Digital Therapeutics: The FDA-Clearance Blueprint That Actually Works

July 25, 2025

Discover the proven FDA-clearance blueprint for digital therapeutics success—key steps, strategies, and insights that actually work.

Digital therapeutics represent a rapidly expanding sector valued at $3.35 billion in 2021, with projections reaching $12.1 billion by 2026. This remarkable growth reflects the increasing adoption of software-based interventions designed to prevent, manage, or treat medical conditions. Some industry observers predict an even more dramatic expansion, estimating the market opportunity could reach $56 billion by 2025.

Since the clearance of the first digital therapeutic device—WellDoc’s DiabetesManager System—in 2010, the field has seen significant international development. Currently, 507 digital therapeutics applications exist across the US, China, Germany, and Belgium. Notably, each region shows distinct priorities: the US and Belgium focus primarily on disease management, while Germany concentrates on addressing mental and behavioral disorders.The FDA plays a crucial role in regulating these innovative solutions, focusing oversight on mobile medical apps that meet specific criteria. Additionally, investment in digital therapeutics has grown impressively at 40% per year over the past seven years according to a 2020 McKinsey & Company report, highlighting both the sector’s potential and the need for clear regulatory guidance.

Understanding Digital Therapeutics in the FDA Context

The regulatory landscape for software-based healthcare interventions continues to evolve as technology advances. For companies developing digital therapeutics (DTx), understanding how these products fit within the FDA’s regulatory framework is essential for successful market entry.

What is digital therapeutics and how it differs from wellness apps

Digital therapeutics provide software-driven therapeutic interventions that work alongside or independently from traditional treatments to manage, treat, or prevent diseases and disorders. Unlike general wellness apps that merely track health metrics or provide basic information, DTx products make specific medical claims and deliver evidence-based interventions directly through software.

The International Organization for Standardization defines digital therapeutics as “health software intended to treat or alleviate a disease, disorder, condition, or injury by generating and delivering a medical intervention that has a demonstrable positive therapeutic impact on a patient’s health”. This definition highlights a crucial distinction: DTx products must demonstrate clinical efficacy through robust evidence.

Key differences between digital therapeutics and wellness apps include:

• Evidence requirements: DTx manufacturers must provide evidence through randomized controlled trials, pragmatic clinical trials, real-world evidence, or combinations thereof.
• Regulatory oversight: DTx products making clinical claims undergo FDA review, whereas wellness apps typically do not.
• Clinical intervention: DTx directly delivers therapeutic interventions, rather than merely tracking or informing.
• Clinical outcomes: DTx aims to produce measurable health outcomes for specific conditions.

SaMD classification and its relevance to DTx

Many digital therapeutics fall under the FDA’s Software as a Medical Device (SaMD) category. The International Medical Device Regulators Forum defines SaMD as “software intended to be used for one or more medical purposes that perform these purposes without being part of a hardware medical device”.

The FDA, together with international regulators through the IMDRF, has developed a risk-based framework for SaMD that directly impacts how digital therapeutics are regulated. This framework classifies software based on:

• The severity of the medical condition it addresses.
• The significance of the information it provides for healthcare decisions.

For digital therapeutics developers, understanding this classification system is critical because it determines the regulatory pathway and evidence requirements. Most digital therapeutics are classified as Class II medical devices, requiring special controls beyond general regulatory requirements to ensure safety and effectiveness.

Prescription vs non-prescription digital therapeutics

Digital therapeutics, much like traditional medications, can be either prescription or non-prescription products. Prescription digital therapeutics (PDTs) require authorization from a licensed healthcare professional. The first FDA-authorized PDT was reSET® for substance use disorders, cleared in 2017.

In contrast, non-prescription digital therapeutics can be accessed directly by consumers without professional oversight. Nevertheless, both types undergo FDA review based on their intended use and risk classification. For instance, Natural Cycles, a non-prescription menstruation tracking application, received FDA authorization through the de novo pathway as a Class II device.

The decision to classify a digital therapeutic as prescription or non-prescription depends on several factors:

• Risk level associated with the intended use.
• Target patient population vulnerability.
• Nature of the condition being addressed.
• Complexity of the intervention.

