Accepted Article

Digital Therapeutics—An Integral Component of Digital Innovation in

Drug Development

Oleksandr Sverdlov1, Joris VanDam2, Kristin Hannesdottir2, and Tricia Thornton-Wells2

1
Early Development Biostatistics, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
2
Novartis Institutes for Biomedical Research, Cambridge, MA.

Correspondence: Oleksandr Sverdlov, alex.sverdlov@novartis.com

One Health Plaza, 135/106
East Hanover, NJ 07936-1080 (USA)
Phone +1 862-778-3659

Abstract: Digital therapeutics represent a new treatment modality in which digital systems
such as smartphone apps are used as regulatory-approved, prescribed therapeutic interventions to
treat medical conditions. In this paper, we provide a critical overview of the rationale for
investing into such novel modalities, including the unmet medical needs addressed by digital
therapeutics and the potential for reducing current costs of medical care. We also discuss
emerging pathways to regulatory approval and how innovative business models are enabling
further growth in the development of digital therapeutics. We conclude by providing some recent
examples of digital therapeutics that have gained regulatory approval and highlight opportunities
for the near future.

Conflict of interest: OS, JVD, KH, and TTW are all employed by Novartis.

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as an
‘Accepted Article’, doi:10.1002/cpt.1036

This article is protected by copyright. All rights reserved.

Accepted Article
Funding: No funding was received for this work.
Accepted Article
Background
Modern drug development is an expensive, lengthy, and high risk enterprise. As of 2014, the
average total R&D cost to bring a new medicine to market was estimated to be $US 2.56B (2013
dollars.1) Despite such significant investment, the overall probability of success (progression
from phase I to US FDA approval) remains disappointingly low; only 9.6% of drug development
programs successfully reach the market.2 Worse still, this appears to be part of a larger trend; a
recent analysis showed a marked decline in overall R&D productivity as measured by the
number of new therapeutic drugs per $US billion R&D spent per annum during the period 1990–
2013.3

In recognition of these challenges, stakeholders in bio/pharma industry, academia and health

authorities have made continuous efforts to develop, promote and implement the best scientific
tools to modernize drug development. For instance, the US Food and Drug Administration
(FDA) published a “Critical Path” White Paper in 20044 and the “Critical Path” Report and List
in 2006,5, 6 which identified key areas for scientific improvement. These included the
development and qualification of new biomarkers, the use of more efficient clinical trial designs
(e.g. adaptive designs7), the use of bioinformatics and development of quantitative disease
models, and the enhancement of the drug manufacturing process. Successful implementation of
these innovative tools requires collaboration across multiple public and private entities (e.g. via
various consortia). It is well acknowledged that the 21st century drug development paradigm has
been changing rapidly, with greater focus on delivering personalized medicine solutions.8, 9 The
goal of targeting the right treatments to the right patients at the right time is at the core of the
FDA’s precision medicine initiative.10 To expedite the drug approval process for serious or life
threatening diseases, the breakthrough therapy designation11 (US) and the adaptive pathways12
(EU) have been launched.

In parallel, the development of social networks, smartphones, wearable devices, and

cloud-based data platforms have enabled the collection, storage and analysis of massive amounts
of clinically relevant data.13 The importance of real-world evidence (data generated outside of
clinical research centers) is increasingly recognized by health authorities.14 The development of
digital analytic tools and advances in data visualization and machine learning empowers
Accepted Article
researchers to transform data into knowledge15 and aid clinical decision-making. Given all this,
synergies between bio/pharma and tech industry companies brings new and unique opportunities
for streamlining clinical research and improving success rates of drug development.16, 17, 18
Digital medicine, defined as “technology-based products undergoing rigorous clinical validation
that will have a direct impact on diagnosing, preventing, monitoring or treating a disease,
condition or syndrome”19 holds realistic promise to move into mainstream medicine and bring
the public healthcare system up to the next, 21st century level.

In this paper, we discuss several important types of digital technology that can enhance the
quality of clinical research and practice. The spotlight will be on digital therapeutics—a new
treatment modality in which digital systems (e.g. smartphone apps) are used as regulatory body
approved, prescribed therapeutic interventions to treat medical conditions. We highlight a unique
business model for developing digital therapeutics, emerging pathways to regulatory body
approval for new digital therapeutics, and the potential of digital therapeutics to reduce the costs
of medical care. We also provide some recent examples of successfully developed and regulatory
body approved digital therapeutics and conclude by identifying promising opportunities for the
near future.

Digital Technologies in Clinical Research

Digital technologies (in the broad sense), if properly used, can be successfully integrated in
clinical trial design, implementation, analysis and dissemination of study results. Table 1
provides a selection of novel digital tools that are already used in clinical research.

Digital Platforms to Streamline Clinical Trial Management

Clinical trial operations is one of the most resource-intensive areas in the development
process. The use of digital platforms for recruitment, retention and remote data collection can
potentially streamline the informed consent process, clinical operations, and can enable site-less
(home-based) clinical trial research.20 Remote monitoring of patients compliance, vital signs and
adverse events can provide for more “at-home” therapy without the need for patients (especially
elderly and kids) to go to doctor’s offices or hospitals. In 2011, the Research on Electronic
Monitoring of Overactive Bladder Treatment Experience (REMOTE), a Phase IV trial by Pfizer,
became the first fully web-based study conducted under the IND application.21 Despite the fact
Accepted Article
that it was terminated early due to a smaller than expected number of eligible patients who
consented to participate, the trial did demonstrate feasibility of using digital technologies to
recruit eligible patients, treat them remotely, and collect data in real-time. The REMOTE trial
ran from March 2011 to August 2012. Since then, there has been vast adoption of mobile
technology by consumers. As a more recent example, Apple’s ResearchKitTM, an iPhone-based
open source platform which was released in March of 2015,22 has been used to facilitate mobile
health (mHealth) real-world clinical research for several recent studies.23, 24, 25
These studies
provide important preliminary findings on the feasibility of mHealth research, while also
revealing potential challenges: lower than anticipated patient engagement (e.g., due to
suboptimal human–computer interfaces), skewed demographics of trial participants (e.g.,
contingent upon smartphone ownership), and potential data-quality issues.26

