Digital Therapeutics and Decentralized Trials: A Match Made in Clinical

Digital therapeutics (DTx), the use of software-based interventions to prevent and treat disease, is one of the biggest areas of growth in life sciences. CB Insights reported that 2021 funding in the digital health industry grew 79% over 2020,¹ and the global DTx market is projected to hit $13.1 billion by 2026, up from $3.4 billion in 2021.² Many say digital therapeutics will rewrite the future of healthcare.³

While it sounds aspirational, the DTx industry isn’t just “pie in the sky.” Studies show improved outcomes from digital therapeutics, either alone or in conjunction with conventional therapeutics, in a broad range of indications, including cancer, ADHD, asthma, schizophrenia, and insomnia. Some examples of products include video games to treat mental- and behavioral-health issues; a digital therapeutic platform that incorporates neurological music therapy, sensors, and AI to help patients who have suffered a stroke or other neurological disorder to rebuild motor skills; and a smartphone app that can conduct electrocardiograms anytime, anywhere.

Successful DTx companies have capabilities in areas that many biopharma companies traditionally do not: big data and advanced analytics, hardware engineering, and human-centered product design. Such capabilities will probably prove essential for pharmaceutical companies as healthcare evolves toward a digital future, but—for now—a growing number of pharmaceutical companies are seeking to explore these capabilities by partnering with DTx companies and developing combination products.

“It’s a good match—agility from DTx startups and scale from big companies,” said Bozidar Jovicevic, former head of digital therapeutics at Sanofi. In 2019, Sanofi partnered with Happify Health to produce a DTx app to improve mental health in patients with multiple sclerosis. The product is in a proof-of-concept decentralized trial with several thousand MS patients.⁴ The first FDA-approved digital therapeutics was Pear Therapeutics’ reSET app to treat substance abuse, launched in partnership with Novartis’ Sandoz unit in 2018.

While the industry is optimistic about the promise of DTx, manufacturers are still navigating unchartered territories around the best practices for clinical research. Likewise, pharmaceutical companies seeking to tighten partnerships with DTx startups to innovate combination products, find themselves in clinical trial limbo.

Often, DTx manufacturers and drug manufacturers who are exploring DTx pairings seek efficacy-validating evidence through clinical trials to earn the confidence of consumers and the attention of payers so that they can get their products reimbursed. FDA or European Medicines Agency (EMA) approval is not always the end goal.

AstraZeneca, for instance, has designed a rigorous and low-patient-burden digital therapeutic to monitor metastatic breast cancer patients. The prescription DTx, which is currently being tested in clinical trials in 23 countries, was developed using insight from a review of medical literature, pulmonary and breast cancer experts, technology review, and real-world evidence gathered through conducting a deep cohort analysis of approximately 500 patients in US health systems. The therapeutic’s aim is to monitor patients’ symptoms and vital signs and, based on algorithms and expert rules, alert a physician as to how well the patient is doing on the treatment to maximize both safety and outcomes.

“Regulation will differentiate between a fitness app a consumer can simply download, with no regulation required, versus something that is scientifically proven to have a direct impact on someone’s health condition or outcome, which a doctor may prescribe,” said Cristina Duran, chief digital health officer for AstraZeneca, in a statement. “In a few years, I think we will see that shift to it being commonplace for your doctor to prescribe a digital therapeutic, a medication, or both.”

On top of today’s regulatory limbo, manufacturers face several additional clinical challenges, including patient recruitment and retention, quality of data, and high costs. At the same time, clinical trial models are rapidly evolving, adding further complexity to companies working to develop innovative digital therapeutics in a post-pandemic environment. Decentralized clinical trials (DCTs) are becoming more common as the preferred model for research in biopharma and offer similar—if not even greater—value to companies conducting studies on digital therapeutics.

Fundamentally, a DTx is software rather than a pill or injectable, so there is no distribution or administering of medicines. There are no physical logistics—no shipping, storing, chain of control, cold storage, or biohazards; plus endpoints can be captured within the DTx application itself, making DCTs ideally suited for DTx studies whether seeking regulatory approval or consumer and payer confidence.

The following are three ways DCTs enable DTx development.

DCTs boost patient recruitment, retention, and engagement

Patient retention and engagement have long been challenges in clinical research, but DCTs have had a uniquely positive impact on digital therapeutics studies. DCTs make participating in research easier and studies more accessible to participants who live far away from study centers. Without the need to perform all assessments at a clinical trial site, sponsors can successfully recruit patients from greatly expanded geographic areas. Opening studies up to more participants, optimizes the patient pool, and reduces the need to over-enroll based on anticipated attrition or drop-out rates to improve cost efficiency.

