Digital therapeutics in Europe: what is the state of play?

Italy is accelerating developments in the field of digital health: the Parliamentary Intergroup Digital Health and Digital Therapeutics, set up in May 2023, introduced in June an initial bill on digital therapeutics (otherwise known as DTx).

But what are digital therapeutics, what is the current development scenario and the regulatory framework? 

What are DTx?

At international level the most widely used definition is that proposed by the Digital Therapeutics Alliance, an association that brings together the main manufacturers and stakeholders of digital therapeutics solutions:
"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."
 

At national level, noteworthy is the definition developed by Farmindustria (the Italian Association of Pharmaceutical Companies) within its Working Paper, published in May  2023, which defines DTx as:
"therapeutic interventions guided by software programs, based on scientific evidence obtained through methodologically rigorous and confirmatory clinical trial, to prevent, manage, alleviate or treat a wide range of disorders and diseases".

There are two different types of DTx:

• DTx in standalone modality, that is, where the DTx become the only way to deliver a therapy. For example, the digitalisation of cognitive behavioural therapy (CBT).
• DTx in plug-in modality, that is, the DTx are used in combination with a medicine (or its operating device, if any) with the aim of enhancing the therapeutic action of the medicine itself, but also monitoring the adherence to the therapy and/or managing any undesirable effects.
   

DTx, in a similar way to medicines, are composed of an active ingredient and digital excipients (components that are able to facilitate the intake). The only difference lies in the digitisation of these components. Consequently, the active ingredient will be an algorithm and the excipients will be  various forms of interface with the user that are capable of enhancing the "bioavailability" of the relevant DTx (such as forms of virtual assistance, reward modality of the patient, reminders, communication channels with their own physicians).

Moreover, DTx go through a clinical evaluation phase that proves their efficacy and safety compared to their declared therapeutic indications.

DTx, finally, show some potentialities connected with working on a digital active ingredient. The chemical or biological active ingredient for traditional medicines must not be modified during the life cycle of the medicine, whereas the digital active ingredient (the algorithm)  can be updated as a result of new evidence generated through new clinical trials in the post-approval period, so as to obtain further therapeutic benefits. This is an important potentiality, whose compliance with the applicable legislation (especially with regard to the protection of patient privacy) will, however, have to be carefully examined.

What are not DTx?

Health apps, or software that allows certain functions to be performed (mainly informative towards patients) which consequently do not require scientifically-based evidence to demonstrate their validity, are not digital therapeutics.

So-called wearable technology (for example, smartwatches) used to collect a whole series of vital parameters would also not amount to digital therapeutics.

Telemedicine or situations in which a physician uses various innovative technologies to deliver health care to the patient, who is not physically in the same place as the physician (tele-visits, tele-consultation and tele-health) is also a separate category and cannot be considered as digital therapeutics.

When can it be useful to use DTx?

If Italy is still on the starting blocks, not so the rest of the world. There are, indeed, a lot of DTx already  approved at international level (for an overview see "L'osservatorio trimestrale DTx Monitoring" published by Indicon) that can be used for the treatment of a wide range of diseases and disorders such as: 

• anxiety;
• depression;
• substance/opiate dependence;
• nicotine dependence;
• obesity and eating disorders; 
• insomnia;
• asthma and chronic obstructive pulmonary disease (COPD);
• high blood pressure;
• diabetes mellitus.

The legal framework

DTx are considered medical devices and, as such, fall within the scope of application of Regulation (EU) 2017/745 on medical devices (MDR). The MDR, however, does not include any express reference to DTx creating, consequently, a lack of regulation. This could be remedied through an extensive interpretation of the concept of software, which is already considered as a medical device by article 2, paragraph 1 of the MDR.

An extension of the regulatory framework provided for medical devices to DTx, could:

• increase the confidence of healthcare workers in these new technologies, with a related increase of the number of prescriptions;
• allow the reimbursement charged on the Italian national health service (NHS) and the participation of DTx in public tenders. 
   

At national level an uncertainty with regard to the competence profile is added to a European framework that is already so confused. For instance, the question arises whether:

• DTx fall only into the category of medical devices and as such under the competence only of the Italian Ministry of Health;

  or

• it is necessary to have the participation of the Italian Medicines Agency, especially with regard to DTx in plug-in modality (concerning the evaluation of reimbursement of the cost which is borne by the Italian NHS, and the determination of the price).

A pioneering country in Europe: Germany 

Through the Digitale-Versorgung-Gesetz (DVG) which came into force in December 2019, Germany has become a forerunner in Europe with regard to the possibility of prescribing, and above all reimbursing, DTx. 