EDC and ePRO

High quality data is a major pre-requisite for drawing reliable conclusions from a clinical
trial. Electronic Data Capture (EDC) has now become standard, and electronic patient-reported
outcome (ePRO) systems increasingly are being adopted in clinical drug development. The key
benefits of using ePRO systems include higher data accuracy and transparency, better patient
compliance, and overall better cost-efficiency compared to paper-based trials.27 Importantly, for
successful implementation of ePRO solutions, both clinical investigators and trial participants
must be trained on ePRO systems in order to meet data entry requirements of the trial protocol.
The FDA and EMA acknowledge the importance of patient-reported outcome data in clinical
trials.28, 29 With the development of smartphones, mobile ePRO systems could become standard
for capturing patient-reported outcome data.30, 31, 32, 33

Digital Endpoints and Digital Diagnostics

Development of digital endpoints is another important innovation effort.34 Particularly in
disorders of the central nervous system (CNS), conventional efficacy measures are pen-and-
paper clinical outcome assessments (COAs), most often in the format of rating scales or
performance outcome measures (PerfOs) administered only at pre-planned study visits. Many of
these measures were developed over 30 years ago. They may lack clinical relevance and may be
highly variable and subjective. Small treatment effect sizes based on these problematic clinical
endpoints require large study samples, which means longer and more expensive trials. Moreover,
Accepted Article
these measures provide limited information on the functioning of CNS circuits, and most of them
can only be used for single time point assessment. All of the above contribute to high attrition
rates in CNS clinical trials. The likelihood of successful approval from phase I of CNS drugs is
currently estimated at 8.4%,2 and there is consensus in the field that a major factor is the
inadequacy of current measures of efficacy for CNS trials. One example of a technology
revolutionizing the R&D progress in a CNS disorder is MRI in multiple sclerosis. The reduction
in the number of MRI lesions has been established to be predictive of the clinical outcome in
relapsing-remitting multiple sclerosis (RRMS), and it is now widely used as a primary outcome
in (non-pivotal) proof-of-concept and dose-ranging trials in RRMS.35, 36

There is also an opportunity to improve conventional pen-and-paper screening/diagnostic

tools used for patient identification and inclusion into clinical trials, which are sometimes the
same as those used for measuring treatment efficacy. For instance, a cognitive and gait dual-
tasking assessment in early Alzheimer’s disease can provide derived digital outcomes that may
distinguish amyloid-positive from amyloid-negative elderly subjects37 and predict falls.38 This
paradigm has also been used to measure treatment effects of Ginkgo Biloba in Mild Cognitive
Impairement (MCI).39 In general, digital endpoints and diagnostics should be rater-independent,
more accurate and more reliable than pen-and-paper COAs. They can potentially provide
valuable information at the individual patient level to supplement clinical outcomes. One
challenge is validation of digital endpoints and diagnostics in the absense of a gold standard. One
can show correlation and even utility of a novel endpoint to predict the conventional endpoint.
However, is this sufficient to deploy the novel endpoint in large-scale studies? Which criteria
should be used to demonstrate that a digital endpoint is “at least as good” as the conventional
rating scale? Currently there is little experience of using digital endpoints as primary outcome
measures in randomized clinical trials; however, the body of knowledge is growing. One recent
example is a multicenter, double-blind, crossover trial of isosorbide mononitrate in patients with
heart failure and a preserved ejection fraction, which used the average daily accelerometer
readout as the primary endpoint.40 The results showed significantly lower exercise activity,
measured in hours of activity per day, in the active-treated group compared to placebo, a
difference not captured in conventional 6-minute walk tests performed during clinic visits.
Accepted Article
Digital Therapeutics
Digital therapeutics can be defined as a health discipline and treatment option that utilizes
digital and often online health technologies to treat a medical or psychological condition.41 For
instance, a digital therapeutic can be a smartphone app to stimulate behavioral change in diet or
exercise, or an app to promote efficient disease management via medication adherence, that
would also help predict disease exacerbations and reduce frequency of symptoms.42 A key
feature of a digital therapeutic is that an individual treatment strategy is “optimized” (e.g. by
applying machine learning techniques to the individual’s observed data), thereby actualizing the
principle of personalized medicine.

Unmet Medical Need Addressed by Digital Therapeutics

Digital therapeutics appear to be pre-eminently suited for the digital delivery of clinical
therapies that are otherwise delivered in face-to-face meetings with live therapists such as,
cognitive behavioral therapies, clinical hypnotherapy or clinical physiotherapy. Digital delivery
of such therapies, e.g. through the smartphone, tablet device, or even a consumer Virtual Reality
headset may have a number of important advantages:

 Digital delivery facilitates access to therapeutic content for its users or patients. Many of
these therapies entail therapeutic exercises, and having access through such exercises on
personal mobile devices allows patients to exercise wherever and whenever they have 15
minutes to spare, as opposed to being more strictly limited to the times and confines of a
meeting with their therapist.
 Related to the above, behavioral therapies have often proven successful in the treatment
of mental health disorders, and thereby access to therapeutic treatment may be associated
with a certain level of stigma. In such cases, it may well be more complicated to explain
to the patients’ direct personal or professional environment, the need for frequent
therapeutic office visits when compared to accessing therapeutic content in the privacy
of a patient’s personal time and environment.
 Moreover, as per our prior definition, a key feature of a digital therapeutic is the
personalization of the therapy based on the individual’s observed outcomes, progress or
other measures. Because the therapy is now delivered and accessed digitally, the digital
therapeutic platform can assess an individual’s performance, progress or proficiency
Accepted Article

with particular subjects or topics of the therapeutic contained on a much more granular
level, allowing for even greater levels of personalization.
It is important to note that the benefits of “personalized therapy” need not be limited to
the use of a digital therapeutic alone; if the digital therapeutic allows for monitoring of a
patient’s progress via some kind of dashboard, then when the patient does visit a
therapist or clinician as part of his/her therapy, data collected by the digital therapeutic
can be used by the therapist to personalize their therapeutic intervention to a much
greater extent than without it. Such integration of the digital therapy in the overall
treatment of the patient could have a critical impact on the treatment’s ultimate
success.43
 And finally, when such therapies are delivered in face-to-face sessions by live therapists,
the quality of therapeutic intervention can be highly variable,44 whereas digital delivery
of the therapeutic ensures consistent quality of therapeutic delivery.

