Digital Therapeutics: Challenges and Opportunities for the Future

Introduction

Digitalisation has transformed various aspects of human life, including healthcare processes. The pandemic has dramatically accelerated this transformation, prompting national healthcare systems, including Italy’s (Servizio Sanitario Nazionale, SSN), to integrate various digital technologies such as electronic health records, telemedicine, mobile health applications, wearable devices, and artificial intelligence into their operations.

Among the diverse range of products in the wellness and healthcare industry, digital therapeutics (DTXs) have emerged as a notable phenomenon, attracting the interest of regulators, pharmaceutical companies, and investors worldwide. DTXs are software programs designed to treat and alleviate various pathologies, including chronic conditions and psychological and behavioural disorders, by generating and delivering medical interventions that have a demonstrable positive therapeutic impact on the patient’s health, akin to medicines.

DTXs represent a disruptive opportunity for the future, benefiting not only patients and clinicians but also the entire healthcare system. They can address unmet needs and unserved areas in healthcare, thus reducing the pressure on healthcare systems. Additionally, DTXs have the potential to lower the costs of health and social care by preventing hospital visits, improving self-management by patients, or providing remote therapy.

The application of DTXs is becoming increasingly widespread in the EU and across the wider world, with several countries developing health technology assessment and reimbursement pathways, although harmonised standards are still to be developed at the EU level. According to the Digital Therapeutics Market Size Overview by Binariks (May 2023), the global DTXs market is valued at around USD6.5 billion, with USD2 billion in the US alone, and is projected to grow at an average rate of 31.5% between 2023 and 2032. In Europe, the DTXs market is valued at USD612 million, with a projected average growth of 23.4% from 2020 to 2030.

This article focuses on DTXs, their regulatory definition and classification, and development pathways in the EU, with particular attention to Italy’s recent strides to close the gap with other European countries and leverage DTXs to promote the sustainability of the SSN.

Digital therapeutics: definition and scope

Digital therapeutics represent an innovative medical methodology. The term encompasses all technologies delivering evidence-based therapeutic interventions via high-quality software programs to prevent, manage, and treat a wide spectrum of medical disorders and diseases, including those related to behavioural and psychological factors as well as chronic diseases.

DTXs can be considered a subset of digital health, often coupled with artificial intelligence and machine learning systems. However, they differ from common wellness apps or medication reminder tools as they require confirmatory, evidence-based investigation to support their intended use and have a therapeutic effect. Unlike digital medicine, DTXs are not mere monitoring apps or measuring software supporting patients and clinicians; they provide medical treatment based on clinical evidence, have a clinically relevant effect on patient health, and produce real-world outcomes.

DTXs share similarities with traditional pharmaceutical products. In classical pharmacology, the active principle is a chemical or biological molecule, whereas, in DTXs, it is a digital algorithm responsible for the clinical effect, whether positive (clinical benefit) or negative (undesired effect). The excipients include various functions that facilitate the administration of the (digital) therapy, such as rewarding or “gamification” tools introducing elements of fun or gratification into the interaction with the patient, reminders, remote assistance modules connecting patient with healthcare personnel or other patients affected by the same disease, and chatbots or virtual assistants.

While pharmacological treatment interacts with a patient’s biology, DTXs achieve their therapeutic effect through interaction with the patient’s thoughts and through correction of dysfunctional behaviours. A key characteristic of DTXs is the active involvement of the patient and/or caregiver, crucial to the success of the treatment pathway. DTXs can work independently (standalone DTXs) or in conjunction with drugs, devices, and other therapies to optimise patient care and health outcomes (companion and combination DTXs).

DTXs utilise various digital health tools: apps, web-based interventions, video games, virtual reality, and hardware components such as wearable measurement devices. These digital interfaces also play a key role in therapy accessibility, treatment adherence, and therapeutic outcomes.

DTXs can address a variety of diseases, ranging from chronic diseases such as diabetes or respiratory diseases, to behavioural and psychological disorders such as anxiety, depression, obesity, insomnia, dementia, addiction (smoking, alcohol, drugs), learning disabilities, and attention deficit disorders.

Digital therapeutics: an unprecedented opportunity for Italy

Italy has the highest average age among European countries and this places a burden on the country’s healthcare sector, with around 50% of people aged 65–75 suffering from chronic diseases. The pandemic has also exacerbated mental disorders among the younger population, highlighting the urgent need to develop, adopt, and implement strategies to manage, treat, and care for chronic health conditions and address unmet healthcare needs.

DTXs could be a strategic tool for Italy for several reasons: they could enhance clinical efficacy by promoting new forms of patient and caregiver engagement, open new development opportunities for the Italian life sciences sector, and significantly contribute to the efficiency and sustainability of the SSN by alleviating pressure from chronic illness management and reducing patient waiting lists.

