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Pam Diamond | Curavit Clinical Research

Pam Diamond, MD

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 re-write the future of healthcare.{3}

The DTx industry isn’t just aspirational. Studies show improved outcomes from DTx, 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 platform that incorporates neurological music therapy, sensors, and artificial intelligence 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.


While exciting, this is still unchartered territory. Regulatory lines are often blurry between prescription DTx, non-prescription DTx, and combination digital therapeutics/traditional medication. It’s worth noting, however, that the U.S. Food and Drug Administration (FDA) has demonstrated its commitment to supporting digital health technologies through the publication of multiple guidance documents and the launch of the Digital Health Center of Excellence, which aims to connect and build partnerships to accelerate digital health advancements, in September 2020. In April 2021, too, the FDA loosened regulations surrounding approval of digital mental health tools to hasten their time to market.{4}

Even so, not all DTx manufacturers choose to seek FDA approval, but they all need to prove efficacy through clinical studies for payers to consider coverage and consumers to consider purchase. Regulatory approval is not always the end goal—or at least, not initially.

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 U.S. health systems.{5} 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.”

Indeed, it’s a complicated and quickly evolving arena in healthcare.

On top of the current regulatory limbo, DTx manufacturers face many of the same clinical trial challenges as traditional drug makers, including those tied to patient recruitment and retention, quality of data, and costs. They also must carefully consider the unique technical security concerns of an all-digital therapeutic and face strategic decisions around either provisioning smart devices or leveraging a “bring your own device” (BYOD) policy. At the same time, clinical trial models are rapidly evolving, adding further complexity for companies working to develop innovative digital therapeutics in a post-pandemic environment. Decentralized clinical trials (DCTs) are becoming a preferred model for research in biopharma and offer even greater benefits to companies conducting studies on digital therapeutics.

Wave Neuroscience, a medical device manufacturing company that specializes in designing software and physics-based personalized brain-based interventions, is moving toward more decentralized clinical trial designs. “DCTs can improve patient recruitment and retention by reducing burden and eliminating geographic barriers,” explained Dr. Erik Won, president and chief medical officer of Wave. “This also results in a more representative sampling of the population, such as patients from rural areas who often don’t have access to major institutions.”

Dr. Won continued, “DCTs can also increase the quality of data by minimizing the Hawthorne Effect—where 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.” Finally, DCTs can be more cost-effective, he added.

When Stars Align: DCTs and DTx

Fundamentally, a DTx is software rather than a pill or injectable, so there is no distribution or administration 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 the goal is regulatory approval or consumer and payer confidence.

In all cases, though, the unique advantage is that the DTx being studied in a trial is also the data collection device, so manufacturers often don’t need extra technologies like an electronic patient-reported outcome (ePRO) system to capture data in a clinical trial. It’s all in one, and this can result in big cost savings.

For example, Texas A&M and Wave Neurosciences are conducting a hybrid clinical trial on the safety and efficacy of magnetic EEG-guided resonance therapy to treat post-traumatic stress disorder (PTSD). This therapy uses transcranial magnetic stimulation, which has been cleared by the FDA for treatment-resistant major depressive disorder, obsessive compulsive disorder, and nicotine cessation. With this algorithm-driven therapeutic, a personalized treatment is delivered via conventional (in-person) appointments. Screening and follow-up visits, in which participant-reported data are collected, take place virtually to the extent possible.

“America is experiencing a crisis in mental health,” said Dr. Won. “Software- and physics-based personalized therapeutics are a modern, non-pharmaceutical, non-invasive option to help in this area. We are testing our therapeutic with an eye to pursuing an FDA marketing approval for the PTSD indication. We are exploring the decentralized trial model to introduce greater flexibility and speed into our research efforts.”

Best Practices for Designing DTx Trials

With the quickly growing and evolving DTx market, and the complexities associated with clinical research, here are five considerations for decentralized trial design:

  1. Know your regulatory roadmap before embarking on a trial.

Because the regulatory pathway for digital therapeutics is not as clear-cut as it is for traditional investigational drugs, it is critical to outline your regulatory roadmap before recruiting the first patient. Feasibility studies can be a good place to start, especially to help map out an expansion plan down the line. Some important considerations also include how future versions of your DTx product will be tested, benchmarked, and evolve over time.

“It is always best to seek meetings with the FDA’s device division [the Center for Devices and Radiological Health] early, and often,” said Dr. Daniel Karlin, chief medical officer at MindMed, a clinical stage biopharmaceutical company developing novel products to treat brain health disorders. Dr. Karlin is also the lead medical advisor to the makers of the first and only FDA-cleared, prescription DTx that improves sleep in adults 22 and older with nightmare disorder or nightmares related to PTSD.

Dr. Karlin continued, “It is easier for DTx providers to secure meetings with the FDA because digital therapeutics are typically less biologically complex and therefore pose less risk. Request a meeting at the start of your development efforts to agree on the claims you plan to make based on the indication for use, and to establish what related evidence will satisfy the FDA. This is fundamental. Also, seek institutional review board [IRB] clearance on anything that could conceivably be research-related before you bring an experimental device to humans for studies.”

Of course, regulatory approval—while often considered the ultimate validation for the safety and efficacy of a drug or device—isn’t the only reason for conducting clinical research, especially with DTx. Health economic outcomes and human factor research are often equally important for product adoption. Even in the digital realm, real-world function and outcomes are important to create products that lead to meaningful outcomes for patients. “All manufacturers want payers and patients to be confident in our product’s efficacy, safety, and economics,” added Dr. Won.

For instance, some DTx products that have minimal risk may not require regulatory approval but are just as valuable as those that do. Decide if regulatory approval is on your short-term or long-term roadmap and design the trial accordingly. If it is not, then there is greater flexibility in study design.