To highlight one specific example, digital therapeutic technologies can be used to effectively
deliver therapeutic interventions based on Cognitive Behavioral Therapy (CBT). Pear
Therapeutics have used CBT to develop a digital therapeutic for the treatment of Substance Use
Disorder.45 Omada Health developed a digitized version of a proven 16-week CBT program to
help a patient lose weight and reduce one’s risk of obesity, hypertension and diabetes.46 Over the
years, CBT has proven to be an effective therapeutic intervention for many conditions, including
insomnia,47 schizophrenia,48 anxiety and depression,49, 50
obesity,51 nonalcoholic fatty liver
disease,52 as well as many primary indications to which these conditions are co-indicated, such as
chronic obstructive pulmonary disease,53 peripheral artery disease,54 and psoriasis.55 Given the
operational complexities of delivering high-quality face-to-face CBT in clinical practice, we
believe that patient needs may be generally underserved, and that digital therapeutic delivery of
CBT can greatly improve treatment outcomes in these many and varied conditions.

Another related example of the use of digital therapeutic technologies is the delivery of
cognitive training. A large library of cognitive training exercises has been around for decades,
yet precisely the ability of digital therapeutic technologies to personalize cognitive training based
on the individual and to select exercises of increasing difficulty based on current cognitive
Accepted Article
functioning, has allowed companies in this space to achieve impressive treatment outcomes.56
For example, Akili Interactive recently reported positive effects from video game training on
cognitive control abilities of older adults.57 Gamification of therapies can be also promising in
pediatric applications as kids and teenagers generally willingly interact with game based
systems.

Digital therapeutics, however, do not necessarily have to focus only on mental function. The
same platforms can be used to effectively deliver and personalize physical therapies that are
typically delivered at the clinic. Companies like Jintronix and Reflexion Health have developed
platforms that deliver, track and personalize physical therapies over gaming consoles in the
context of post discharge rehabilitation.58, 59

Finally, the use of technologies for the development of digital therapeutics does not have to
be limited to apps for mobile devices and gaming consoles; particularly the use of consumer
Virtual Reality devices appears to support truly immersive therapeutic experiences—with
sometimes impressive clinical results.60

Other Digital Therapeutic Technologies

Opportunities to utilize “…digital and often online health technologies to treat a medical or
psychological condition” are not limited to the digitization of clinical therapies that are otherwise
delivered in face-to-face settings.

The field of bioelectronics medicine uses electronic devices to modulate individual cell
behavior, typically by triggering a targeted response of the nervous system. Arguably the field
itself has been around for many years, with earlier applications such as the use of transcutaneous
61
electrical nerve stimulation (TENS) for transcutaneous pain relief, and the use of electrical
stimulation in nervous system recovery.62 The continued advance and miniaturization of
technology, however, has allowed these technologies to trigger increasingly selective therapeutic
responses, and has led to novel initiatives such as GSK and Verily’s $715M investment in the
launch of a new bioelectronics venture.63

In September 2016, the FDA approved the first fully autonomous artificial pancreas
system—a digital system which automatically calculates and autonomously administers the right
dose of insulin, for an individual patient at a particular point in time, based on a series of recent
Accepted Article
blood glucose measurements.64 The system is intended for the management of Type 1 diabetes
mellitus in patients fourteen years or older, and it is available by prescription only. The clinical
evidence that formed the basis for approval came from two clinical trials: the Safety Evaluation
of the Hybrid Closed Loop (HCL) System in Type 1 Diabetes (ClinicalTrials.gov identifier:
NCT02463097),65 and the Performance Evaluation of the Enlite® 3 Sensor to Support a Full 168
Hours (7 Days) of Use (ClinicalTrials.gov identifier: NCT02246582).66 The results of these trials
showed favorable benefit-risk properties of the MiniMed 670G System, and the Center for
Devices and Radiological Health (CDRH) issued an approval order on September 28th 2016,
after only 3 months of review. While this device is specifically targeted for the treatment of Type
1 diabetes, this concept of “closing the loop” from sensing to dosing may well benefit the
treatment of many other indications, including many other endocrine disorders and generally
through precision dosing.

While these respective approaches use different digital technologies in different ways, they
all represent examples of how digital technologies can be used to treat medical disease. It is
certainly not beyond imagination that at some point in the future such technologies would
converge: a behavioral therapy or game is used to assess a person’s mood or cognitive
impairment (“digital endpoint”), on the basis of which the digital system automatically calculates
and autonomously delivers (“closing the loop”) a modulation of a specific biological pathway
(“bio-electronic medicine”).

Regulatory Perspectives on Digital Therapeutics

In the US, Digital Therapeutics fall under the purview of the CDRH at the FDA. By the
definition adopted here, i.e. by the very intent of digital therapeutics to “…treat a medical or
psychological condition”, the FDA considers these to be Mobile Medical Applications (MMAs).
With that said, there is a pretty significant group of MMAs for which the FDA intends to
exercise enforcement discretion—and will not expect manufacturers to submit premarket review
applications or to register and list their apps with the FDA. Examples of MMAs that fall under
such enforcement discretion include apps that help patients organize and track their health
information or that provide easy access to information related to conditions or treatments, and
also apps that help patients self-manage their disease or condition (e.g. coaching and wellness)
without providing specific treatment suggestions.67 For example, if the goal of a digital
Accepted Article
therapeutic app is to provide information, tools and coaching for its users to adapt healthy
lifestyle habits, it would typically fall under FDA’s enforcement discretion, irrespective of the
therapeutic benefit that such healthy lifestyles may entail. MMAs which do not fall under this
enforcement discretion will be classified and regulated as Class I, Class II or Class III devices—
depending on an analysis of safety/risk, and on intended use and indications for use, as illustrated
in Figure 1.

