Patient access to new digital therapies: challenges and opportunities of digital therapeutics in the EU

Elisa Stefanini

Portolano Cavallo, Milan

estefanini@portolano.it

Claudio Todisco

Portolano Cavallo, Milan

ctodisco@portolano.it

Introduction

The popularity of digital therapeutics (DTx) in increasing worldwide. In the United States, the Food and Drug Administration has already approved several DTx, some of which are reimbursed by health insurance or covered under corporate benefits, while others are paid for by patients, often through subscription. In the EU, Germany is the leader in regulation and reimbursement of DTx. In 2019, the Digital Healthcare Act (DIGA) introduced fast-track assessment of DTx reimbursement. Similarly, France and Belgium are also implementing DTx reimbursement systems, while in Italy a bill for DTx regulation was presented to Parliament in June 2023 but to date, it has not become law.

Nevertheless, the use of digital therapies in the EU is still limited. One of the main reasons is the lack of an adequate and uniform regulatory framework, from the clinical and technological evaluation of digital therapies to their authorisation and possible reimbursement by various countries’ health and insurance systems.

Digital therapeutics: definition and main features

There is no legal definition of digital therapeutics within the EU. Therefore, we must refer to a definition provided in December 2023 by the ISO standards, as: ‘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.’ (ISO/TR 11147:2023).

In particular, DTx are a subset of medical device software. They are health software classified as medical devices in consideration of their medical purpose demonstrated in clinical studies. They are also, in turn, a subset of the broad area of health software, which includes health apps, telehealth and telemedicine, and a wide range of health information technologies used by patients and healthcare providers.

DTx can be used independently (‘stand-alone software’) or in combination with medicines, devices, or other therapies, provided that the software is the driving component of the therapeutic effect. Indeed, DTx comprise a digital active principle (the therapeutic algorithm responsible for the clinical outcome) and digital excipients such as, for example, services to remember to take the pills or virtual assistants or other support functions as remote assistance from healthcare personnel or even chatbots and virtual assistants, aimed at keeping the patient engaged.

Classification and validation issues

As stated above, from a regulatory point of view, DTx are categorised as medical devices under the definition in Regulation (EU) 2017/745, MDR. This is the Guidance issued in October 2019 by the Medical Device Coordination Group which is particularly relevant for their classification, especially in addressing borderline cases where classification is unclear.

As with any other medical device, the regulatory path to validate DTx in the EU depends on their class. Indeed, according to the MDR (Rule 11), medical device software is divided into four categories based on risks associated with its intended use: from Class I (low risk) to Class III (high risk).

Class I devices only require a self-declaration of the manufacturer for the purpose of the CE mark, while all the other classes require involvement of a notified body in assessing the devices.

The MDR explicitly classifies two categories of medical device software: (1) software intended to provide information which is used to take decisions with diagnosis or therapeutic purposes (Class IIa or IIb or III, depending on the seriousness of the potential consequences on a person’s health); and (2) software intended to monitor physiological processes (Class IIa or IIb, depending on potential impact on patient health. All other software fall within Class I.

Therefore, as software with therapeutic purposes are not specifically mentioned, it could be argued that DTx fall under Class I and indeed many DTx on the market are classified as Class I. However, it seems questionable that highly innovative software with massive potential impact on patients’ health (especially in certain therapeutic areas where the risk could be actually high) are not assessed by a notified body. To date, the risk classification of DTx is still an open point and it is also likely to be affected by any possible choice taken at national level on the requirements for the reimbursement.

The classification system is only one of the main areas of doubts around the DTx validation process. There are other concerning issues, including:

• How to address the rapid developments and changes of DTx​

As with all software, DTx have rapid cycles of innovation and development that can result in many software upgrades. Legislation needs to be able to address these cases without requiring continuous assessments.

• Lack of harmonisation

Another major challenge is the lack of harmonisation of other regulations applicable to DTx, with particular regard to the data protection regulation. Indeed, in addition to EU GDPR, several Member States have further regulatory requirements related to security and privacy, in particular concerning the need of consent for any secondary use of the data. The topic is very sensitive in Italy where data protection requirements are particularly restrictive This could result in a big obstacle to the research and development of these digital therapies.

• The absence of an EU standardised framework for value assessment

As such an assessment is conducted at a national level, the evidence needed for DTx may vary from one country to another. For instance, it is not always clear what type and how many clinical investigations are needed for the purpose of having the product reimbursed by national health services. For example, German authorities require local clinical studies and the draft Italian Bill on DTx requires at least two clinical studies with high quality evidence. In the long term, the value assessment of DTx could also be affected by the implementation of EU Regulation on HTA which will apply from January 2025.

DTx based on Artificial Intelligence: new challenges from the AI Act

Future DTx regulation will also be full of new challenges. In particular, the interplay between the MDR and the brand-new Artificial Intelligence Act (AIA), which should be published shortly, although its application is delayed of a couple of years.

Indeed, according to the AIA, most of the medical devices based on AI systems – and this is generally the case of DTx – are likely to be classified as high-risk systems.​ This means that the requirements for AI systems set out in the AIA will be checked as part of the existing conformity assessment procedures under the MDR, so that the issuance of the CE certification by the notified body will certify that all the assessment, including those related to the safety of the AI system have been successfully performed. This may raise some further challenges. For instance, assessing the compliance of software as medical devices based on AI systems requires special knowledge and technical expertise, which might be lacking within the notified bodies.