FDA authorization of these products follows the same general framework used for other medical devices, with 65% of prescription digital therapeutics authorized through the 510(k) pathway and 35% through the De Novo pathway. Furthermore, studies have shown that 100% of examined prescription digital therapeutics underwent at least one study with a clinical primary endpoint, and 90% were evaluated using at least one randomized controlled trial.

FDA Regulatory Pathways for Digital Therapeutics

“Both pathways involve the submission of detailed data reports and product descriptions that inform the creation of patient and clinician labeling/instructions for use if the product is authorized.” — Dr. Sean D. Sullivan, Professor and Dean, University of Washington School of Pharmacy 

Navigating the FDA’s regulatory framework requires strategic planning for digital therapeutics developers. The pathway to market depends primarily on how the FDA classifies a product—a process that determines both the level of regulatory scrutiny and the evidence requirements needed for clearance.

Class I, II, III device classification explained

The FDA classifies medical devices, including digital therapeutics, into three categories based on their risk profile and the level of regulatory control needed to ensure safety and effectiveness:

• Class I (Low Risk): These devices pose minimal potential harm and are subject only to general controls. Approximately 74% of Class I devices are exempt from premarket notification requirements. However, few digital therapeutics fall into this category due to their direct therapeutic claims.
• Class II (Moderate Risk): Most digital therapeutics receive this classification, requiring both general controls and special controls specific to the device type. For instance, digital therapeutics for psychiatric disorders follow requirements under 21 CFR 882.5801, while those for gastrointestinal conditions fall under 21 CFR 876.5960.
• Class III (High Risk): These high-risk devices require the most stringent controls, including premarket approval (PMA). Class III devices either support or sustain human life, prevent health impairment, or present potential unreasonable risk.

The classification process fundamentally centers on the intended use of the product and its indications for use—not merely the technology itself. Consequently, similar software products may receive different classifications based on their specific therapeutic claims.

510(k) clearance vs De Novo pathway

Digital therapeutics typically enter the market through one of two primary pathways:

The 510(k) clearance pathway requires demonstrating “substantial equivalence” to a legally marketed predicate device. This means showing that the new device is as safe and effective as an already-cleared device. Approximately 61.5% of prescription digital therapeutics have utilized the 510(k) pathway. The average review time for 510(k) submissions is about 193.4 days.

The De Novo pathway applies when no suitable predicate device exists—often the case for novel digital therapeutics introducing first-of-kind technologies. This pathway creates a new regulatory classification for the device. Around 38.5% of prescription digital therapeutics have gone through De Novo classification, with an average review time of approximately 251.1 days.

Initially, breakthrough digital therapeutics typically follow the De Novo route, subsequently creating predicates that similar products can reference through the 510(k) process. For example, the first FDA-authorized prescription digital therapeutic, reSET for substance use disorders, utilized the De Novo pathway in 2017, establishing a precedent for subsequent applications.

Special controls for Class II DTx devices

Beyond general regulatory requirements, Class II digital therapeutics must comply with special controls—specific measures designed to provide reasonable assurance of safety and effectiveness. These requirements are tailored to the particular risks associated with each device type.

For digital therapeutics, common special controls include:

• Clinical performance testing demonstrating therapeutic effectiveness for specific conditions using validated measures.
• Software verification, validation, and hazard analysis documentation.
• Comprehensive labeling requirements, including instructions for use, system requirements, and appropriate warnings.
• Specific documentation addressing cybersecurity concerns.

Importantly, these special controls often mandate clinical data to demonstrate safety and effectiveness. Even when using the 510(k) pathway, digital therapeutics developers typically need to conduct clinical trials to show substantial equivalence to a predicate.

As the digital therapeutics market evolves, the FDA continues refining its regulatory approach through initiatives like the Software Pre-Certification Pilot Program launched in 2020, aimed at streamlining the review process for software-based medical devices while maintaining rigorous safety standards.

Blueprint Components for FDA Clearance Success

Successfully bringing digital therapeutics to market requires mastering four critical components of FDA submissions. Each element must be meticulously addressed to demonstrate product safety and effectiveness.