Class III is a designation for devices posing the most significant risk of illness or injury, and
Class III devices are subject to the Premarket Approval (PMA) review process. The previously
mentioned autonomous artificial pancreas system64 was approved as a Class III medical device.

For Class II devices (subject to regulatory requirements referred to as “special controls”) and
Class I devices (for which “general controls” will suffice) a 510(k) premarket submission is
required. A 510(k) compares the device to one or more similar devices that are already legally
marketed, and claims the new device to be substantially equivalent. If no such marketed devices
exist, a De Novo submission for a Class I or Class II device must be made. For example, Pear
Therapeutics’ digital therapeutic for the treatment of Substance Use Disorder45 was approved
through a De Novo submission for a Class II medical device. One of Pear’s next products, a
digital therapeutic specifically indicated for the treatment of Opioid Use Disorder, received
Expedited Access Pathway, to be approved under a 510(k) claiming substantial equivalence to
the already approved digital therapeutic for Substance Use Disorder.68

It is important to note that FDA clearance can be sought and obtained either for the safety,
or for the indications for use of the digital therapeutic or device, or both. For instance, an MMA
that is used to capture, store and catalog measurements (such as heart rate, lung murmur, blood
glucose or pulse oximetry) from a Class II medical device, or that can be used to control the
functioning of that sensory device, would be considered a Class II medical device itself and
would be required to submit for FDA clearance. Clearly, however, the mere capture, storage and
journaling of measurements from sensory devices do not necessarily have any therapeutic effect
on the disease; i.e. FDA clearance for a device does not imply therapeutic effect of the device.
Furthermore, the text of the FDA clearance should be carefully consulted to understand the
indications for use of the device.
Accepted Article
Conversely, MMAs can have therapeutic effect and can be used in the treatment of medical
or psychological conditions, without having sought or obtained FDA clearance. This is
particularly the case for digital therapeutics that fall under the FDA’s enforcement discretion. As
stated previously, MMAs that help patients self-manage their disease or condition (e.g. coaching
and wellness) fall under the category for which the FDA intends to exercise enforcement
discretion, even though the therapeutic benefits of self-management, coaching and wellness are
relatively well proven. For example, Omada Health for weight loss and Clickotine for smoking
cessation have not sought FDA clearance, while they both have generated pretty compelling
clinical data demonstrating therapeutic effect of their treatments.46, 69

Emerging Business Models for Digital Therapeutics

Conceptually, digital therapeutics can be prescribed with or without combinations with a
pharmacotherapy, as illustrated in Figure 2 below.

For example, a digital therapeutic based on CBT can be prescribed as a stand-alone

treatment (“digital monotherapy”) for the treatment of a particular indication. In fact, a
significant amount of research has been published examining the question whether in certain
indications CBT is more effective than treatment with a drug (“pharmacotherapy”).70

Moreover, the use of a digital therapeutic could be prescribed along with a

pharmacotherapy. For example, the treatment guidelines from the American Psychiatric
Association for the treatment of Depression suggest that moderate to severe major depressive
disorder should be treated with a combination of psychotherapy and antidepressant medication.71
This is potentially a more interesting approach. Behavioral therapies like CBT have a proven
effect on brain chemistry,72 which is arguably the very purpose of pharmacological treatment.
Yet the potential complementary nature, or synergistic interaction, of these respective
intervention modalities, has been the topic of much less research. Such interaction is not only
limited to digital and pharmacological treatments targeting the same indication, but could also
pertain to co-indications. For instance, anxiety co-occurs with a number of different chronic
conditions, such as inflammatory diseases, respiratory diseases, and oncology. Whereas a lot of
pharmacological therapies exist for the treatment of inflammation, respiratory distress and
Accepted Article
cancers, and whereas behavioral therapies have proven to be greatly effective in the treatment of
anxiety, much less is understood about the synergistic effect of treating both at the same time.

Arguably, both the development of a digital monotherapy as well as the combination of a

digital therapy with a known and existing pharmacotherapy have faster and lower-cost paths to
patients and paths to creating medical value, than the development of new molecular entities.
Therefore, it could be an interesting opportunity for the biopharmaceutical industry to explore
capabilities of these novel digital therapeutic technologies to enhance overall outcomes of
pharmacological treatment.

Conceivably, one could also imagine the development of a new molecular entity, combined
with a digital therapeutic technology, planned for from the onset as part of a “drug–device”
combination therapy. This could potentially create more medical value for patients than “just”
bringing the new molecule to market by itself. However, the current market dynamics of new
drug development may not be conducive to assuming such additional risk in the development of
the new molecule, even if the addition of the innovative technology could create incremental
medical value. As such, we do not see the use of digital therapeutic technologies be incorporated
into the “core drug development” approach in the near term without significant adjustment to the
classical pharma business model which focuses primarily on new molecular entities.

Presumably, these approaches represent increasing levels of treatment effectiveness.

Regardless, at least the reverse perspective will hold: if there is no presumed greater efficacy in a
more complex therapeutic approach that will take more time and more resources to develop, or if
early research studies do not demonstrate greater efficacy, then further investment in the more
complex therapeutic approach will likely fade.

Digital Therapeutics Coming to Market

A number of technology and market evolutions appear to be converging to somewhat of
a “perfect storm” in the creation of digital therapeutics. 16

The continued advancement and miniaturization of digital technologies is a constant

driver of innovation. The ubiquitous presence of mobile technologies in our daily lives
greatly facilitates access to any kind of services and content—including those that are
therapeutic in nature. The coming of age of cloud based technologies and better protection
Accepted Article
of data privacy allows for safe and effective communication of healthcare-related content
between patients and providers. The progressive miniaturization of sensing technologies
allows for increasingly personalized healthcare interventions; every new sensor offers a new
opportunity to therapeutically intervene in the course of the disease.

