Pathologies and technologies for digital therapeutics: An analysis of global clinical trials

Software with a medical purpose brings the promise of a revolution in patient care and management, through advanced connectivity and data analytics. It represents a promising facet of modern healthcare, harnessing the power of software and Artificial Intelligence to deliver diagnosis, monitoring or evidence-based interventions. Among medical software, Digital therapeutics (DTx) hold a position of prominence as they are intended to be used directly by patients and require evidence of efficacy. As a new therapeutic approach based on digital technology, the commercialization and clinical application of Digital Therapeutics (DTx) are rapidly increasing, with growing demand for their expansion into new clinical areas [ 1 ]. According to the ISO/TR 11147:2023 definition, DTx are “health software intended to treat or alleviate a disease, disorder, condition, or injury by generating and delivering a medical intervention that has a demonstrable positive therapeutic impact on a patient’s health” [ 2 ]. A binding definition is still lacking, but the medical purpose of these products qualifies them as Medical Devices in most countries worldwide. As such, they are subject to strict regulations, such as the Medical Devices Regulation (MDR) in the European Union (EU) [ 3 ], where software intended for medical purposes - such as treating, curing, preventing disease, or supporting medical diagnosis - is called medical device software (MDSW) [ 4 ]. The same category goes under other names in other jurisdiction, such as Software as a Medical Device (SaMD)/ Software in a Medical Device (SiMD), e.g., in the USA, Japan, South Korea [ 5 ]. However, the class of MD or MDSW remains too broad to be perceived by consumers and manufacturers as a clearly identifiable category of marketed products, as it includes software intended for both healthcare professionals and patients. That is why regulatory harmonization on the definition of these technologies, not only DTx, but any MDSW not embedded in a hardware medical device and intended to be used by a layperson, alone or assisted by a healthcare professional, for a specific medical purpose. These products could be defined as a patient-managed Digital Medical Devices (pDMDs), of which DTx represent the subgroup with a therapeutic purpose. The classification and nomenclature of pDMDs, including DTx, have been treated extensively in a previous paper [ 6 ]. Currently, DTx are either available on the market or under development for a wide range of medical conditions, including diabetes, oncology treatment management, and neuropsychiatric disorders such as anxiety, depression, and substance use disorder [ 7 ]. Although DTx have specific characteristics - most notably, their therapeutic use by non-healthcare professionals - most public and regulatory authorities do not assign them a distinct regulatory category from other MDs or even medical device software [ 3 ]. In addition, market access and reimbursement policies, along with financial support for efficacy studies, vary consistently between regions and countries worldwide, but prove crucial in encouraging manufacturers to accept the challenge of researching and marketing DTx. In Europe, Germany has been the first country, since 2020, to provide a reimbursement mechanism through public insurance coverage (which covers about 90% of the population) and fast track for DTx with DiGA ( Digitale Gesundheitsanwendungen , Digital Health Applications) and selective contracts. To qualify as DiGA, a medical device software must be Class I or IIa, intended to be used only by the patient (or by the patient and the healthcare provider) and have clinical evidence gathered in at least one retrospective comparative study. France introduced a reimbursement and fast-track mechanisms for DTx and other pDMD, such as remote patient monitoring products (RPM), since 2023, through the PECAN ( Prise En Charge Anticipée Numérique ) pathway (one year non-renewable reimbursement) or through the Droit Commun pathway for technologies demonstrating sufficient clinical value. In Germany and France, the legislator has also provided a 12-month conditional reimbursement supporting completion of studies to generate clinical evidence [ 8 ]. Other European countries have not been offering so far for DTx market access pathways leading to reimbursement, although in some of them, such as the UK and Italy, initiatives aimed to assess those technologies in view of reimbursement are being discussed. In the USA, the situation is heterogenous, starting with no coverage by Medicare to partial coverage by Medicare Advance to full coverage for Class II and Class III MDs by private insurance companies. This study aims to provide an overview of the state-of-the-art in digital therapeutics through a comprehensive screening of DTx clinical trials globally conducted, in order to highlight prevalent therapeutic areas, leading countries, and types of devices developed or in development.