Furthermore, Italy has the potential to become an international hub for the development and manufacture of DTXs. The DTXs sector largely comprises small and medium enterprises (SMEs) with strong territorial connections, suited to innovative system research and development due to their lean organisational structure built around a few highly skilled experts. SMEs account for over 90% of Italy’s entrepreneurial undertakings, with increasing public expenditure support since 2015. Italy is also a centre of excellence in information and communication technologies (ICT) and life sciences.

This scenario shows that Italy is conducive to collaboration between multidisciplinary teams to develop innovative solutions. An ecosystem with active healthcare and social services, complemented by institutions and enterprises in the life sciences and digital sectors, is essential for DTX development.

Digital therapeutics in the EU: regulatory classification and main pathways for assessment and reimbursement

Despite their potential benefits, the use of DTXs in the EU is still limited, although significant progress has been made in integrating DTXs into market access and care pathways in some member states.

From a regulatory standpoint, in most EU member states, DTXs are generally classified as medical device software (MDSW) under Medical Device Regulation (EU) 2017/745 (MDR). Under Article 2 of the MDR, medical devices include software intended by the manufacturer to be used, alone or in combination, for specific medical purposes such as diagnosis, prevention, monitoring, prediction, prognosis, treatment, or alleviation of diseases or disabilities. As MDSW, DTXs must comply with the MDR’s efficacy, security, and certification requirements, including CE marking by a notified body for commercialisation.

However, the MDR does not specifically regulate DTXs, and the general provisions on MDSW do not always capture the peculiarities of digital therapies. This results in a lack of harmonisation among member states in interpreting regulatory requirements and evidentiary standards for DTXs’ value assessment, which is crucial for reimbursement decisions. Despite these challenges, several countries have successfully implemented pathways for DTXs’ assessment and reimbursement, serving as models for policymakers and regulators in Italy.

Germany pioneered market access pathways for DTXs with the Digital Healthcare Act (Digitale Versorgung Gesetz, DVG) in 2019. The Act established a “fast-track” process for qualifying apps (“DiGA”). Upon successful assessment within three months of application, DTXs are included in a central directory of digital health applications, making them eligible for reimbursement, albeit currently limited to standalone DTXs with low-to-medium risk (MDR Class I and IIa).

Belgium offers another example with “mHealthBelgium”, a platform launched by the federal government collecting apps CE marked as medical devices. Apps in the platform are classified according to a three-level validation pyramid. Only apps at level 3, for which “added socio economic value” can be provided, are eligible for definitive reimbursement by the National Institute for Health and Disability Insurance.

France has also implemented a new fast-track market access path for digital medical devices (including DTXs) of all risk classes and telemonitoring solutions (Prise en Charge Anticipée, “PEC-AN”) since 31 March 2023. DTXs can receive temporary reimbursement for one year without conclusive clinical evidence, provided they meet initial prerequisites such as CE marking under the MDR; technical certification on cybersecurity, interoperability, and GDPR standards; clinical outcome evaluation for a full year; and a sufficient display of innovation in terms of patient care enhancement or healthcare system improvements. Approved applicants can then complete the evidence file and apply for inclusion in the standard reimbursement process to receive coverage for several years.

Digital therapeutics in Italy: the evolving scenario and development of a legal framework

First steps towards recognition of DTXs’ value

In line with experiences in neighbouring European countries, Italy began an in-depth debate in 2019 involving national agencies, academic institutions, research centres, networks of experts, and the Ministry of Health to address DTX-related issues.

The 2021 National Recovery and Resilience Plan (NRRP), designed for post-pandemic economic recovery, emphasises community-based care and healthcare digitalisation. This includes the development of a telemedicine platform capable of integrating, and interacting with, a catalogue of digital health services, such as DTXs, which can be implemented at both the national and regional levels. Digital health is a key pillar of the NRRP, with EUR1.6 billion allocated to its Mission 4: education and research. Furthermore, the national guidelines on tele-rehabilitation services approved by the State-Region Committee in November 2021 recognise DTXs as “enabling technologies”.

As at time of publication (June 2024), around 13 Italian companies, including innovative start-ups and SMEs, are involved in DTX production and development. Out of 28 Italian digital tools classified as DTXs, 21 are in development and seven are recognised as Class I medical devices.

The regulatory landscape

Despite the insightful debate and increasing interest in DTXs, Italy has yet to produce specific regulations or adopt development and reimbursement pathways for these products.

However, the growing recognition of DTXs’ therapeutic value and cost-effectiveness for the sustainability of the SSN has prompted national regulatory institutions and legislators to focus on DTX development and its “place in therapy”, creating the organisational, regulatory, and financial conditions for Italy to catch up with other EU member states.