The FDA in the US, and other regulatory agencies in other regions, have been
undertaking considerable efforts to streamline their respective regulatory frameworks to
support the development, evaluation, and when warranted, clearance of novel digital
therapeutics “at digital speed”.73

As healthcare systems around the world continue to evolve toward “pay for
performance” reimbursement models, in lieu of the pervasive pay for service models, this
drives stakeholders in this healthcare systems to take an increasingly holistic look at the
factors that drive overall health outcomes of their patient populations, and to combine or
bundle services, pharmacological interventions, behavioral interventions, novel sensors and
other technologies towards achieving, as well as monitoring, tracking and demonstrating
sustained health outcomes for these populations. Perhaps a particularly illustrative example
is the treatment of diabetes. Various pharmacological interventions are available for
effective treatment of diabetes, but patients can now also use continuous blood glucometers
to measure and track appropriate management of their disease. There is even a fully
integrated closed loop system, intended to automatically monitor blood sugar and adjust
administration of insulin in people with Type 1 diabetes.64 With so many tools and
interventions to diagnose, treat and track progression of diabetes, it is perhaps not surprising
that, for example, the innovative US Health Insurance company Aetna recently launched an
outcomes-based contract for managing blood glucose levels in diabetic patients it insur es.74

It is also informative to examine the increased convergence between the “digital” and
“biopharmaceutical” business models.17, 18 Digital innovation in many other industries may
be commonly characterized by rapid time to market, iterative “trial and error” product
development lifecycles, and the development of a loyal customer base from early versions
of the partially unfinished product. The biopharmaceutical market can be characterized as
almost the polar opposite—with lengthy, cautious and progressive product development
Accepted Article
cycles in well-defined and limited patient populations in order to protect and safeguard the
health of patient populations. In the development of novel biopharmaceutical therapies, any
other approach would be profoundly unethical. Yet the inherent greater safety associated
with various types of digital therapeutics, as outlined in this article, may offer attractive
opportunities for biopharmaceutical companies to accelerate their innovation lifecycle, to
shorten their time to market in launching novel therapies—particularly when such markets
are considered to be rewarding treatment outcomes as opposed to pay for service. At the
same time, these lengthier and more sustained product development lifecycles that are
common in the biopharmaceutical industry, may help drive a step change in the
development of digital therapeutics by enabling a sustained vision, resources and funding
that may be required to realize the true therapeutic value of these technologies for the many
underserved patient populations worldwide.

The clinical testing of digital therapeutics brings unique challenges as well as opportunities.
The randomized, double-blind, placebo- and/or active controlled trial design is the gold standard
for generating clinical evidence.75 One challenge in a clinical trial evaluating a digital therapeutic
is that technical characteristics of the device or software may be upgraded/improved over the
course of the trial, and the technology itself may become outdated before the trial ends. Blinding
in a digital intervention trial also may be problematic. The use of a “sham” control group may be
unethical in some cases (e.g. if “sham” injections are required). The remote informed consent
process raises privacy concerns: is it sufficient to have a subject hit ‘OK’ button to be considered
consented, or do they need to demonstrate comprehension by passing a quiz on what the consent
form means? Lower than expected patient engagement can result in a large amount of missing
data which may render trial results inconclusive. At the same time, clinical trials for digital
therapeutics bring unique opportunities; e.g., the use of novel, adaptive designs.76 Since digital
data are more readily ingestible than non-electronic data, design adaptations can be made in real-
time thereby improving trial efficiency. Some innovative designs based on theory of behavior
change have been developed.77 The FDA provides a viewpoint on unique considerations for
medical device clinical trials which can be useful in this setting.78
Accepted Article
Conclusion and Outlook
In the 21st century, the “most valuable resource is no longer oil, but data”.79 Digital
technologies can generate terabytes of potentially useful medical data and provide powerful tools
for clinical research. If used judiciously, digital technologies can modernize drug development
by improving clinical operations, data quality, endpoints, and even treatment outcome. The
uptake of digital technologies in bio/pharmaceutical industry has been slow, yet it is gaining
momentum.

Digital therapeutics provide a new approach to treatment and disease management in which
digital systems help patients manage their own health and disease conditions. Digital
therapeutics utilize the infrastructure of Internet, mobile phone, and the novel gains in artificial
intelligence, machine learning and big data analytics to optimize treatment for a given individual,
thereby embracing the principle of personalized medicine. Driven by current trends towards an
aging society, prevention and effective management of chronic diseases is more relevant than
ever. Digital therapeutics can provide safer and less expensive options than traditional treatment,
which, in turn, can save hundreds of billions of dollars in the healthcare.

Similar to pharmaceuticals, digital therapeutics require rigorous testing in randomized

controlled clinical trials to provide reliable evidence of safety and effectiveness. However, unlike
in regular drug development, the timelines to develop a digital therapeutic can be substantially
reduced because some steps such as toxicity studies are not applicable. Clinical trials to assess
digital interventions pose new logistical, statistical, and ethical challenges, but at the same time
they provide unique opportunities for implementing innovative research designs and big data
analytic techniques. A synergy between bio/pharma and tech companies can expedite
development of innovative digital medicinal products.

Health authorities also acknowledge potential of digital medicine and encourage such
innovation efforts. The FDA has an explicit statement that the CDRH Digital Health Program
“seeks to better protect and promote public health and provide continued regulatory clarity by:
(1) Fostering collaborations and enhancing outreach to digital health customers, and (2)
Developing and implementing regulatory strategies and policies for digital health
technologies”.73 While many of these efforts are still in the pilot stage, increasing research and
Accepted Article
development investment will continue to demonstrate the enormous potential impact of digital
therapeutics in the very near future.

Acknowledgement
The authors would like to thank their Novartis colleagues: Ieuan Clay, Jen Praestgaard, Tilo
Hache, and Jang-Ho Cha, as well as two anonymous referees for their insightful comments
which helped improve the original version of this paper.
Accepted Article
References
1. DiMasi, J.A., Grabowski, H.G. & Hansen, R.W. Innovation in the pharmaceutical
industry: New estimates of R&D costs. Journal of Health Economics 47, 20-33 (2016).