One emerging DTx company that uses a cognitive behavioral therapy to create mobile apps aimed at managing and preventing chronic diseases recently initiated a DCT for its latest digital therapeutic. The product is designed to measure and unveil early detection, management, and de-escalation opportunities for individuals who are at risk for, or are managing, cardiovascular disease. The decentralized model was a natural fit for the midsize company.

The study’s principal investigator said the company chose a DCT versus a traditional brick-and-mortar trial model to improve and diversify patient recruitment as well as to remove population bias. “Patients are starting to demand more convenient methods of participating in research,” she explained. “DCTs remove so many burdens that stand in the way of recruiting patients for trials.”

Mike Aratow, MD, FACEP, co-founder and chief medical officer of Ellipsis Health, a DTx company that developed the first voice vital sign to quantify and manage depression and anxiety at scale, also noted the significance of DCTs on patient recruitment. “A decentralized model not only aids patient recruitment because it removes many of the burdens associated with traditional trials, but it also makes it easier to reach underrepresented groups and those from a wider geographic landscape, providing real-world evidence and ecological validity. In traditional research, a significant amount of the medical data can’t be reproduced due to issues around patient retention and patient participation.”

Feel Therapeutics develops digital biomarkers and therapeutics for mental health using a proprietary wrist-worn wearable device.It monitors various physiological signals continuously to extract metrics and insights on patients’ psychological and physical health. Feel CEO George Eleftheriou agrees that DCTs help optimize patient recruitment and improve engagement and retention.

“Wearable and digital technologies remotely measure endpoints while engaging participants in an unprecedented way, which naturally aligns with digital therapeutics that are intended to integrate into patients’ everyday lives,” he said. “It is indicative that participants in our digital programs use our app for over 55 minutes per week.”

Decentralization improves cost efficiency

In 2020, Insider Intelligence predicted the global DTx market would hit $9 billion by 2025, but a year later sharply upped that forecast to $56 billion.⁵ This boon is largely driven by the surging need for therapeutic treatments for chronic and behavioral conditions—areas where digital therapeutics thrive. Despite this market growth, the DTx industry is still in its infancy with most companies considered start-ups with modest resources. Cost efficiency is central to their success—and another reason why a decentralized clinical trial model complements the DTx business strategy.

DCTs save costs, in part, by saving time. For instance, the single biggest time drain in drug clinical trials is patient recruitment, which can take up to 30% to 40% of the duration of the entire trial process and contribute to a study’s high price tag. Similarly, recruiting a diverse patient population and keeping them engaged for DTx studies is draining. By expanding the geographic area for recruitment, DCTs speed recruitment across a more representative patient population. By removing many of the burdens incurred by traditional trials, too, DCTs decrease drop-out rates in DTx studies.

In addition to the financial windfall that comes with saving time, DCTs require less staffing and eliminate the need for sites and infrastructure. In fact, for many growing DTx companies, lengthy brick-and-mortar trials are overkill as they don’t have the same scope or needs as a randomized Phase II FDA study for a new pill. The DCT model enables researchers to customize digital therapeutics trials based on exact needs, scaled according to their unique patient population and commercialization strategy.

For example, often the technology that DTx companies need to run a trial is materially different from the technology needed for a trial studying traditional medicines. Further, much of the software needed for a DTx trial is already baked into the DTx app being studied, so many of the robust components required for traditional clinical trials involving prescription drugs are not needed. DTx companies can save substantially—reducing the costs by a factor of 20 or more—by cherry-picking just the technology needed to run the DCT rather than paying for the full functionality of a comprehensive application. Curavit saved one DTx company $375,000 just by using a scaled back ePRO built into the digital therapeutic app rather than investing in an elaborate, name-brand system to do the same.

This benefits the patient, too. Patients who use one app to complete all trial forms find participation much easier than using different devices or going into a site for repeat visits. Again, a better patient experience decreases study drop-out for even greater savings and improved trial data.

Data quality improves with DCTs

Decentralized trials enable DTx companies to collect real-world data direct from patients where they are most comfortable, which has quantifiable impact on data quality.

Erik Won, MD, president and chief medical officer of Wave Neuroscience, a DTx company that specializes in treating brain disorders and optimizing brain performance, explained, “DCTs increase the quality of data by minimizing the Hawthorne Effect—a reactivity in which individuals modify an aspect of their behavior in response to their awareness of being observed, also known as ‘white coat syndrome’—because patients are in their home environment.”