A significant step was the creation of a Parliamentary Intergroup on DTXs in May 2023, aimed at fostering rapid regulation, recognition, and dissemination of DTXs in Italy. Additionally, a bill concerning “Provisions on digital therapies” was submitted to the Italian Chamber of Deputies. The legislative proposal aims to align Italy with other EU states like Germany, where DTXs have been operational for years. The bill, which consists of four articles, sets out guiding principles for the inclusion of DTXs into the essential care levels that the SSN must provide to all citizens free of charge, thereby facilitating their reimbursement process.

Article 1 provides a legal definition of DTXs, partially reflecting the definition introduced by the International Organization for Standardization (ISO) in the document ISO/TR 11147:2023 concerning “Health informatics — Personalized digital health — Digital therapeutics health software systems”. DTXs are defined as “software mediated by therapeutic interventions with a specific therapeutic indication and designed to prevent, manage, or treat a medical disorder or disease by changing patient behaviour with the aim of improving clinical outcomes”. The bill clarifies that DTXs, like medicines, have an active ingredient and excipients, but in a digital form. The active ingredient is a therapeutic algorithm responsible for the clinical outcome, while excipients (virtual assistance, reminders, and reward services) are classified as “value-added services” necessary to ensure the best patient experience and long-term use of the therapy.

In line with most EU states, the bill confirms that DTXs, due to their nature, purposes, and mechanisms of action, should be classified as medical device software (MDSW). As such, they fall under the purview of the MDR and must be CE-marked for commercialisation.

The bill, in its current form, delineates a select number of application areas, encompassing cardio-metabolic diseases, endocrinology and diabetology, neuroscience and mental health, respiratory diseases, and rehabilitation. However, it is plausible that the proposed law will eventually incorporate a provision for conducting systematic reviews and meta-analyses of scientific literature. This would serve to identify those medical areas and diseases for which there is substantial evidence of effectiveness.

Articles 2 and 3 of the bill propose establishing ad hoc bodies to accelerate DTX evaluation and monitor their adoption in Italy. Under the provisions of the bill, an implementing decree will mandate the Ministry of Health to establish a ten-member DTXs Evaluation Committee. This committee, chaired by a representative from the National Agency for Regional Health Services (AGENAS), will be tasked with drafting preliminary guidelines for the fast-track evaluation of DTXs for inclusion in the “essential levels of care”, a prerequisite for their reimbursement. To keep pace with the ongoing evolution of DTXs, the proposal commendably empowers AGENAS to create a Permanent Observatory for DTXs to regularly monitor the scientific and technological advancements of these therapies, reporting annually to the parliamentary chambers.

The concluding article of the bill addresses the key regulatory aspects, with special focus on DTX reimbursement. As stipulated by the bill, AGENAS will be tasked with identifying the digital therapies that qualify for inclusion in the essential level of care (ELC) via a fast-track process, similar to the systems currently in place in Germany and France (as discussed above).

Furthermore, the bill stipulates that for DTXs to be considered for inclusion in the ELC, they must undergo a minimum of two clinical trials that yield “high quality evidence”. While the bill does not detail the nature of these studies, it is noteworthy that the first DTXs Monitoring Report, presented by the Parliamentary Intergroup in October 2023, provides certain guidelines on evaluating DTXs for reimbursement. The Report explains that DTXs must meet high standards, including robust scientific evidence of clinical safety and efficacy. The Parliamentary Intergroup suggests that the clinical evaluation of DTXs should commence with a pilot study as an exploratory phase, which should then be followed by a pivotal study. The robustness of such studies will be evaluated based on key criteria, including randomised clinical trials, patient involvement during the development phase, and publications in peer-reviewed scientific journals.

Undeniably, the bill represents a positive shift in Italy’s stance on the matter, paving the way for an imminent ad hoc regulation for DTX assessment and market access. However, it is anticipated that over the coming months, the bill will undergo various modifications and amendments to address several critical and as yet unresolved aspects. These include defining a health technology assessment (HTA) process for DTXs and determining the extent of the Italian Medicines Agency (AIFA)’s involvement in this process.

In November 2023, AGENAS, in collaboration with Farmindustria (Italy’s primary pharmaceutical industry association), launched a project to develop an HTA framework and specific regulatory guidelines for DTX reimbursement, thereby enabling patient access to effective therapies. The project’s rationale is to establish an HTA pathway for each DTX, similar to pharmaceuticals, and to define criteria for assessing their additional therapeutic value, health gain, budget impact and cost-effectiveness. This is aimed at ensuring that informed decisions are made regarding procurement, reimbursement and use. The working group’s conclusions, along with the monitoring of the effects resulting from the implementation of the EU’s Health Technology Assessment Regulation (2021/2282), which will be applicable from January 2025, will be crucial in refining the bill and advancing its approval process. They will also aid in the identification of a catalogue of DTXs that can interact with, and be integrated into, the national telemedicine platform.

