HI-PLUS: design of a cluster-randomized trial evaluating structured case management with telemonitoring to improve quality of life in heart failure.

In recent years, the availability and use of digital technologies in healthcare has increased dramatically. Among these digital healthcare products, digital therapeutics (DTx) use software to both generate and deliver an intervention for preventing, treating, or managing a disease or health condition. Yet, many commercially available DTx lack accessible, rigorous scientific evidence of their efficacy or effectiveness or enter the market without appropriate regulatory authorization, leading to the United States (US) Food & Drug Administration (FDA) issuing Warning Letters. Moreover, rigorous evaluation of DTx is vital due to the potential for harm, as found for an online digital training for patients with suicidal thoughts which was found to increase self-harm. To ensure appropriate regulation and evaluation accounting for the specificities of DTx in comparison to other medical devices without software components (e.g., rapid, continual evolution and dynamic nature), the FDA has issued multiple guidance documents for digital tools (e.g., software as a medical device, software/mobile applications, artificial intelligence) and initiated a pilot program for software precertification. Despite these initiatives, most DTx are still regulated through the same traditional regulatory pathways as medical devices without software components, which range from simplified processes for lower risk devices which can claim substantial equivalence to a predicate device and thus may not require clinical evidence (Premarket Notification (510(k)) to more rigorous regulatory reviews requiring valid proof of safety and effectiveness from clinical investigations for higher risk devices (Pre-market approval [PMA]). Prior research on mapping the evidence supporting the development and evaluation of DTx has taken a bird’s-eye view of these processes. Studies either (1) examined all studies assessing DTx without linking them to individual products or (2) evaluated specific elements of these studies for individual DTx (e.g., availability of effectiveness/efficacy studies and their timing relative to commercial availability or FDA-authorization; highest level evidence available). Therefore, as in other contexts, examining the totality of evidence of DTx, that is integrating and appraising all available evidence and relevant clinical and regulatory factors, will provide a better understanding of the current research processes used to develop and evaluate DTx across their full life cycles.