Digital therapeutics





Introduction


Remote therapy and digital therapeutics encompass a number of therapeutic modalities, from e-prescribing, remote surgery, eHealth, and virtual care to digital devices as therapies. Digital therapeutics are well suited for the “one-to-many” model of care, where the reach of physicians to treat patients can overcome time, place, and personnel constraints that can limit healthcare access and delivery. Such therapies, whether digitally enabled, digitally enhanced or otherwise, must be as all approved therapies now are: evidence-based, rigorously evaluated with proven safety and efficacy, and appropriately regulated. This section will focus mainly on digital therapeutics which can be delivered remote from the “normal” or usual site of care provision. Remote surgery will be discussed in more detail in the next chapter.


A good framework for considering digital therapeutics as a distinct class is as delivering medical interventions directly to patients to treat, manage, or even prevent disease or dysfunction. There are 10 core principles or criteria that the Digital Therapeutic Alliance list, which must be adhered to in order for a product to be considered a digital therapeutic ( Table 9.1 ).



Table 9.1

List of 10 core principles that all products claiming to be a digital therapeutic must adhere to as per the Digital Therapeutic Alliance (DTxAlliance.org) https://dtxalliance.org/wp-content/uploads/2021/01/DTA_DTx-Definition-and-Core-Principles.pdf .

































1 Prevent, manage, or treat a medical disorder or disease
2 Produce a medical intervention that is driven by software
3 Incorporate design, manufacture, and quality best practices
4 Engage end users in product development and usability processes
5 Incorporate patient privacy and security protections
6 Apply product deployment, management, and maintenance best practices
7 Publish trial results inclusive of clinically meaningful outcomes in peer-reviewed journals
8 Be reviewed and cleared or certified by regulatory bodies as required to support product claims of risk, efficacy, and intended use
9 Make claims appropriate to clinical evaluation and regulatory status
10 Collect, analyze, and apply real-world evidence and/or product performance data


Many digital therapeutics are regulated as “software as a medical device.” Despite the multiple names and forms of such therapies, global regulators have been scrambling to keep pace with how to classify, regulate, and designate such therapies. While the Food and Drug Administration (FDA) has cleared (note the distinction) or approved digital therapeutic products for over a decade now, the European Medicines Agency (at the time of writing) has not yet designated a regulatory pathway for evaluation and commercialization of digital therapeutics. Despite regulatory uncertainties and no clear indication as to whether insurers or payors will cover or reimburse such therapies, companies focused on digital therapeutics have thrived and seen investor interest surge as the COVID-19 pandemic of 2020 disrupted healthcare delivery.


Digital therapeutics also offer many opportunities not just for patients and physicians, but also for health systems. The lower risk profile of many digital therapeutics, as well as lower development costs and shorter duration from concept to commercialization, requires less capital investment. As regulatory uncertainty around digital therapeutics diminishes, digital therapeutics may help lower the costs of healthcare.


Regulatory considerations for digital therapeutics


While the development of digital therapeutics for urological conditions is in its infancy, other specialties have seen FDA approvals following submission of trial data demonstrating superiority, using both de novo and 510(k) pathways for medical devices. Others, namely Cognoa, who partnered with EVERSANA, received Breakthrough Designation from the FDA for their digital diagnostic and therapeutic for autism spectrum disorder. To put this in context, Breakthrough Designation is awarded by the FDA to help expedite the development and approval of treatments that treat a serious condition and where preliminary clinical evidence indicates that the treatment may demonstrate substantial improvement over available therapies on a clinically significant endpoint. The FDA clarifies that clinically significant endpoints are those that measure an effect on irreversible morbidity (or mortality), further punctuating the recognition that digital therapeutics can disrupt and offer real benefits over pharmaceutical or other treatments, which have been the mainstay of therapy for a number of conditions for over half a century.


The regulatory framework for the approval of digital therapeutic interventions is not as defined as that for physical devices or pharmaceuticals. In 2017, the FDA introduced a Software Precertification Pilot Program which aimed to help inform the development of a regulatory model to assess such innovations. While the FDA has subsequently released discussion documents and draft guidance is available, it is clear that a comprehensive and well-defined pathway requires a great deal of time and many case examples before more certainty exists for those developing such therapies.