Additional barriers to DTX development in Italy

Beyond the need to define a clear regulatory framework for approval, assessment, and reimbursement of DTXs, there are additional legal, technical, and cultural barriers that hinder their adoption and integration into clinical practice. These barriers need to be addressed to fully harness the potential of DTXs.

Firstly, DTXs enable the collection, processing, analysis, and easy sharing of sensitive patient health data with clinicians, healthcare providers, insurance companies, cloud storage providers, family members, and others. Access to, and use of, such data raises complex legal issues related to patient privacy, the responsibilities of those treating the data, and the measures to ensure compliance with the GDPR (EU Regulation 2016/679). Additionally, since DTXs combine a medical device with software distributed on a complex architecture (mainly a DTX application installed on the user’s mobile device and a cloud data storage platform), they are at high risk of cyber-attacks. These attacks could lead to the theft, corruption, loss or unauthorised disclosure of data, as well as illegal access to such data and privacy violations.

In Italy, there is an ongoing and in-depth debate over adequate measures to protect patient privacy and ensure the safety and integrity of data.

Regarding the processing of personal data acquired through digital therapies, preliminary indications from the Italian DTX Monitoring Report 2023 suggest that the healthcare facilities which provide the service and clinicians are generally considered to be data controllers. It is debatable whether the medical device manufacturer should be classified as a data processor. The division of roles between the medical device manufacturer and the healthcare operators (data controllers versus data processors) is expected to be clarified through regulatory reviews or interpretive guidelines issued by the Italian data protection authority. Indeed, there could be instances of co-ownership of data processing responsibilities due to distinct activities such as post market surveillance or healthcare providers’ access to patient data to evaluate the effectiveness of a given therapy/treatment.

Concurrently, the Italian scientific community is working on guidelines to counteract cyber threats by providing security controls for information processed by DTX systems. These guidelines could integrate the security practices and principles established for medical devices by the Medical Device Coordination Group (MDCG) in their 2019 Guidance on Cybersecurity for Medical Devices and the document issued on 18 March 2020 by the International Medical Device Regulators Forum (IMDRF), with models reflecting the ISO/IEC 27000 standards family.

From a different perspective, a cultural shift is necessary to promote the use of DTXs in Italy. Healthcare providers require specific training to properly prescribe DTXs to their patients. Patients, meanwhile, need to be educated about DTXs to effectively engage with them. Furthermore, DTXs necessitate professionals with specialised skill sets to collect and analyse the data, as well as to monitor the proper functioning of the devices and applications. Italy, being a country with low appetite for change, still lacks full awareness of the potential value of DTXs. There are also challenges in making digital solutions interoperable with current digital and data collection systems in addition to basic infrastructure shortcomings. A synergistic effort by policymakers, developers, and stakeholders is therefore required to improve investment in digital infrastructure and to provide education about DTXs, which is critical for building trust in emerging technologies.

Conclusions

In a world where care delivery is increasingly patient-centred, data-driven, and reliant on real-time information, DTXs offer alternative therapeutic options that have the potential to significantly enhance the overall quality of care, providing substantial benefits to both patients and clinicians. These technologies enable a more comprehensive patient management approach, tailored to individual needs, while simultaneously facilitating real-time data collection and analysis, and ultimately leading to improved continuous monitoring of treatments and patient responses. Furthermore, with pertinent patient information readily available, physicians can practise more efficiently, significantly reducing patient waiting times.

Healthcare systems can also benefit from integrating DTXs into their care processes, aiming to address unmet needs and reduce the health and social costs associated with many pathologies. Healthcare systems, such as Italy’s, which are grappling with an aging population and increased demand for healthcare due to chronic diseases, could greatly benefit from the use of such technologies.

While DTXs represent a promising innovation in the field of digital medicine, particularly in the medium to long term, their use raises complex legal, social, organisational, and ethical challenges that need to be adequately addressed for their deployment. These challenges extend beyond the need for rigorous clinical evaluation and regulation in terms of approvals and reimbursement, to include issues related to data privacy and security, the digital divide, health equity, and the reliability and validity of machine learning algorithms.

Significant progress has been made in several EU member states to provide market access and reimbursement pathways, despite the absence of harmonised standards. Particularly noteworthy are the advances in Italy, where policymakers, regulatory authorities, and the scientific community are actively working to establish a simplified regulatory framework in line with the models developed and the regulations established in other EU states. This framework allows for rapid validation and reimbursement of DTXs, along with a clear definition of the level of evidence required for recognition of products already approved in other healthcare, epidemiological, and cultural settings.

In the coming months, it will become clear whether the efforts made so far will yield the desired results. This includes enabling developers and companies to bridge the “valley of death” between incubation and commercialisation of DTXs, allowing the healthcare system to integrate such disruptive innovation into clinical practice, and providing investors with a reliable framework for their funding.