Digital Therapeutics regulations in US, EU and Japan

This PowerPoint presentation provides a comprehensive overview of the current regulatory landscape governing digital therapeutics in the United States, European Union, and Japan, offering valuable insights on the regulatory perspective of DTx.

1. Digital Therapeutics Regulations in US, EU and Japan Prepared by: Gargi Vaghela M.Pharm Regulatory Affairs

2. Contents: Introduction to Digital Therapeutics ( DTx ) Digital health DTx regulations in US DTx regulations in Japan DTx regulations in Europe Comparison of DTx in different countries References 2

3. Digital health Digital health refers to the use of digital technologies to improve and enhance healthcare delivery, outcomes, and patient experiences. It encompasses a wide range of technologies, including mobile health (mHealth), telemedicine, electronic health records (EHRs), wearables, health information systems, and other digital tools and platforms. The primary objective of digital health is to leverage technology to make healthcare more accessible, efficient, and effective, both for patients and healthcare providers. Digital health interventions can help reduce costs, improve care quality, and increase patient engagement and satisfaction. 3

4. Introduction to Digital Therapeutics ( DTx ) Digital therapeutics refer to a category of digital health interventions that use software-based technologies to prevent, manage, or treat medical conditions. The Digital Therapeutic Alliance states: “Digital therapeutics (DTx) deliver medical interventions directly to patients using evidence-based, clinically evaluated software to treat, manage, and prevent a broad spectrum of diseases and disorders.” 4 Therapeutics (Tx) refer to a drug, medical device, or software that helps prevent, treat, or manage a disease or condition.  Digital Therapeutics ( DTx ) is a subcategory of Tx in which the administration of the therapy has been digitized. 4

5. Digital therapeutics in healthcare: Reimagining care delivery | Netscribes 5

6. Impact of DTx to key stakeholders: 6

7. Teleconsultation Remote patient monitoring Monitoring and improving patient adherence Cloud-based patient data management Site-less clinical trials DTx in Post Covid Era 7

8. DTx is regarded by the USFDA as a mobile medical application (MMAs). Applications helping patients organize and track their health information Applications providing easy access to information related to conditions or treatments Applications helping patients self-manage their disease or condition (e.g., wellness applications) without providing specific treatment DTx regulations in US FDA Guidance doc: Policy for Device Software Functions and Mobile Medical Applications 8

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10. FDA approval pathways: Digital Health is regulated by the Center for Devices and Radiological Health ("CDRH") Many products follow a traditional medical device regulator pathway: 510(K) for devices that have a predicate device. Examples: WellDoc , Voluntis and Palo Alto Health Sciences De Novo for novel devices CDRH has established the Digital Health Innovation Action Plan ("DHIAP") which outlines the pathway for approval for new digital health products In 2017 the CDRH launched a pilot program known as the Digital Health Software Precertification ("Pre- Cert") program in an effort do establish a new regulatory framework for digital health Program is for products that develop software-as-as-medical device (" SaMD ") Focused on the technology developer, and then the specific product July 2019: Pear Therapeutics submitted the first application for FDA marketing authorization through the pre- cert program for Somryst , a digital cognitive behavioral therapy for the treatment of adults with chronic insomnia and depression 10

11. Example Somryst ®  is the first and only prescription digital therapeutic indicated to treat chronic insomnia. Somryst is intended to improve insomnia symptoms by providing neurobehavioral intervention (cognitive behavioral therapy for insomnia – CBT-I) to adults 22 years of age and older with chronic insomnia. 11

12. Example Clickotine , by  Click Therapeutics , is a smartphone app for smoking cessation, designed to deliver the essential features of the US clinical practice guidelines (USCPG) and engineered to engage smokers by personalizing intervention components. The program provides a personalized 8-week program for each patient that can be combined with nicotine-replacement therapy including gum, patch, or lozenges. Some key features advertised as part of the Clickotine app include: Personalized messaging Controlled breathing Real-time social support Replacement distractions Money saved 12

13. DTx regulations in Japan 13 MHLW implemented revision for PMD Act, which established regulations for SaMD (Software as a Medical Device) for the first time. Published the "Guidance for Application of SaMD Approval Adopted IDATEN system to facilitate post-approval updates in Medical devices (incl. SaMD) Released new guidelines for determining whether software constitutes a Medical Device (MD). MHLW and PMDA established offices dedicated to SaMD development (under DASH). IDATEN system: Improvement Design with Approval for Timely Evaluation and Notice DASH: Digital Transformation Action Strategies NOV 2014 MAR 2016 AUG 2020 MAR 2021 APR 2021 13

14. The Software as Medical Device (SaMD) Digital Transformation Action Strategies in Healthcare (DASH) for Japan (also known as "DASH for SaMD") went into effect in 2020. It intends to provide prompt patient access to cutting-edge SaMD by publicising the fundamental review concept, setting up a thorough consultation, arranging an ideal review mechanism, improving the regulatory framework, and allowing for early commercial use.  In March 2021, the "Guideline for the applicability to Medical Devices for SaMD" was released. 14