In the United States of America, some digital therapeutics must undergo randomized controlled trials under the premarket approval process to demonstrate acceptable safety and efficacy. Digital therapeutics are inherently different though from pharmaceuticals, the form of which remains stable and composition unchanged over time. Many digital therapeutics that are essentially software as a medical device have the potential and indeed often require frequent updates following FDA review, much as the operating system on servers, computers, and smart devices do. Other digital therapeutics that utilize machine learning or other artificial intelligence (AI) as a component may evolve as they “learn” the optimal features over time.


Digital therapeutics in urology


The current field of digital therapeutics is largely focused on chronic conditions or those that are modifiable by means of behavioral change. The therapy, which was otherwise an in-person service, is provided as a digital product which may be over-the-counter or prescription only. Similar to a prescription medicine, the prescription-only digital therapeutic is prescribed and the patient is ultimately directed to the manufacturer who, by various means, enrolls the patient onto the digital therapeutic. Digital therapies often make use of an access code or other time-constrained access modality to enable the use of a mobile application as prescribed and as per the digital therapeutics approved label. Web dashboards are often available, which allow patients and physicians to monitor progress and compliance. While the field of digital therapeutics is still in its infancy, the number of approved and available therapies currently focused on patients exclusively with urological conditions is limited. Throughout this chapter, an overview is provided of digital therapeutics currently approved or in development in contexts which are relevant to urology. While some may currently be approved for specific conditions, they are of utility to the care of patients with urological complaints, which may benefit the urologist in helping to provide more holistic care and may even provide inspiration for adaption and help improve care of patients with other conditions.


Example use cases of digital therapeutics


Preventative care


Livongo is a digital therapeutic product for diabetes, diabetes prevention, weight management, and hypertension. It is, however, not FDA approved. It is still commercially available though. Livongo is operated by Teladoc Health, a large virtual care company, which says they are “creating a truly unified and personalized consumer experience; developing technologies to connect to patients and extend the reach of care providers; delivering the highest standard of clinical quality at every touchpoint; and enhancing health decisions and outcomes with smart data and actionable insights.” They are by their own description a consumer company, and despite their name, are not a health company. The underlying concept though, allows for preventative care which is relevant to those with metabolic syndrome, for example, a condition highly prevalent amongst urology patients—and was present in ∼39% in a study conducted in male urology patients ( ).


Wellthy CARE Digital Therapeutics Platform also provides an offering for lifestyle modification and enables weight loss in patients with obesity and metabolic syndrome. They offer a yearlong program, which includes a health coach, supports for diet modification, physical activity, and remote patient monitoring of glycemic control and blood pressure. They conducted a single arm study involving 196 participants over a period of 52 weeks ( ). While there was no control arm, those who were in the highest quartile in terms of app engagement lost 3 kg of weight compared to those in the lowest quartile who lost 1.2 kg. While further work is required to fully validate this specific platform, it does offer a positive signal of the potential utility of such interventions in preventative care.


Preoperative assessment


Urologic patients undergoing surgical procedures require careful preoperative evaluation and planning prior to surgery. Failure to assess the preoperative needs of these patients could potentially lead to increased intraoperative and/or postoperative morbidity. The effect may be temporary, such as increased postoperative dementia in geriatric patients taking certain preoperative medications ( ), or more insidious, as seen with increased complications in patients with suboptimal nutrition prior to radical cystectomy ( ). In addition to increased morbidity, an incomplete preoperative assessment can have financial implications for both the patient and the hospital system. For example, a prospective cross-sectional study from 2011 looked at surgical cancellation rates in 25 hospitals and found that approximately 8% of elective urological surgeries were canceled and rescheduled within 24 h of the scheduled procedure ( ). Medical administrative reasons, such as incomplete medical work, have been cited as a major source of many of the cancellations. Such digital tools and therapies can help improve patient compliance with pre-operative care instructions, and with nutritional status, and even help in the completion of the pre-operative assessment itself.


Managing chronic conditions


Another robot doing in the rounds is Catalia Health’s Mabu. Mabu, an abbreviated form of the Japanese word “Mabudachi”, meaning close friend, uses AI and psychological modeling to encourage and motivate people to take their medications. It isn’t just an alarm clock on wheels, but it aims to build relationships with patients and customizes its conversations to keep patients adhering to dosing regimens for longer. It is currently being used in helping patients with congestive heart failure, rheumatoid arthritis, chronic kidney disease as well as being integrated into clinical trials to help record and report patient reported outcomes and improve treatment adherence in ambulatory trials. It can also be used to facilitate telemedicine visits and also connects with other devices to collect and report data. The solution offered by Catalia Health does not require the user to configure the robot in anyway, other than turn it on when they unbox the robot. As it is equipped with its own cellular modem, it aims to be more accessible to more patients, independently report data and provide 24/7 monitoring or as programmed.