  1. Map out an immediate and long-term commercial strategy.

Given how quickly the DTx marketplace is evolving, the best that can be done may be to sketch out a preliminary commercialization strategy that has plenty of leeway to deviate from that path, if necessary. For instance, if your therapeutic will not be intended for regulatory approval, you may need to focus on a consumer strategy that focuses on everyday wellness. If you know this up front, you can design your clinical trial around endpoints that mirror your target consumer’s biggest pain points. However, if your end-goal is to develop a DTx that will be used in combination with an FDA-approved drug, then you will need to design your trial based on endpoints relevant to that drug maker’s target patient population.

  1. Carefully consider and incorporate protections against technical security breaches.

Data security and privacy are crucial for all clinical trials, but especially when studying DTx that are 100% tech-driven and, therefore, potentially vulnerable to more issues. One of the most important decisions that needs to be made up front is whether the protocol will strictly enforce a BYOD strategy (which could prevent some patients from participating) or require the sponsor to provision devices to all participants (which could be cost-prohibitive)—or some combination thereof. Each option comes with different security considerations, so decide this up front.

Regardless of device strategy, all data collected on the smartphone will need to be encrypted and then sent to a secure central platform in the cloud that follows all regulatory compliance parameters. Additionally, invest in a platform provider or tech-enabled CRO that maintains a strict security perimeter, including a “zero-trust” architecture with individual logins and audit trails for everyone who has access to the data every time they log in or out—this, on top of the digital therapeutic app’s security standards.

  1. Develop digital endpoints that are fully validated and meaningful to patients.

Traditional medicine trials measure against accepted endpoints that are validated in accordance with standards set forth by the IRB and regulatory organizations. However, DTx studies are typically measuring novel digital endpoints that are different for each DTx app and do not have a history of vetted benchmarks against which to be validated. Even so, reviewers will need to ensure that the novel endpoints aren’t bogus, and this can require some extra steps and creativity.

In many cases, endpoint validation in DTx studies requires a comparison to something similar that has been already validated or the use of previously vetted ratings scales. For example, when conducting a depression study, the DTx sponsor may first administer the Columbia-Suicide Severity Rating Scale—a suicidal ideation and behavior rating scale created by researchers at Columbia University, University of Pennsylvania, University of Pittsburgh, and New York University—to potential participants at screening. The patient’s score can be the baseline for the study, so if the DTx is efficacious, that score should drop and serve as a validated digital endpoint for symptoms of depression.

Similarly, DTx studies may leverage ePROs to administer quality-of-life questionnaires compared against prior research already accepted and validated by the IRB and FDA. Another way to validate endpoints in a decentralized DTx trial is to incorporate an initial site visit with a clinician who can compare the measurement of, say, a wearable device against an equivalent onsite, hospital-grade machine. Doing so can prove the wearable is as valid a measuring tool as another.

Finally, as important as endpoint validation is patient validation—in other words, identify the measurements or endpoints that are meaningful to patients. For example, with Fern Health’s digital musculoskeletal platform, the company shifted the focus of pain management from pain relief to functional restoration. Early on, the company found that functional pain endpoints are more important to patients in the long term than pain relief alone and made that critical adjustment.

  1. Assess the use of DTx placebos or sham apps early and often.

In a DTx clinical trial, dummy or “sham” apps are often used as a control in comparison to the actual treatment or intervention app—like a placebo pill used in a randomized control trial. There are unique considerations in using sham apps, however, including the potential for an unintentional placebo effect.

Here is the challenge: It is very difficult to make a sham app similar enough to the real one, which means patients often suspect that they were not assigned to the treatment arm. In addition, patients who do interact with the sham app can experience a placebo effect that negatively skews study results. For instance, patients in the treatment arm of a study would typically show significant symptom improvement compared to the non-treatment arm, but when using a sham app, that disparity is not as dramatic.

The FDA has not yet ruled on whether placebos or “sham” apps must be used in DTx trials, but the agency often prefers a sham control. DTx companies that opt not to use a sham control will need to work very hard to find creative ways to design an FDA-acceptable trial that won’t be criticized—even then, there is no guarantee that the FDA will accept the results.

“It is highly unusual to view sham controls as unnecessary in clinical trials,” said Dr. Karlin. “Not only do regulatory bodies prefer sham-controlled evidence in digital therapeutics studies, but also clinicians. Reluctance to use sham apps will cause companies to struggle to get both FDA clearance and physician buy-in, which is critical for commercial success with patients.”

Dr. Karlin’s team for the PTSD DTx leveraged a sham control on a wearable device that, rather than buzz when detecting a nightmare, simply recorded it. “When we assessed the reliability of our blind through a survey of our trial participants, we found that most did not know whether they were using the real therapeutic or the sham,” he noted. “This helped validate the research because it meant that we could reliably compare the active intervention with the placebo for more meaningful results. Randomization and sham control are not magic bullets, but they’re the best options we have right now.”

As the Digital World Turns…

There’s still a lot to be learned in the DTx 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. Remaining flexible and open-minded will be critical to succeed in this evolving and exciting area—as the digital world turns.


  1. Taylor NP. 2022. Digital Health Funding Jumps to New High. MedTech Dive. See full resource here.
  2. Market and Markets report. 2021. Global Digital Therapeutics Market Projected to Reach USD $13.1 Billion by 2026. ReportLinker. See full resource here.
  3. Taranto B. 2021. The Growing Power of Digital Healthcare. TechCrunch. See full resource here.
  4. Staff report. 2021. DTx Trends and Companies to Watch in the Growing Digital Health Industry. Insider Intelligence. See full resource here.
  5. Galbraith S. 2021. Digital Therapeutics: Augmenting Patient Outcomes. AstraZeneca. See full resource here.
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