{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:55:15Z","timestamp":1792000515705,"version":"4.4.0"},"reference-count":26,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Milan - PSR Piano di Sostegno alla Ricerca 2025 - LIINEA 2","id":[{"id":"https:\/\/ror.org\/00wjc7c48","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosdigitalhealth.org"],"crossmark-restriction":false},"short-container-title":["PLOS Digit Health"],"abstract":"<jats:p>\n                    CDigital therapeutics (DTx) are software-based medical devices that deliver evidence-based therapeutic interventions directly to patients. While the clinical use of DTx is expanding rapidly, regulatory fragmentation and the absence of harmonized legal definitions hinder their assessment and reimbursement policies, as well as their integration into healthcare systems. There is currently a lack of comprehensive overviews of DTx clinical development, which are essential for informing policy, research and regulatory priorities. This paper provides an updated overview of randomised clinical trials involving DTx. 254 eligible trials on DTx, (defined according to ISO\/TR 11147:2023) registered through January 2025 were identified through a search on C\n                    <jats:italic>linicalTrials.gov<\/jats:italic>\n                    . Mobile applications represent the most prevalent technology (65%), followed by web-based tools and virtual reality (20%). Psychiatric disorders are the primary therapeutic target (52% of the studies) with insomnia, depression, and anxiety being the most addressed conditions. Trials were primarily conducted in North America (41%) and Europe (32%), where Germany, Spain, and Italy represent the most active countries. The analysis of clinical trials registrations on ClinicalTrials.gov reveals a heterogenous geographical distribution of DTx development but also a clear direction in the type of conditions for which they are mostly indicated, namely psychiatric and nervous system disorders. The fragmented policies on DTx reimbursement, even among EU countries, and the different capacity of governments to fund DTx research and development emerge as key factors, along with cultural and ethical issues, in determining the willingness of the industry to invest in these devices.\n                  <\/jats:p>","DOI":"10.1371\/journal.pdig.0001750","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:31:03Z","timestamp":1791999063000},"page":"e0001750","update-policy":"https:\/\/doi.org\/10.1371\/journal.pdig.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pathologies and technologies for digital therapeutics: An analysis of global clinical trials"],"prefix":"10.1371","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0753-5414","authenticated-orcid":true,"given":"Paolo","family":"Rocco","sequence":"first","affiliation":[{"name":"University of Milan","place":["Milan, Italy"],"department":["Department of Pharmaceutical Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3333-2848","authenticated-orcid":true,"given":"Valentina","family":"Pagella","sequence":"additional","affiliation":[{"name":"University of Milan","place":["Milan, Italy"],"department":["Department of Pharmaceutical Sciences"]},{"name":"INDICON S.r.l. Societ\u00e0 Benefit","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7049-4152","authenticated-orcid":true,"given":"Umberto M.","family":"Musazzi","sequence":"additional","affiliation":[{"name":"University of Milan","place":["Milan, Italy"],"department":["Department of Pharmaceutical Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0465-8478","authenticated-orcid":true,"given":"Sara","family":"Manellari","sequence":"additional","affiliation":[{"name":"University of Milan","place":["Milan, Italy"],"department":["Department of Pharmaceutical Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3760-1865","authenticated-orcid":true,"given":"Elena Paola","family":"Lanati","sequence":"additional","affiliation":[{"name":"INDICON S.r.l. Societ\u00e0 Benefit","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7723-441X","authenticated-orcid":true,"given":"Paola","family":"Minghetti","sequence":"additional","affiliation":[{"name":"University of Milan","place":["Milan, Italy"],"department":["Department of Pharmaceutical Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,14]]},"reference":[{"issue":"1","key":"pdig.0001750.ref001","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41746-023-00777-z","article-title":"Digital therapeutics from bench to bedside","volume":"6","author":"C Wang","year":"2023","journal-title":"NPJ Digit Med"},{"key":"pdig.0001750.ref002","unstructured":"International Organization for Standardization. Health informatics \u2013 personalized digital health \u2013 Digital therapeutics health software systems. 