The DVG has provided for the possibility of physicians to prescribe DTx to patients (see paragraph §33a, book V of the Sozialgesetzbuch (SGB)) guaranteeing at the same time the reimbursement through the state insurance mechanism, the Gesetzliche Krankenversicherung (GKV).

In order to be prescribed and consequently reimbursed, the DTx  must be included in a special list, the DiGA (digitale Gesundheitsanwendungen), upon positive evaluation by the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), the German regulatory authority that carries out functions similar to those of AIFA in Italy (paragraph § 139e, book V of the SGB).

At present, there are 55 DTx listed in the DiGA, and the number is growing – in December 2022 there were 33. Further information is available here.

The Italian experience 

The widespread use of DTx in Italy is on the starting blocks and limited by several factors. We spoke about this with Dr Alessandro Ferri, president of Advice Pharma, an Italian company that develops IT engineering solutions and provides services in the medical-scientific field.

Among the main obstacles, Dr Ferri identifies "the lack of a regulatory framework as a major obstacle to market entry for products and companies that would already be ready to invest in the sector." The simplest way, he adds, "would be to consider DTx only as medical devices and therefore not subject to the competence of AIFA for the purposes of assessing reimbursability and price, but in Italy there seems to be an intention to consider DTx as something additional to medical devices, based on the fact that DTx manage a service/care process. A profile that I do not feel is totally wrong." . A further hypothesis would be the establishment of an ad hoc body dedicated exclusively to DTx but this "might lead to further delays to the entry into the Italian market of DTx, damaging, above all, Italian patients who would not have access to devices already available in other countries."

While on the one hand the Ministry and the regulatory authorities are willing to talk about DTx, on the other, they are struggling to define a synthesis and an action plan with a definite timeframe. Dr Ferri recalls that "the use of DTx is not aimed at patients who can only be treated/cured by drugs (think of oncological diseases):  they are products that represent an efficiency, a digitalisation of already known treatment paths, guaranteeing benefits that are scientifically proven through a path of clinical trials."

This is in contrast to the position in Germany, where from the outset, the competent regulatory authority has followed a clear path. In a short time it has defined a regulatory framework and the necessary resources have been allocated. The German healthcare system is now already in the second phase of the problem: "only a few  physicians actually prescribe DTx. What seems to be lacking is a material action that allows prescribing physicians to have sufficient scientific information and, therefore, the confidence to prescribe digital therapeutics. The fact that, for DTx to function, a part of the activity is dematerialised, does not exclude the need to demonstrate their therapeutic efficacy, as is the case for medicines and other medical devices, by providing complete and correct information to healthcare professionals. DTx are real therapies, they are not mere patient monitoring devices, and as such they must be communicated. This makes us believe that the participation of pharmaceutical companies, alongside the medium-small or start-up companies that were the first to move into this field, is essential for the development of DTx".

Another crucial issue is that of liability, in the light of the enormous amount of data that DTx generate. Dr Ferri notes that "the patient must be aware of the fact that the physician cannot actively monitor the data 24/7 together with that of all the other patients under their care. Therefore, the companies producing the DTx have to give the patients correct and complete information in this regard, for example at a contractual level, providing an appropriate disclaimer, and identifying, at the same time, according to the disease/disorder subject of therapy, suitable procedures for the management of any adverse events. The challenge is to guarantee that the physician does not incur risks as a result of having to handle such a considerable amount of data, and that, at the same time, the patient receives treatment and the necessary care".

Osborne Clarke comment

The pandemic experience has shown that one of the biggest difficulties for the Italian NHS (especially in some regions) has been the lack of flexible mechanisms that would allow the management of less seriously ill patients outside hospitals. 

Starting from this assumption, the PNRR (the National Recovery and Resilience Plan) has among its objectives the strengthening of territorial assistance making "the home the first place of care" and consequently increasing the number of patients having care at home, while reducing the need for emergency department access, hospitalisation, and risks connected with it (considering the whole topic of nosocomial infections and related damage). 

If the new face of healthcare is this, then it is not clear why obstacles should be created to the entry of DTx into the Italian healthcare system. In particular, considering that:

• DTx act to digitalise therapeutic pathways already known and widely tested;
• DTx do not pretend to intervene in diseases that can be treated only with medicines, but on disorders often connected with a psycho-physical sphere;
• DTx, while taking note of the existing change in the physician-patient relationship, do not negate the role of the physician, who is still called to support the patient along the treatment pathway (at this point, digitalised).

Companies are ready to innovate and now it is the task of the institutions to decide whether to run with the ball or not. If they decide to play (as seems to be the case),  they must be ready to implement a strategy that allows the match to be won and not to get stuck in an interminable Italian-style tournament (as often happens).

This is the first in a series of Insights dedicated to the development in Italy of digital therapeutics with the aim of analysing their potentiality and importance, and considering the opinions of various stakeholders.