable sensor data can also be a biomarker as defined by FDA5 and the EMA.4 It is important to note, however, the definitions from these agencies are not entirely congruent. While FDA clearly defines biomarker categories and characteristics as well as the distinctions from COAs, EMA provides a specific definition for digital biomarkers that, among other things, blurs the distinction between COAs and biomarkers. In addition, the emergence of the term "digital biomarker" has led to further conflation of the definitions of biomarkers and COAs in the scientific literature.8
Why do these definitions matter? If there is no consensus on the definitions of and distinctions between COAs and biomarkers in the context of sensor-based DHTs, tribal language within scientific communities emerges and produces inefficiencies. Since drug development is multi-national and multi-jurisdictional, common terminology is essential but unattained. To further illustrate this point, the Mobilise-D project funded by the Innovative Medicines Initiative in Europe uses the following definition in relation to wearable sensor-derived measures of mobility: “A mobility outcome is a biomarker that provides a quantification of each patient’s mobility.”9 This definition looks odd to those of us who would consider mobility a COA concept based on FDA’s biomarker and COA definitions, but it highlights the fact that whether a measure derived from wearable sensors is considered a biomarker or a COA can depend on the jurisdiction. That is a problem.
Similar problems have existed and have been solved through collaboration. Critical Path Institute’s (C-Path’s) eCOA Consortium and Patient-Reported Outcome Consortium have a joint “Lexicon” project aimed at ensuring that eCOA system providers and clinical trial sponsors speak a common eCOA language. It’s time to expand beyond C-Path to engage other stakeholders, such as the European Federation of Pharmaceutical Industries and Associations (EFPIA), Foundation for the National Institutes of Health, FDA, and EMA, to reach consensus on conflicting DHT definitions and terminology in the regulatory context. To help fulfill the potential of DHTs in medical product development, the eCOA Consortium is seeking a productive path toward doing just that.
EFPIA is building on this and other sources of established terminology in an upcoming paper that calls for alignment on DHT-related concepts and terminology. C-Path looks forward to engaging with EFPIA, FDA, EMA, and other stakeholders to help reach the full potential of sensor-based DHTs in drug development through consensus on a common language that is essential for success.
Authored on behalf of Critical Path Institute’s eCOA Consortium by Elena S Izmailova, Chief Scientific Officer, Koneksa Health; Christine Guo, Chief Scientific Officer, ActiGraph; and Stephen J Coons, Senior Vice President, Clinical Outcome Assessment Program, Critical Path Institute