The technological landscape of DTx was examined to categorize the main types of digital platforms employed across the identified clinical trials. Five categories were identified: mobile applications (apps), web apps, video games, virtual reality (VR), and apps used in combination with wearable devices. Here, a mobile app is defined as an application developed specifically to be used on mobile devices. However, applications accessible via both the web and mobile devices were also included in this class. Mobile applications (65.35%, n = 166) stood out as the prevailing technology among the identified trials ( Fig 2 ), a remarkable growth of 155%, compared to data from a similar study run in 2021, which reported 65 studies employing an app as their technological platform. 7 In addition to this main category, web apps account for 20.08% (n = 51) of technological devices, followed by virtual reality 6.69% (n = 17). Finally, videogames and apps associated with wearable devices or sensors are less common, accounting for 5.12% (n = 13) and 2.76% (n = 7), respectively. The analysis of the therapeutic areas addressed by digital therapeutics (DTx) in the reviewed clinical studies revealed a clear predominance of treatments of psychiatric disorders, which accounted for 51.57% of the total (n = 131). Of these, insomnia, depression and anxiety constitute the most prevalent pathologies ( Table 1 ). The high number of DTx for anxiety and depression can be attributed to their increasing global prevalence [ 11 ], further exacerbated by the COVID-19 pandemic [ 12 ], and the well-established efficacy of cognitive behavioural therapy (CBT), a common component of DTx [ 13 ]. CBT is also frequently used and effective in the treatment of opioid use disorder (OUD), where it supports behaviour change and relapse prevention [ 14 ]. Additionally, in disorders such as bipolar disorder, personalized approaches — e.g., online psychoeducation and tailored digital interventions — have shown greater effectiveness compared to standard treatments [ 15 ]. Psychiatric disorders were followed, at a significantly lower share, by nervous system disorders (11.02%; n = 28) where cognitive rehabilitation via digital devices is increasingly recognized as a promising approach to enhance brain neuroplasticity 9 . Neoplasms (benign, malignant, or unspecified) accounted for 5.51% (n = 14), the same for metabolism and nutrition disorders (5.51%; n = 14) ( Table 1 ). In oncology, digital tools support care by enabling the collection of electronic patient-reported outcomes (ePROs) and remote monitoring, leading to better symptom management, reduced symptom distress, fewer unplanned hospitalizations, and ultimately, improved quality of life and survival [ 16 ]. In the context of metabolic diseases, digital therapeutics have become an established tool for lifestyle intervention in the management of diabetes. These technologies empower patients to take greater control of their condition through self-management, while also providing clinical decision support that benefits both patients and healthcare providers [ 17 ]. Studies related to other technologies were present in less significant quantity: general disorders and administration site conditions (4.33%; n = 11), cardiac disorders (4.33%; n = 11), musculoskeletal and connective tissue disorders (3.94%; n = 10). Notably, within neurology, the use of tablets, smartphones, and virtual reality software has enabled more effective training by providing enhanced sensory stimulation 9 . Additional categories included respiratory, thoracic, and mediastinal disorders (4.64%; n = 9), renal and urinary disorders (2.36%; n = 6), gastrointestinal disorders (2.36%; n = 6), reproductive system and breast disorders (1.97%; n = 5), and injury, poisoning, and procedural complications (1.97%; n = 5). Finally, the following areas were identified with very low frequency: hepatobiliary disorders (n = 2), followed by immune system disorders and ear and labyrinth disorders with only 1 device each. North America accounts for 40.96% (n = 104) of the total number of studies. Europe comes next with 32.28% (n = 82) of the total, then Asia (18.50%, n = 47), South America (2.36%, n = 6) and Oceania (1.97%, n = 5, all studies carried out in Australia) and Centre America (0.39%, n = 1). It is important to note that 9 studies (3.54%) did not report a specific country of origin, highlighting a limitation in the geographical traceability of DTx research efforts. In Europe, Germany ranks as the leader in the field, accounting for 17 studies (6.69% of worldwide trials), followed by Spain (3.94%, n = 10), Italy (3.15%, n = 8), France and the United Kingdom (both at 2.36%, n = 6). A fragmented pattern was observed in other European countries, each contributing one or two studies (e.g., Austria, Greece, Poland) ( Table 2 ). In Asia, significant contributions came from South Korea (5.91% of worldwide trials, n = 15) and China (6.69%, n = 17). The temporal distribution of the clinical trials included in this analysis provides additional insight into the evolution of the digital therapeutics (DTx) field ( Fig 3 ). Although only a limited number of studies were registered before 2020 (8 trials in 2020), a marked increase