Clinical validation requirements for DTx

Digital therapeutic products must undergo rigorous clinical validation through randomized controlled trials and ongoing real-world evidence generation. 

The FDA evaluates DTx across six primary domains:

• Safety
• Benefit
• Durability
• Usability
• User engagement
• Behavior change

Clinical endpoints must be reproducible, valid, and quantify what was intended to be measured. Specifically, protocols should clearly define endpoints and pre-specify clinically relevant effects based on published standards or consensus among independent clinicians.

Usability testing under IEC 62366 and ISO 14971

Implementing IEC 62366-1 usability engineering proves essential for developing digital therapeutics. This international standard offers a clear framework for identifying, analyzing, and mitigating usability risks arising from user interactions. Throughout development, manufacturers must conduct multiple rounds of formative evaluations with healthcare professionals, patients, and caregivers to continually refine product designs. The third edition of ISO 14971, released in December 2019, complements this process by emphasizing the importance of defining benefit and state-of-the-art technology when evaluating residual risk.

Labeling and patient instructions compliance

The FDA strictly regulates labeling for digital therapeutics under Title 21 of the Code of Federal Regulations. Section 201(m) defines labeling as “all labels and other written, printed, or graphic matter upon any article or any of its containers or wrappers, or accompanying such article”. Notably, “accompanying” extends beyond physical association to include posters, pamphlets, instruction books, and even advertising materials.

Cybersecurity documentation for FDA submission

As connected medical devices become standard, cybersecurity documentation has grown increasingly crucial. In June 2025, the FDA released final guidance on “Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions”. Plus, submissions for “cyber devices” must include a cybersecurity management plan, processes for reasonable assurance of cybersecurity, and a Software Bill of Materials (SBOM). Throughout the process, manufacturers must demonstrate cybersecurity resilience in a dynamic threat environment rather than simply providing retrospective justifications.

Case Studies of FDA-Approved Digital Therapeutics

Examining real-world FDA-cleared digital therapeutics (DTx) offers valuable insights into successful regulatory strategies and clinical applications. These case studies demonstrate how innovative technologies transform traditional treatment approaches through software-driven interventions.

reSET and reSET-O for substance use disorders

In September 2017, reSET made history as the first FDA-authorized prescription digital therapeutic for substance use disorders (SUD). Developed by Pear Therapeutics, this groundbreaking mobile application works alongside standard outpatient therapy to improve patient outcomes. Its companion product, reSET-O, specifically targets opioid use disorder (OUD) patients on buprenorphine treatment.

Clinical trials demonstrated that patients using reSET with outpatient therapy showed significantly improved abstinence from substances and better treatment retention compared to standard care alone. Primarily, these applications deliver cognitive behavioral therapy through interactive content that shifts patients’ focus toward finding activities more rewarding than substance use.

The economic impact of these interventions is equally impressive. Medicaid patients treated with reSET-O experienced meaningful increases in buprenorphine adherence and 45% fewer emergency room visits.

Somryst for insomnia and depression

Somryst represents another milestone as the first FDA-cleared digital therapeutic for chronic insomnia in adults. This 9-week prescription digital therapeutic delivers cognitive behavioral therapy for insomnia (CBT-I) through a mobile application, addressing a condition affecting millions worldwide.

Clinical trials showed remarkable effectiveness, with 62.8% of users achieving treatment response by week 9 compared to just 14% in the control group. Moreover, these benefits persisted long-term, with 56.2% maintaining response at six months.

EndeavorRx for ADHD in children

In June 2020, EndeavorRx became the first FDA-approved game-based digital therapeutic. Designed for children ages 8-12 with ADHD, this innovative approach transforms treatment into an engaging video game experience.

The approval followed five clinical studies involving over 600 children. Results showed that after four weeks of treatment, one-third of children no longer had measurable attention deficits on at least one measure. Importantly, half of parents observed meaningful improvements in their child’s daily functioning after just one month of use.