2023. https:\/\/www.iso.org\/standard\/11147.html"},{"key":"pdig.0001750.ref003","unstructured":"Regulation (EU) 2017\/745 of the European Parliament and of the Council on medical devices. 2017. https:\/\/eur-lex.europa.eu\/legal-content\/EN\/TXT\/?uri=CELEX%3A02017R0745-20260719"},{"key":"pdig.0001750.ref004","unstructured":"Medical Device Coordination Group. Guidance on Qualification and Classification of Software in Regulation (EU) 2017\/745 \u2013 MDR and Regulation (EU) 2017\/746 \u2013 IVDR (MDCG 2019-11). 2019. https:\/\/health.ec.europa.eu\/document\/download\/b45335c5-1679-4c71-a91c-fc7a4d37f12b_en"},{"key":"pdig.0001750.ref005","unstructured":"Digital Therapeutics Alliance. Understanding DTx\/ DTx By Country. https:\/\/dtxalliance.org\/understanding-dtx\/dtx-by-country\/ Accessed 2026 September 3."},{"key":"pdig.0001750.ref006","doi-asserted-by":"crossref","first-page":"101506","DOI":"10.1016\/j.imu.2024.101506","article-title":"Patient-managed digital medical devices: Do we need further regulation?","volume":"47","author":"P Minghetti","year":"2024","journal-title":"Informatics in Medicine Unlocked"},{"key":"pdig.0001750.ref007","doi-asserted-by":"crossref","first-page":"106319","DOI":"10.1016\/j.cmpb.2021.106319","article-title":"Introduction of digital therapeutics","volume":"209","author":"JS Hong","year":"2021","journal-title":"Computer Methods and Programs in Biomedicine"},{"key":"pdig.0001750.ref008","unstructured":"Tokarska J, Foxon G, Zakrzewska K. Evaluation and reimbursement of digital therapeutics in Germany, France, Belgium and England. In: Copenhagen, Denmark. https:\/\/www.ispor.org\/docs\/default-source\/euro2023\/isporeurope23tokarskapt21poster131258-pdf.pdf?sfvrsn=17e2dac7_0"},{"key":"pdig.0001750.ref009","unstructured":"Therapeutics Alliance DTA. Is this product a DTX?. https:\/\/dtxalliance.org\/wp-content\/uploads\/2022\/09\/DTA_FS_Is-This-Product-a-DTx.pdf 2022. Accessed 2026 September 3."},{"key":"pdig.0001750.ref010","unstructured":"National Library of Medicine. ClinicalTrials.gov. https:\/\/clinicaltrials.gov\/ Accessed 2026 September 3."},{"issue":"4","key":"pdig.0001750.ref011","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0284091","article-title":"Increasing digitalization is associated with anxiety and depression: A Google Ngram analysis","volume":"18","author":"GW Teepe","year":"2023","journal-title":"PLoS One"},{"issue":"5","key":"pdig.0001750.ref012","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1004008","article-title":"Digital solutions to promote adolescent mental health: Opportunities and challenges for research and practice","volume":"19","author":"J Bantjes","year":"2022","journal-title":"PLoS Med"},{"issue":"6","key":"pdig.0001750.ref013","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0285622","article-title":"Effects of digital cognitive behavioral therapy for depression on suicidal thoughts and behavior: Protocol for a systematic review and meta-analysis of individual participant 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Health"},{"key":"pdig.0001750.ref024","article-title":"The Digital Therapeutics Real-World Evidence Framework: An Approach for Guiding Evidence-Based Digital Therapeutics Design, Development, Testing, and Monitoring","volume":"26","author":"M Kim","year":"2024","journal-title":"J Med Internet Res"},{"key":"pdig.0001750.ref025","article-title":"Ethics in the governance of data and digital technology: An analysis of European data regulations and policies","author":"D Eke","year":"2024","journal-title":"AI and Ethics"},{"issue":"1","key":"pdig.0001750.ref026","doi-asserted-by":"crossref","first-page":"2493139","DOI":"10.1080\/21642850.2025.2493139","article-title":"Bridging the digital health divide: a narrative review of the causes, implications, and solutions for digital health inequalities","volume":"13","author":"MJ Western","year":"2025","journal-title":"Health Psychol Behav Med"}],"container-title":["PLOS Digital 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