was observed from 2021 onwards. The number of registered studies increased from 20 in 2021 to 57 in 2022 (+185%) to 59 in 2023 (+4%) and 75 in 2024 (+27%). The number of studies registered in january 2025 (n = 14) suggests that the trend is not going to reverse. Overall, these findings suggest that DTx have attracted increasing attention within clinical research, as reflected by the growing number and diversity of registered clinical trials. The temporal evolution of therapeutic areas further illustrates how the field has developed over time. Psychiatric disorders remained the most represented therapeutic area throughout the study period. However, their share progressively decreased, from 70% of all registered studies in 2021 to 60% in 2022, 56% in 2023, and 39% in 2024. Rather than reflecting a reduction in research activity within mental health, this trend results from an increase in the number of studies conducted in other therapeutic domains. Indeed, while psychiatric applications continued to represent the largest share of registered trials, growing research activity was observed in areas such as nervous system disorders, neoplasms, metabolism and nutrition disorders, cardiac disorders, and musculoskeletal conditions. These findings suggest that, although mental health represented the primary focus of early DTx development, the field has progressively expanded towards a broader range of clinical indications, highlighting an increasing diversification of research efforts over time. The distribution of study status further highlights the dynamic nature of the field. While 99 studies (38.98%) were completed at the time of the data extraction, a substantial proportion remained in active development, including recruiting studies (34.25%; n = 87), active but not recruiting studies (9.45%; n = 24), and not-yet-recruiting studies (16.14%; n = 41). Only a small number of studies were enrolling by invitation (1.18%; n = 3). The large proportion of ongoing studies indicates that the evidence base supporting DTx continues to expand and that numerous technologies are still undergoing clinical evaluation. Among completed studies, the mean study duration was 13.6 months, median 11.1 months and range 1.4 - 44.8 months. These findings suggest that the clinical evaluation of DTx is generally conducted over relatively short- to medium-term timeframes, although substantial variability exists across studies. With regard to study sponsorship, most trials were funded by organizations classified as “Other” by ClinicalTrials.gov (61.02%; n = 155), a category that includes universities, hospitals, research institutions, non-profit organizations, and other sponsors not falling within industry or governmental classifications. Industry-funded studies accounted for 37.80% of the total (n = 96), whereas only a limited number of studies were funded by federal agencies (0.79%, n = 2) or other governmental organizations (0.39%, n = 1). Beyond these classifications, the analysis of sponsors and collaborators revealed frequent partnerships involving academic institutions, healthcare organizations, public research bodies, and digital health developers. Several studies were conducted through collaborations between technology companies and universities or hospitals, while others involved national research institutes and public funding agencies. Taken together, these findings suggest that DTx development is supported by a plurality of stakeholders and sponsorship models, rather than being driven by a single category of funders, suggesting that DTx development frequently involves collaborations among academic, clinical, and commercial stakeholders.

Digital therapeutics are emerging as a promising evolutionary step in healthcare, holding the potential to significantly enhance the well-being of individuals. The temporal evolution of registered clinical trials indicates a rapid expansion of DTx, accompanied by a progressive diversification of the therapeutic areas addressed, beyond mental health. However, their widespread adoption is slowed down by challenges of cultural, ethical, economic, and regulatory origin. From the regulatory point of view, a harmonised legal definition of digital therapeutics is needed, ideally at the European level. In this context, ISO 11147 set a precedent which now holds formal significance and could serve as a starting point for national policies. From the economic standpoint, it is crucial to provide a pathway towards reimbursement policies for DTx, and ideally for all pDMDs, and the allocation of dedicated funds. From the ethical point of view, a balance must be struck between protecting patient privacy and making data available for research. Ensuring data interoperability through standardized languages and a federated data network is essential, allowing data to be used not only for primary purposes but also for secondary analyses. Concerning the cultural barriers to the adoption of DTx, it’s essential to ensure that digital health technologies are well-understood by healthcare providers and the public. This includes comprehensive training for health professionals and thorough information dissemination to patients and their carers about potential benefits of digital therapeutics.