Evolving FDA Programs Supporting DTx Innovation

“Experts identified advantages of expediting development and of FDA flexibility in applying its standards to new drugs and medical devices, but highlighted concerns that patients may not be adequately informed about the risks of shorter review times or about uncertainties in the evidence that result.” — Dr. Aaron S. Kesselheim, Professor of Medicine, Harvard Medical School 

The FDA has progressively refined its approach to digital therapeutics (DTx) regulation, creating specialized pathways to foster innovation while maintaining rigorous safety standards.

Software Precertification Pilot Program

From 2017 to 2022, the FDA explored a novel regulatory paradigm through its Software Precertification (Pre-Cert) Pilot Program. This initiative aimed to streamline the review process by evaluating the developer rather than primarily focusing on individual products. Nine diverse companies participated, including Apple, Fitbit, Johnson & Johnson, and Pear Therapeutics. Despite promising concepts, the FDA concluded in September 2022 that implementing the approach under current statutory authorities was impractical. Nevertheless, the pilot provided valuable insights that could inform future regulatory frameworks pending legislative changes.

Breakthrough Devices Program for faster review

For digital therapeutics addressing life-threatening or irreversibly debilitating conditions, the Breakthrough Devices Program offers an accelerated pathway to market. As of September 2024, the FDA has granted 1,041 Breakthrough Device designations. To qualify, devices must meet two key criteria: address life-threatening conditions and provide more effective treatment than existing options. Digital therapeutics companies can benefit from prioritized review, interactive communications, and senior management engagement throughout the development process. In 2023, Click Therapeutics received Breakthrough designation for its prescription digital therapeutic treating episodic migraine.

Safer Technologies Program (STeP) for low-risk DTx

Introduced as a complement to the Breakthrough program, STeP serves digital therapeutics treating non-life-threatening or reversible conditions. Eligibility requires demonstrating significant safety improvements, such as reducing adverse events, device failures, or use-related hazards. Unlike Breakthrough and STeP are mutually exclusive programs—devices can qualify for one or the other, but not both. 

Currently, these evolving programs reflect the FDA’s commitment to “empower stakeholders to advance health care by fostering responsible and high-quality digital health innovation”. Primarily, these initiatives aim to balance efficient regulatory pathways with maintaining necessary safety standards for innovative digital therapeutics.

Conclusion

Digital therapeutics stand at the forefront of healthcare innovation, transforming how patients receive treatment through software-based interventions. Throughout this article, we explored the complex FDA clearance landscape that developers must navigate to bring these powerful tools to market. The remarkable growth trajectory—from $3.35 billion in 2021 to a projected $12.1 billion by 2026—underscores the significant role these technologies play in modern healthcare.

Understanding the distinction between wellness apps and true digital therapeutics remains fundamental to regulatory success. Digital therapeutics must demonstrate clinical efficacy through robust evidence, unlike general wellness apps that merely track health metrics. Additionally, the classification system (Class I, II, III) determines the level of scrutiny products face, with most digital therapeutics falling under Class II designation.

The regulatory pathways—510(k) clearance and De Novo classification—offer different routes to market based on product novelty. Pioneering solutions typically utilize the De Novo pathway, subsequently creating predicates for similar products to follow through the more streamlined 510(k) process. Regardless of pathway, developers must address four critical components: clinical validation, usability testing under international standards, compliant labeling, and comprehensive cybersecurity documentation.

Success stories like reSET for substance use disorders, Somryst for insomnia, and EndeavorRx for ADHD demonstrate the tangible benefits of properly executed regulatory strategies. These breakthrough products have shown impressive clinical outcomes while creating precedents for future innovations. Furthermore, the FDA continues evolving its approach through programs like the Software Precertification Pilot and the Breakthrough Devices Program, albeit with varying degrees of implementation success.

The future looks bright for digital therapeutics developers who master this regulatory blueprint. As these technologies become increasingly sophisticated, they will undoubtedly play a central role in addressing healthcare challenges. Most importantly, patients stand to benefit from expanded access to evidence-based interventions delivered through the convenience of software applications. The companies that carefully navigate these regulatory waters today will surely lead the digital health revolution tomorrow.

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