Table 1 Hypotheses development and framework main components

Study type and randomization

H1.1

Study type is affected by: (a) study needs and domain choices, (b) product development and study phase, (c) availability of sources of evidence

H1.2

Study type is NOT affected by: (a) target disease, (b) product features.

H2

Decisions about study randomization and control depend on: (a) study needs and domain choices, (b) product development and study phase

Patients and study duration

H3.1

Decisions about which patients to include in the studies depend on: (a) study needs and domain choices, (b) product development and study phase, (c) spread and burden of the disease

H3.2

The number of patients to include in a study depends on: (a) study needs and domain choices, (b) product development and study phase

H3.3

The decision about whether and how to train patients in studies depends on: (a) patients’ digital literacy, (b) patients’ awareness of the disease, (c) product ease-of-use, (d) patient’s support by healthcare ecosystem actors

H4

The study duration depends on: (a) product development and study phases, (b) scalability of the product features, (c) target disease

Comparators and study arms

H5.1

The choice of comparators depends on: (a) target disease, (b) routine treatments for that disease, (c) patient groups, (d) product features

H5.2

DTx based on asynchronous digital content should be compared to ‘digital placebos’ whose digital content has no therapeutic effect

H5.3

DTx products’ active ingredients should be assessed separately, when possible, especially in early-stage studies (e.g., CBT, game, chat, alerts)

H5.4

The effects of pharmaceuticals and medical devices to be used in addition to the DTx should be isolated

H5.5

The number of arms/cohorts does not depend directly on the product features, but it is affected by the healthcare ecosystem actors accessing those features (e.g., patients, clinicians, caregivers, and healthcare structures)

Outcomes and scales

H6.1

Clinical evidence should be gathered through interactive product features (e.g., diary, social media, symptoms reporting) and, relying as much as possible on PROMs and validated scales

H6.2

Quality of Life (possibly measured using non-disease-specific standard scales) should be considered in the study of any DTx. This can help in carrying out cost-utility analyses

H6.3

Since ‘Perceived Usefulness’, ‘Usability’, and ‘Acceptability’ represent critical factors in the patient’s adoption of Digital Therapeutics, such outcomes should be included in the study of any DTx. They should be measured using both objective and subjective tests

H6.4

Economic analyses should be carried out separately, and only after, clinical studies and analyses of the organizational impact of the DTx: what are the changes in process, structure, and culture?

H.6.5

The patient dropout from studies and actual use of a DTx must be assessed since it might hide insights about ethical aspects (e.g., social/economic barriers) hindering the use of the digital therapy

H6.6

«One does not fit all»: profiling target users of a digital therapy is necessary to make sure that the patient is willing to get more empowered in the management of his disease by using the DTx

Sources of evidence

H7

Study design and needed evidence must guide the strategic selection of the sources of evidence. There is a need for study plans to manage the use of RWE from a statistical standpoint