It also triggers additional complications from a data protection perspective. This is because notified bodies should be required to check the quality and the accuracy of the input data according to the AIA, yet it is unclear how deep their investigation on the compliance of certain GDPR requirements can go, especially when data refers to non-EU patients.

Finally, it is very likely that the increased scope of the assessment may have an impact on the timing and cost of the certification of the device.

Reimbursement of DTx in the EU

Reimbursement is a matter addressed at country level in the EU and widely depends on the availability of funds to dedicate to DTx.​ ​There is no standardised reimbursement route for DTx in most EU countries​. In some countries, there is no reimbursement at all, while in others some progresses has been made on this matter.

Germany is in the lead in this area both in the number of applications relating to digital therapeutics currently authorised and reimbursed by German health insurers, and for having equipped itself as of 2019 with a simplified procedure for the evaluation, approval, and reimbursement of such technologies, albeit limited to standalone therapies only with low to medium risk.

There is a similar situation in Belgium, where since 2021 DTx can be reimbursed by the National Institute for Health and Disability Insurance. France adopted a procedure for the reimbursement of DTx in 2023. The procedure allows temporary reimbursement (for one year) for certain types of DTx which may become permanent provided that objectives are reached concerning the proof of clinical and/or organisational benefits.

In Italy, on the other hand, ad hoc rules for the use of DTx are currently lacking, although an ad hoc Bill for regulation of DTx was tabled in June 2023. Since these are medical devices, the Ministry of Health currently oversees the matter, starting with issuing authorisation for clinical investigation for the purposes of CE marking. Questions remain as to whether the AIFA or the Ministry of Health should oversee evaluation for the purposes of reimbursement.

To date, two digital therapies are being tested in Italy that have been given the green light by the Ministry of Health.[1] The first is KidneYou, an application developed by AstraZeneca and AdvicePharma for the treatment of CKD (chronic kidney disease) which delivers therapeutic intervention for the management of patients’ eating and exercise habits by constantly monitoring their health status. The second is DTxO, a digital therapy for outpatient obesity management, developed by AdvicePharma with Theras Lifetech. It provides customised diet plans, advice, exercise programmes, assessment programmes, and cognitive-behavioural support, sometimes using gamification techniques.

Other issues around the development of DTx

From a factual perspective, there are other main challenges relating to the development of DTx in the EU. For instance, it has been highlighted that there is a low awareness and recognition of the DTx value among doctors. Indeed, current evidence suggests that health and care practitioners (HCPs) are reluctant to prescribe DTx (eg, a German study found out that within the first 12 months after DiGA’s implementation, only 14 per cent of eligible HCPs had prescribed at least one DiGA). Therefore, the education and training of doctors will be particularly important in spreading the use of DTx.

Another major issue concerns the inadequacy of IT infrastructures in many countries, especially in terms of interoperability of systems used in the healthcare sector. In Italy this is a big challenge, as the healthcare system is organised at regional level and there are 20 Regions, each with its own electronic system with huge problems of interoperability with the others. Of course, this situation does not help the development of digital therapies and their integration in day-to-day patient care.

EFPIA’s recommendation to support DTx in Europe

A recent report issued by the European Federation of Pharmaceutical Manufacturers & Associations (EFPIA)[2] has analysed the main obstacles to the development and spread of DTx in Europe. This report concludes with a number of possible recommendations, in particular:

• The harmonisation of the rules for scientific and technological assessment of digital therapies in the various EFPIA Member States by means of a flexible approach that takes into account the specific technology (starting with its rapid and constant evolution, which means the therapeutic software/algorithm is subject to frequent updates) and overcomes the existing disparities between the various national legislation, including in terms of the treatment of the data collected. The implementation of the new Regulation (EU) 2022/2282 on Health Technology Assessment procedures, applicable as of January 2025, marks a major step towards establishing uniform DTx assessment criteria.
• Setting up early access pathways to DTx therapies by EFPIA Member States, including when their experimental evaluation is pending. In addition to fostering dissemination and awareness of DTx among patients and healthcare professionals, this would enable the collection of data on standard administration of the therapy (ie, real world data collected outside the experimental context). That data could support clinical investigation activities aimed at marketing. A similar procedure already exists for medical devices, including under certain conditions (urgency, necessity, and unavailability of similar devices on the market) the use of medical devices without CE markings.[3] However, this is an exceptional procedure subject to very strict requirements.
• Definition by EFPIA Member States of a separate reimbursement paths for DTx, whether they are standalone or used in combination with drugs (in the latter case, one possibility is a unitary reimbursement covering the cost of the drug and the digital therapy), also establishing specific criteria for the prescription of treatments by medical personnel, as distinguished from therapies that can be provided to patients without the involvement of a doctor (similar to over-the-counter medicines). This should be accompanied by joint initiatives by the various stakeholders (institutions, healthcare personnel, associations, and companies) designed to promote awareness of these new tools and provide information on their correct use and their potential for efficient and effective treatment.