2. Biotechnology Innovation Organization (BIO). Clinical Development Success Rates

2006–2015. <https://www.bio.org/press-release/bio-releases-largest-study-ever-clinical-
development-success-rates>

3. Lendrem, D., Senn, S.J., Lendrem, B.C. & Isaacs, J.D. R&D productivity rides again?
Pharmaceutical Statistics 14, 1-3 (2015).

4. U.S. Food and Drug Administration. Innovation or Stagnation: Challenge and

Opportunity on the Critical Path to New Medical Products (March 2004).
<https://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPath
OpportunitiesReports/ucm077262.htm>

5. U.S. Food and Drug Administration. Innovation or Stagnation: Critical Path

Opportunities Report (March 2006).
<https://www.fda.gov/downloads/ScienceResearch/SpecialTopics/CriticalPathInitiative/
CriticalPathOpportunitiesReports/UCM077254.pdf>

6. U.S. Food and Drug Administration. Innovation or Stagnation: Critical Path

Opportunities List (March 2006).
<https://www.fda.gov/downloads/ScienceResearch/SpecialTopics/CriticalPathInitiative/
CriticalPathOpportunitiesReports/UCM077258.pdf >

7. Dragalin, V. Adaptive designs: terminology and classification. Drug Information Journal

40(6), 425-435 (2006).

8. Simon, R. Clinical trials for predictive medicine. Statistics in Medicine 31, 3031-3040
(2012).

9. Ruberg, S.J. & Shen, L. Personalized medicine: Four perspectives of tailored medicine.
Statistics in Biopharmaceutical Research 7(3), 214-229 (2015).
Accepted Article
10. U.S. Food and Drug Administration. The Precision Medicine Initiative.
<https://www.fda.gov/ScienceResearch/SpecialTopics/PrecisionMedicine/default.htm>

11. U.S. Food and Drug Administration. Fact Sheet: Breakthrough Therapies.
<https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendm
entstotheFDCAct/FDASIA/ucm329491.htm>

12. European Medicines Agency. Adaptive Pathways.

<http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_conten
t_000601.jsp>

13. Rosa, C., Campbell, A.N.C., Miele, G.M., Brunner, M. & Winstanley, E.L. Using
e-technologies in clinical trials. Contemporary Clinical Trials 45, 41-54 (2015).

14. U.S. Food and Drug Administration. Real World Evidence.

<https://www.fda.gov/ScienceResearch/SpecialTopics/RealWorldEvidence/default.htm>

15. Efron, B. & Hastie, T. Computer Age Statistical Inference: Algorithms, Evidence, and
Data Science. Cambridge University Press (2016).

16. Hird, N., Ghosh, S. & Kitano, H. Digital health revolution: perfect storm or perfect
opportunity for pharmaceutical R&D? Drug Discovery Today 21(6), 900-911 (2016).

17. Wang, C.K. Shaking up biotech/pharma: Can cues be taken from the tech industry? SLAS
Technology 22(3), 233-236 (2017).

18. Steinberg, D., Horwitz, G. & Zohar, D. Building a business model in digital medicine.
Nature Biotechnology 33(9), 910-920 (2015).

19. Elenko, E. Underwood, L. & Zohar, D. Defining digital medicine. Nature Biotechnology
33(5), 456-461 (2015).

20. Hirsch, I.B., et al. Incorporating site-less clinical trials into drug development: A
framework for action. Clinical Therapeutics 39(5), 1064-1076 (2017).

21. Orri, M., Lipset, C.H., Jacobs, B.P., Costello, A.J. & Cummings, S.R. Web-based trial to
evaluate the efficacy and safety of tolterodine ER 4 mg in participants with overactive
bladder: REMOTE trial. Contemporary Clinical Trials 38, 190-197 (2014).
Accepted Article
22. Apple Introduces ResearchKit, Giving Medical Researchers the Tools to Revolutionize
Medical Studies (March 9th, 2015). < https://www.apple.com/newsroom/2015/03/09Apple-
Introduces-ResearchKit-Giving-Medical-Researchers-the-Tools-to-Revolutionize-Medical-
Studies/>

23. Chan, Y.F.Y., et al. The asthma mobile health study, a large-scale clinical observational
study using ResearchKit. Nature Biotechnology 35(4), 354-362 (2017).

24. Doerr, M., et al. Formative evaluation of participant experience with mobile eConcent in
the app-mediated Parkinson mPower study: A mixed method study. JMIR Mhealth
Uhealth 5(2), e14 (2017).

25. McConnell, M.V., et al. Feasibility of obtaining measures of lifestyle from a smartphone
app: The MyHeart Counts cardiovascular health study. JAMA Cardiology 2(1), 67-76
(2017).

26. Kvedar, J.C. & Fogel, A.L. mHealth advances clinical research, bit by bit. Nature
Biotechnology 35(4), 337-339 (2017).

27. José, N.C. & Langel, K. ePRO vs. paper. Applied Clinical Trials (Jun 01, 2010).
<http://www.appliedclinicaltrialsonline.com/epro-vs-paper>

28. U.S. Food and Drug Administration. Guidance for Industry: Patient-Reported Outcome
Measures: Use in Medical Product Development to Support Labeling Claims (December
2009). <https://www.fda.gov/downloads/drugs/guidances/ucm193282.pdf>

29. European Medicines Agency. Committee for Medicinal Products for Human Use
(CHMP). Reflection Paper on the Regulatory Guidance for the Use of Health-Related
Quality of Life (HRQL) Measures in the evaluation of Medicinal Products. (London, 27
July 2005).
<http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500003637.pdf>

30. Davis, T. How mobile technology is evolving in clinical trials. Applied Clinical Trials
(12 May, 2014). <http://www.appliedclinicaltrialsonline.com/going-mobile-how-mobile-
technology-evolving-clinical-trials>
Accepted Article
31. Yeomans, A. The future of ePRO platforms. Applied Clinical Trials (28 Jan, 2014).
<http://www.appliedclinicaltrialsonline.com/future-epro-platforms>

32. Coons, S.J., et al. Capturing patient-reported outcome (PRO) data electronically: The
past, present, and promise of ePRO measurement in clinical trials. Patient 8, 301-309
(2015).