15. Example Japanese start-up CureApp launched the “CureApp HT Hypertension Treatment Assistance App”, an application to assist in the treatment of hypertension.  Japan’s Central Social Insurance Medical Council (Chuikyo) of the Ministry of Health, Labor, and Welfare approved insurance coverage for CureApp HT. According to data from the Chuikyo, the MHLW estimates that the number of patients using the application is approximately 70,000. 15

16. DTx regulations in Europe The European Federation of Pharmaceutical Industries and Associations (EFPIA) has established a Digital Therapeutics Working Group to provide guidance on regulatory and policy issues related to DTx in Europe. The new German Digital Healthcare Act (DiGA) establishes particular conditions for the use of DTx at the federal level. The Academy of Managed Care Pharmacy (AMCP) established specific criteria for the companies to qualify as DTx during a recent forum to address current market difficulties and possibilities in the field of DTx . 16

17. Regulation (EU) 2017/745 is a directive of the European Union governing the marketing and clinical testing of medical devices intended for human use. Additionally laying the foundation for data usage and protection was the General Data Protection Regulation (GDPR) , which was amended and put into force in May 2018. In 2019, the German parliament approved the Digital Healthcare Act , which enables physicians to suggest digital health apps that the country's healthcare system would cover. 17

18. Regulatory Framework for Digital Therapeutics US EU Japan   Regulatory Agency FDA European Commission PMDA, MHLW DTx Regulation Class II 510(k) or De Novo Class IIa, Ilb Class II Pre-submission Yes No Yes Approval Timeline 9-12 months 2 years 12 months Alternate Pathways Wellness; Exempt; Enforcement Discretion Class I Exempt 18

19. US EU Japan DTx Clinical Data Requirements Sham-controlled RCT generally required RCT generally required RCT generally required for novel devices Clinical Data Portability Must be relevant to US demographics and SOC; Must follow GCP Must demonstrate state of the art Must follow GCP Clinical data must be obtained on Japanese population Government Reimbursement Limited / emerging; additional data typically required  Yes / emerging depending on market; additional data required Yes; Same data may potentially be used International Standards IMDRF Framework ✔ ✔ ✔ IEC 62304 - SDLC ✔ ✔ ✔ ISO 13485- QMS - ✔ ✔ ISO 14971- Risk Management ✔ ✔ ✔ 19

20. Conclusion: DTX is reforming the landscape for new medicines Can significantly influence healthcare delivery Can impact product reimbursement processes Emergence of new data-sharing processes Inception of new payment models Digital therapeutics empower patients, healthcare providers with intelligent and accessible tools for addressing a wide range of conditions through high quality, safe, and effective data-driven interventions. Digital health initiatives are progressing worldwide, driven by market forces and increased focus on digital health across the healthcare ecosystem. Consumer health industry players must overcome any hesitation and uncertainties by considering the basic business model aspects, such as market assessment, differentiation, integration, validation, pricing, marketing, data privacy, and innovation. 20

21. References: Articles: Rassi -Cruz, M., Valente, F., & Caniza , M. V. (2022). Digital therapeutics and the need for regulation: how to develop products that are innovative, patient-centric and safe. Diabetology & Metabolic Syndrome, 14(1), 48. Hong, J. S., Wasden , C., & Han, D. H. (2021). Introduction of digital therapeutics. Computer Methods and Programs in Biomedicine, 209, 106319. Wang, C., Lee, C., & Shin, H. (2023). Digital therapeutics from bench to bedside. npj Digital Medicine, 6(1), 38. Sverdlov, O., & van Dam, J. (Eds.). (2022). Digital Therapeutics: Strategic, Scientific, Developmental, and Regulatory Aspects. CRC Press. Sunyaev , A., Fürstenau , D., & Davidson, E. Creating Patient Value from Implementing Digital Health Technologies and Reimagining Care Pathways. 21

22. References: Regulatory Framework for Digital Therapeutics in the APAC Region | EVERSANA ( Accessed on 28/04/23) us-lshc-digital-therapeutics.pdf (deloitte.com) (Accessed on 28/04/23) Digital therapeutics in healthcare: Reimagining care delivery | Netscribes (Accessed on 2/05/23) 000243106.pdf (pmda.go.jp) (Accessed on 2/05/23) Clickotine https://clickotine.com/wp-content/themes/clicktx/src/assets/images/phones.svg (Accessed on 2/05/23) Digital Therapeutics Regulation for DTx Manufacturers | Orthogonal.io (Accessed on 5/05/23) Introduction to Digital Therapeutics ( DTx ) | Orthogonal.io (Accessed on 4/05/23) Digital Therapeutics Vs Traditional Pharmaceuticals | Orthogonal.io (Accessed on 5/05/23) Home - Digital Therapeutics Alliance (dtxalliance.org) Transforming Global Healthcare by Advancing Digital Therapeutics (Accessed on 2/05/23) Digital Therapeutics ( DTx ) | European Data Protection Supervisor (europa.eu) (Accessed on 2/05/23) Somryst ® - Pear Therapeutics (US) (Accessed on 3/05/23) Japan-Regulatory-and-Reimbursement-Pathways.pdf (dtxalliance.org) (Accessed on 5/05/23) 22 Web Links:

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