Won continued, “With a decentralized trial, we get the best of both worlds. We can use other mechanisms to ensure that patients are following protocols while ensuring compliance. For instance, we record EEGs using wearables and ask patients to complete simple online surveys.”

Ellipses Health’s Aratow added, “By going to patients rather than having them come to us, the data collected is far more accurate and reflects real- world evidence.” Ellipses Health captures authentic voice using a mobile app so patients can stay comfortably in their homes.

DCTs also enable DTx researchers to capture data and endpoints directly within the therapeutic itself for seamless data capture and less potential for “lost” information. Patients can complete a survey on the same device (i.e., iPhone) as the app, improving engagement and reducing burdens. While the same benefits can be achieved for traditional drug product trials, these require an additional device or piece of software such as an ePRO, whereas a DTx trial participant only must learn and use a single app.

“DCTs enable us to collect passive, continuous, and objective data from users 24/7/365 and move from episodic patient-reported outcomes to continuous data collection,” added Feel’s Eleftheriou. “This rich data provides real-world evidence and allows us to explore novel biomarkers or digital endpoints in neuroscience and other chronic conditions with a high prevalence of mental health comorbidities, such as MS, certain cancers, and cardiac problems.”

The questions around regulatory approval

DTx companies operate in a nebulous regulatory environment, even as the FDA works to clarify requirements. For example, the agency has demonstrated its commitment to supporting digital health technologies recently through the publication of multiple relevant guidance documents as well as the founding of the Digital Health Center of Excellence (DHCoE) in fall of 2020. The DHCoE provides regulatory advice and support to the FDA’s regulatory review of digital health technology, claiming that it is “setting the stage for advancing and realizing the potential of digital health.” In April 2021, too, the FDA loosened regulations surrounding approval of digital mental health tools to hasten their time to market.5

Yet, the regulatory landscape is complex, evolving quickly, and differently in each country. Regulatory approval is not always required to go to market, disincentivizing studies. Many DTx manufacturers are left to make decisions on their own on whether they choose to seek regulatory approval, depending on their commercialization strategy. It’s also challenging to design comprehensive clinical studies for novel treatment approaches, and expensive to run them. Most companies are taking a bifurcated approach—seeking FDA approval for one variation of their product and not for another, while leaning into the DCT model to gather convincing evidence and stand out from the competition, plus earn trust from patients.

Wave Neurosciences follows FDA guidelines for conventional trials, while also finding ways to adapt these in non-FDA studies to maintain regulatory compliance. The company references these as “bridge” studies—in other words, a clinical trial that is smaller, faster, less expensive, and designed to gather enough validated data to determine if taking the next step to an FDA-approval study makes sense. In these cases, especially, a DCT model makes it much easier and faster to conduct a bridge trial for DTx companies looking to determine what the next best steps should be for their product and commercialization strategy.

“All DTx manufacturers, whether a pharmaceutical company dabbling in this area or a pure DTx company, want payers and patients to be confident in their therapeutics’ efficacy, safety, and economics,” said Wave’s Won. “We leverage the flexibility of a decentralized trial to capture the data we need to get our products on formulary, even if we don’t always apply for regulatory approval.”

The marriage of digital therapeutics and digital trials

There’s still a lot to be learned in the digital therapeutics market, but they are here to stay with growing reliance, trust, and adoption of digital health products. COVID-19 pushed researchers to lean into the decentralized model for research, and the pandemic has simultaneously fueled a growing need for DTx products—an ideal marriage of process and product. While it’s true that many of the same benefits of DCTs that apply to traditional drug trials governed by the CDER also apply to DTx apps governed by CDRH, DCTs may offer even greater value to any company manufacturing DTx either in combination with other medicines or alone.

Joel Morse, CEO, Curavit Clinical Research

References

1. “Digital Health Funding Jumps to New High,” by Nick Paul Taylor; MedTech Dive (Jan 21, 2022). See full resource: https://bit.ly/37SjPWx
2. “Global digital therapeutics market projected to reach USD $13.1 billion by 2026,” ReportLinker (July 2021). https://bit.ly/3JDOJQJ
3. “The Growing Power of Digital Healthcare,” by Bill Taranto; TechCrunch (Dec 20, 2021). https://tcrn.ch/3DnBvoZ
4. “Sanofi Breaks into Digital Therapeutics with Mental Health App,” by Beth Snyder Bulik; FiercePharma (Sept 16, 2019). https://bit.ly/3DaOPN7
5. “DTx Trends and Companies to Watch in the Growing Digital Health Industry,” Insider Intelligence, (July 29, 2021). https://bit.ly/3IwNb9P