Since a binding legal definition of DTx is still lacking in the EU, the identification of DTx in this work has been based on both the ISO/TR 11147:2023 definition 2 and the Digital Therapeutics Alliance’s DTx evaluation process [ 9 ]. DTx meeting the following criteria have been included in the analysis: software with a medical purpose, i.e., treating or alleviating a disease, disorder, condition, or injury or employed in secondary or tertiary prevention; software intended to be used by the patient, alone or with the support of healthcare providers; software, the medical purpose of which, is achieved through the main digital function (the physician can have a supportive role); software that is stand-alone or combined with other components to form a system (a combination of interacting elements organised to achieve one or more purposes), functioning through general purpose hardware (smartphones, tablets, computers, watches, headphones) or input/output devices (wearables, sensors). The following products were excluded from the study: software without a medical purpose, which include software app for general wellbeing or remote monitoring products; software for primary prevention or to promote wellness and a healthy lifestyle; software that exclusively supports data recognition or diagnosis (remote monitoring products); software designed solely to support communication or exchange of medical referrals between healthcare professionals and patients; healthcare professionals-facing software; software designed to assist HCPs in diagnosing, monitoring or managing patients’ data; software integrated with a specific hardware medical device, to be used only in that combination. A search was conducted on clinicaltrials.gov [ 10 ] to identify clinical trials investigating DTx, with the aim of creating a database updated as of January 2025. The following key words were entered into the field: “Intervention/Treatment”: “Digital Therapeutics”, “Digital Therapeutic”, “Digital Therapy”, “Digital Therapies”. Initially, 1888 clinical trials were identified and transferred to an Excel spreadsheet to select and compare the data of interest. The selection was limited to studies classified under the “Study Type” and “Study Status” categories as “Interventional”, “Randomized”, or “Not Applicable (NA)”. Pilot studies were also included. Non-randomised studies as well as those marked as “Terminated” or “Withdrawn”, i.e., studies terminated earlier than planned or before the start of the trial, were excluded ( Fig 1 ). This choice was informed by existing literature, which shows that approved Digital Therapeutics (DTx) have been evaluated mostly through randomized clinical trials (RCTs) [ 1 ]. Following these criteria, 1290 clinical trials remained. The data sheets of these trials were carefully examined and further screened according to the previously defined selection criteria. If the information was not sufficient to qualify the device as a digital therapy, a more in-depth investigation was conducted by consulting the manufacturer’s website. This way, 254 clinical studies fulfilling the selection criteria were identified. The resulting dataset ( S2 Dataset ) served as the foundation for further analyses concerning the type of technology developed, the therapeutic areas addressed and the countries leading DTx development (the country where the trial was conducted). The countries in which the clinical studies were conducted were grouped by continent (further details can be found in S1 Appendix ). The selected studies were classified according to the therapeutic area targeted and grouped into the following macro areas according to Medical Dictionary for Regulatory Activities Terminology (MedDRA), SOC level: immune system disorders; c ardiac disorders; ear and labyrinth disorders; gastrointestinal disorders; general disorders and administration site conditions; Injury, poisoning and procedural complications; metabolism and nutrition disorders; musculoskeletal and connective tissue disorders; neoplasms benign, malignant and unspecified; nervous system disorders; psychiatric disorders; renal and urinary disorders; reproductive system and breast disorders; respiratory, thoracic and mediastinal disorders. The list of clinical trials collected was used as the starting point for further analyses such as: type of device, therapeutic area and geographical distribution. A limitation of the study stems from basing the analysis solely on ClinicalTrials.gov, which may have caused an underestimation of European and Asian trials included only in regional registries.

Methodology and source analysis: parameters and subclassification used during the analysis. Table A. Number of developed technologies by country. Table B. Type of technological device for different therapeutic areas. Table C. Therapeutic areas addressed in different geographical regions. (DOCX) - Excel dataset containing the 254 clinical trials included in the study and the variables used for classification and analysis. (XLSX)