33. Byrom, B., et al. Measurement equivalence of patient-reported outcome measure

response scale types collected using Bring Your Own Device compared to paper and a
provisioned device: Results of a randomized equivalence trial. Value in Health, to appear
(2018).

34. Clay, I. Impact of digital technologies on novel endpoint capture in clinical trials.
Clinical Pharmacology and Therapeutics 102(6), 912-913 (2017).

35. Selmaj, K. et al. Siponimod for patients with relapsing-remitting multiple sclerosis
(BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurology 12(8),
756-767 (2013).

36. Farber, R.S., Harel, A. & Lublin, F. New agents for relapsing forms of multiple sclerosis.
Annual Review of Medicine 67, 309-321 (2016).

37. Nadkarni, N.K., Perera, S., Snitz, B.E., Lopez, O.L. & Klunk, B.E. Influence of brain
amyloid positivity on cognitive dual-task load-induced gait slowing in cognitively
normal, mobility unimpaired older adults. Alzheimer’s & Dementia 13(7 Suppl) 285-286
(2017).

38. Muir-Hunter, S.W. & and Wittwer, J.E. Dual-task testing to predict falls in community-
dwelling older adults: a systematic review. Physiotherapy 102(1), 29-40 (2016).

39. Gschwind, Y.J., et al. Ginkgo biloba special extract LI 1370 improves dual-task walking
in patients with MCI: a randomised, double-blind, placebo-controlled exploratory study.
Aging Clin Exp Res 29(4), 609-619 (2017).

40. Redfield, M.M. et al. Isosorbide mononitrate in heart failure with preserved ejection
fraction. The New England Journal of Medicine 373(24) 2314-2324 (2015).
Accepted Article
41. Wikipedia. Digital Therapeutics. <https://en.wikipedia.org/wiki/Digital_therapeutics>

42. Kvedar, J.C., Fogel, A.L., Elenko, E. & Zohar, D. Digital medicine’s march on chronic
disease. Nature Biotechnology 34(3), 239-246 (2016).

43. Kevdar, J.C. The Internet of Healthy Things.1st ed. Boston (MA): Partners Connected
Health (2015).

44. Brauhardt, A., et al. Therapist adherence in individual cognitive-behavioral therapy for
binge-eating disorder: Assessment, course, and predictors. Behaviour Research and
Therapy 61, 55-60 (2014).

45. Pear Therapeutics Obtains FDA Clearance of the First Prescription Digital Therapeutic to
Treat Disease (September 14th, 2017). <https://www.prnewswire.com/news-releases/pear-
therapeutics-obtains-fda-clearance-of-the-first-prescription-digital-therapeutic-to-treat-
disease-300520068.html>

46. Sepah, S.C., Jiang, L. & Peters, A.L. Long-term outcomes of a web-based diabetes
prevention program: 2-year results of a single-arm longitudinal study. J Med Internet Res.
17(4), e92 (2015).

47. Luik, A.I., Kyle, S.D. & Espie, C.A. Digital Cognitive Behavioral Therapy (dCBT) for
insomnia: A state-of-the-science review. Curr Sleep Medicine Rep. 3, 48-56 (2017).

48. Firth, J. & Torous, J. Smartphone apps for schizophrenia: A systematic review. JMIR
Mhealth Uhealth 3(4), e102 (2015).

49. Firth, J., et al. Can smartphone mental health interventions reduce symptoms of anxiety?
A meta-analysis of randomized controlled trials. Journal of Affective Disorders 218, 15-
22 (2017).

50. Firth, J., et al. The efficacy of smartphone-based mental health interventions for
depressive symptoms: A meta-analysis of randomized controlled trials. World Psychiatry
16, 287-298 (2017).
Accepted Article
51. Castelnuovo, G., et al. Cognitive behavioral therapy to aid weight loss in obese patients:
current perspectives. Psychology Research and Behavior Management 10, 165-173
(2017).

52. Moscatiello, S., et al. Cognitive-behavioral treatment of nonalcoholic fatty liver disease:
A propensity score-adjusted observational study. Obesity 19(4), 763-770 (2011).

53. Heslop, K., et al. Effectiveness of cognitive behavioural therapy (CBT) interventions for
anxiety in patients with chronic obstructive pulmonary disease (COPD) undertaken by
respiratory nurses: the COPD CBT CARE study: (ISRCTN55206395). BMC Pulmonary
Medicine 13(62), (2013).

54. Garnefski, N., Kraaij, V., Wijers, E. & Hamming, J. Effects of a cognitive-behavioral
self-help program on depressed mood for people with peripheral arterial disease. Journal
of Clinical Psychology in Medical Settings 20(2), 186-191 (2013).

55. Piaserico, S., et al. Efficacy of biofeedback and cognitive-behavioural therapy in psoriatic
patients: A single-blind, randomized and controlled study with added narrow-band
Ultraviolet B therapy. Acta Dermatology Venereologica, 96(217), 91-95 (2016).

56. Kiran, S., Godlove, J., Advani, M. & Anantha, V. Personalizing rehabilitation for stroke
survivors—A big data approach. Clinical Rehabilitation and Recovery Moderated Poster
Tour American Heart Association (23 Feb 2017)
<https://aha.scientificposters.com/epsAbstractAHA.cfm?id=1>

57. Anguera, J.A., et al. Video game training enhances cognitive control in older adults.
Nature 501, 97-101 (2013).

58. Valiani, V., et al. New adaptive home-based exercise technology among older adults
living in nursing home: A pilot study on feasibility, acceptability and physical
performance. Journal of Nutrition Health and Aging 21(7), 819-824 (2017).

