Research & Development of Digital Therapeutics
Digital Therapeutics (DTx) are an emerging class of medicines that deliver evidence-based therapeutic interventions to patients.
DTx are based on high quality software programs to prevent, manage or treat a broad spectrum of physical, mental, and behavioural conditions1.
DTx form an independent category of evidence-based products within the broader digital health landscape, and are distinct from pure-play adherence, diagnostic, and telehealth products2.
In a similar way to the drug, we can identify in the composition of DTx both active ingredients and excipients, in a digital form.
While the “digital active ingredient” is primarily responsible for the clinical benefit, “digital excipients” (virtual assistant, Natural Processing Language systems, digital reward systems, digital medicines reminders, connection with the doctor, connection with other patients, clinical record form, etc.) are necessary to ensure the best user experience to the patient and to allow the prolonged use of the therapy (digital bioavailability).
In order to allow interaction with patients, the digital active ingredient and digital excipients must take a patient facing digital form, as a smartphone application, a videogame, a virtual reality program and others.
Although there are many similarities with the drug Research & Development (R&D) process, DTx R&D is characterized by some specific aspects that must be considered both in the design phase and in its execution.
The first step of the DTx R&D is performed in the “pre-clinical laboratory environment” and consists in the development of the therapeutic intervention to be submitted to the subsequent digitization.
This intervention can be selected from the scientific literature (as for many cognitive – behavioral therapies already undergoing clinical trials in the “analogue version“) and converted to digital format, as a different way to deliver an existing therapeutic intervention (as pointed out by a recent review of a DTx3).
A different approach consists in the ex novo elaboration of a therapeutic intervention, using elements of therapies described in the literature that are combined with each other on the basis of the personal experience of the experts (patients4 , specialists, practitioners, other) involved in this phase of research.
The combination of digital active ingredient and digital excipients, in a digital form suitable for the best use by a patient, is the output of this pre-clinical phase of development.
Once the first version of the software in its digital form is obtained, the clinical development starts. The pilot development aims to produce the data and information that will allow an appropriate assessment of the opportunity to continue the development of the therapy. Since full development is by far the most expensive phase in terms of resources and time, the decision to continue or stop development must be based on data to avoid wasting money and time in a therapy that does not have the opportunity to offer a real benefit to the patient.
The first test to perform in this phase concerns the evaluation of the usability and acceptability of the application by the patient. This test may be performed on healthy volunteers or on patients with the disease to be treated, in order to have a better representativeness of the result and must involve subjects with different levels of culture and aptitude for the use of technology.
Following this test, the first pilot clinical study is performed on a limited number of patients, in which DTx is administered to the patient under controlled conditions of use, both with and without control, using – in the case of the treatment of depression – self-administered evaluation parameters.
The objective of this study is to obtain preliminary indications on the efficacy and tolerability of DTx and subjective evaluations of the patient on its use.
The results of the pilot phase may lead to a review of the algorithm and a change in the digital active ingredient in order to improve the expected therapeutic outcome. It is also possible to upgrade the excipients with new value-added utilities to improve the user experience.
On the basis of these results and activities, the decision to commit to full development can be taken, considering both technical aspects (quality of the software, interface, utility, etc.) and strategic and commercial aspects (competitors, costs, probability of inclusion in medical practice, etc.).
The full development phase consists of one or more confirmatory randomized controlled clinical trials (RCTs) that must generate the evidence of benefit of the new DTx for its approval by the regulatory authority, reimbursement by public health systems or insurance companies, prescription by the doctor and use by the patient.
The design of the RCTs varies with the expected use of the DTx. If used in combination with a specific drug, such as trazodone or esketamine in the case of antidepressant therapy, the trial should demonstrate the therapeutic superiority of the combination over the drug and not inferiority with respect to tolerability.
In the case of standalone use, in addition (add-on) to the patient’s usual therapy, the trial should demonstrate the therapeutic superiority of DTx over digital placebo, both added to the usual therapy.
In DTx RCTs, the digital placebo is represented by an app (or the appropriate digital form) similar to the DTx app, providing only generic and descriptive information on health without any kind of intervention.
The digital active ingredient tested in the confirmatory clinical trial cannot be changed or modified, except within “windows of possible modification“5 identified among the standards and ethical principles of the development of DTx.
Since DTx can contain a Clinical Record Form, both observational research and clinical trials in the real life setting are the most appropriate ways of performing clinical studies. They may be much easier to perform – at least from the logistical and organizational point of view – and allow to progressively and continuously test the therapeutic effect of the subsequent changes and evolutions of DTx.
Post marketing surveillance
After marketing, post-marketing surveillance is necessary in order to identify potential adverse effects of DTx. Dependence from DTx is an expected adverse effect.
- Digital Therapeutics Alliance. What are Digital Therpeutics? https://dtxalliance.org/dtx-solutions/
- I. Sim. Mobile Devices and Health. N Engl J Med 2019; 381 : 956 – 68
- National Institute For Health And Care Excellence. Digital psychological therapy briefing Deprexis for adults with depressionhttps://www.nice.org.uk/Media/Default/About/what-we-do/NICE-advice/IAPT/iab-deprexis.pdf
- S. Grosjean et al. The Design Process of a mHealth Technology. The Communicative Constitution of Patient Engagement Through a Participatory Design Workshop. ESSACHESS. Journal for Communication Studies, vol. 12, no 1(23) / 2019 : 5-26
- J. Torous et al. Towards a consensus around standards for smartphone apps and digital mental health. World Psychiatry 18:1 – February 2019