59. Virtual Physical Therapy Helps Revolutionize Home Health Care (December 5th, 2016)
<https://www.healthitoutcomes.com/doc/virtual-physical-therapy-helps-revolutionize-
home-health-care-0001>
Accepted Article
60. A Tech Startup Is Using Virtual Reality as a Weapon Against Cancer (September 13th,
2017), <https://futurism.com/a-tech-startup-is-using-virtual-reality-as-a-weapon-against-
cancer/>

61. Francis J. & Dingley J. Electroanaesthesia—from torpedo fish to TENS. Anaesthesia

70(1), 93-103 (2015).

62. Krucoff, M.O., Rahimpour, S., Slutzky, M.W., Edgerton, V.R., Turner, D.A. Enhancing
nervous system recovery through neurobiologics, neural interface training, and
neurorehabilitation. Frontiers in Neuroscience 10(584) (2016).

63. GSK and Alphabet's Verily create $715M joint venture in bioelectronics (August 1st,
2016). <https://www.fiercebiotech.com/medical-devices/gsk-and-google-s-verily-create-
715m-joint-venture-bioelectronics>

64. U.S. Food and Drug Administration, Center for Devices and Radiological Health
(CDRH). Approval Letter for the 670G System (PMA Applicant: Medtronic MiniMed,
Inc.) (September 28, 2016).
<https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160017a.pdf>

65. Study NCT02463097: Safety Evaluation of the Hybrid Closed Loop (HCL) System in
Type 1 Diabetes. <https://clinicaltrials.gov/ct2/show/study/NCT02463097>

66. Study NCT02246582: A Performance Evaluation of the Enlite® 3 Sensor to Support a

Full 168 Hours (7 Days) of Use.
<https://clinicaltrials.gov/ct2/show/study/NCT02246582>

67. Examples of Mobile Apps For Which the FDA Will Exercise Enforcement Discretion
(Last Updated: August 1st 2016),
<https://www.fda.gov/MedicalDevices/DigitalHealth/MobileMedicalApplications/ucm36
8744.htm>

68. Pear Therapeutics receives Expedited Access Pathway designation from FDA for
reSET-O™ prescription digital therapeutic to treat opioid use disorder (18 Oct, 2017).
<http://www.businesswire.com/news/home/20171018006174/en/Pear-Therapeutics-
Receives-Expedited-Access-Pathway-Designation>
Accepted Article
69. Iacoviello, B.M., et al. Clickotine, a personalized smartphone app for smoking cessation:
Initial evaluation. JMIR Mhealth and Uhealth 5(4), e56 (2017).

70. Treatment Options: CBT or Medication. Association for Behavioral and Cognitive
Therapies. <http://www.abct.org/Help/?m=mFindHelp&fa=CBT_Or_Medication >

71. American Psychiatric Association. Practice Guideline for the Treatment of Patients with
Major Depressive Disorder, 3rd Edition (2010).
<https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.
pdf>

72. Porto, P.R., et al. Does cognitive behavioral therapy change the brain? A systematic
review of neuroimaging in anxiety disorders. Journal of Neuropsychiatry and Clinical
Neurosciences, 21(2), 114-125 (2009).

73. U.S. Food and Drug Administration. Digital Health.

<https://www.fda.gov/medicaldevices/digitalhealth/>

74. Medtronic Announces Outcomes-Based Agreement with Aetna for Type 1 and Type
2 Diabetes Patients. (June 26 th, 2017).
<http://newsroom.medtronic.com/phoenix.zhtml?c=251324&p=irol-
newsArticle&ID=2283068>

75. European Medicines Agency. ICH E9: Statistical Principles for Clinical Trials
(5 February 1998).
<http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/
Step4/E9_Guideline.pdf>

76. Bhatt, D.L. & Mehta, C. Adaptive designs for clinical trials. The New England Journal of
Medicine 375(1), 65-74 (2016).

77. Collins, L.M., Murphy, S.A. & Strecher, V. The Multiphase Optimization Strategy
(MOST) and the Sequential Multiple Assignment Randomized Trial (SMART): New
methods for more potent eHealth interventions. American Journal of Preventive Medicine
32(5 Suppl) S112-S118 (2007).
Accepted Article
78. Faris, O. & Shuren, J. An FDA viewpoint on unique considerations for medical-device
clinical trials. The New England Journal of Medicine 376(14), 1350-1357 (2017).

79. The Economist. The World’s Most Valuable Resource Is No Longer Oil, but Data
(May 6th, 2017). <https://www.economist.com/news/leaders/21721656-data-economy-
demands-new-approach-antitrust-rules-worlds-most-valuable-resource>

Figure Legends:
Figure 1: High-level illustration of the regulatory framework for digital therapeutics – as
implemented by the FDA in the US

Figure 2: Various “drug-digital” combinations can be brought to market at varying time,

cost and value points
Accepted Article
Table 1:
Digital
Technology
Electronic
platforms
recruitment,
retention, and
for
Different types of digital technologies in clinical research
Goal(s)

Improve trial
management
Opportunities




Faster recruitment
More efficient communication
Improved informed consent
process
Challenges

data collection  Better compliance
 Higher retention
 De-centralized (home-based)
trials
EDC, eSource, Improve quality of  Higher cost-efficiency
ePRO, data compared to paper
 Earlier data analysis
Digital Improve assessment  Increased accuracy, speed and
endpoints of treatment effect reliability of drug signal
or treatment benefit detection
 Improved clinical
meaningfulness of data
 Reduced need for clinical site
visits
 Shift from treatment to
prevention (due to longitudinal
data monitoring)
Digital Improve treatment  Reduced time from conception
therapeutics of interventions to their
dissemination
 Safer, less costly and more
accessible (when approved)
 Potential for use in pediatric
applications around
gamification of therapies




Selective subset of patients
Data-quality issues
Low patient engagement
Need of rigorous testing of
merits of e-platforms
 May be prone to user errors
 Require training
 Potential workflow conflicts
 More data does not always imply
better data
 Require validation
 Data provenance
 Lack of standards and regulation
 Data privacy, security,
confidentiality concerns
 Evidence for efficacy is still
sparse
 Design of clinical trials may not
be straightforward
 Constantly emerging
technologies make uptake more
difficult
Accepted Article
Accepted Article