Proteus Digital Health spent almost 20 years developing ingestible sensors and gained regulatory approval in 2017 for its “smart pill” from the FDA. The technology is incorporated into medications; a feat possible because the sensor employed was the size of a grain of sand and is coated on one side with copper and on the other with magnesium. When the pill is swallowed, gastric acid helps complete the circuit and generates a detectable, albeit tiny, electric current, which is detected by a sensor patch worn by the patient on their abdomen. This in turn connects with a mobile app and can be shared with those monitoring compliance. It helps complete a timestamp of when the medication was actually taken and so can determine adherence and compliance with a level of accuracy and granularity, which is hard to match for an oral ingestible medication which is self-administered. The patch is also a multimodal sensor and can measure activity and sleeping patterns, heart rate, and temperature. Some of the potential applications of the system included improving access to medications. Some payers and health systems will not provide some high-cost treatments to patients who are at risk of nonadherence. A pilot study examining this claim was performed and included 28 patients who were given treatment for hepatitis C that incorporated the smart pill technology. Of the 28 participants, 26 were cured and 94% of prescribed doses were taken ( ). While this technology, its development, and the achievements of those who developed it and validated its utility are to be commended, it should also be noted that it may be used as a cautionary tale. At its pinnacle, Proteus Digital Health were valued at over $1.5 billion US dollars, and despite FDA approval of their technology in 2017, they were bankrupt by 2020, when their underlying assets including intellectual property were bought for $15 million US dollars by a pharmaceutical company who clearly understand the value proposition of the technology.


A multicenter randomized controlled trial of pelvic floor muscle training with a motion-based digital therapeutic device was performed versus pelvic floor muscle training alone for the treatment of stress-predominant urinary incontinence by a group of investigators from Massachusetts General Hospital, Northwestern University, the University of Oklahoma, Cedars Sinai, the Cleveland Clinic, Eastern Virginia Medical School, and the University of Alabama, and published in January 2022. They randomized 77 women but had to halt the trial early due to device technical considerations. However, before termination, those randomized to the intervention group installed a mobile application to their smartphone and paired with the device: Renovia Inc’s leva digital therapeutic, which is an intravaginal insert equipped with accelerometers and which communicates wirelessly with the smartphone app. This in turn provides visual feedback to the patient. After 8 weeks, the primary outcomes, including change in Urinary Distress Inventory and the Patient Global Impression of Improvement, did not show any improvement between groups; however, the median number of stress urinary incontinence (SUI) episodes decreased from baseline by 1.7 per day in the intervention group compared to 0.7 in the control group, P = .047 ( ).


A subsequent and larger prospective randomized controlled superiority trial, conducted remotely from September 2020 to March 2021, had 363 patients randomized to the same intervention as described in the earlier study by Weinstein et al. This larger subsequent study was powered to detect a difference in efficacy of pelvic floor training by using the levia digital therapeutic device with a home training program to reduce severity of symptoms and episodes of urinary incontinence. This trial demonstrated a significant reduction in both the median number of SUI episodes on the 3-day bladder diary (4 episode reduction vs. 3 episode reduction for the control group; P = .005) and also demonstrated significant improvements in both the UDI-6 score and PGI-I score ( ).


Digitally enabled treatments


As mentioned earlier in this chapter, there are many digitally enabled treatments focused at behavioral modification including weight loss and also chronic conditions such as diabetes which are of relevance to urology patients, but there are many more in various phases of development and, indeed, an entire world of possible digital therapeutics (and perhaps, also ailments) as the use of new technologies becomes more widespread. Treatments can be enabled by digital sensors, wearable devices, virtual reality headsets, and smart home devices. Helping a patient to adhere to a particular diet or fluid-intake schedule, or to pursue and continue a particular exercise routine or medication regimen can all be easily enabled through existing devices, software, and software as a service (SaaS) providers.


In late 2018, PEAR Therapeutics became the first company to have a mobile digital therapeutic, which significantly improved clinical outcomes in treatments for opioid use disorder, approved by the FDA ( ). PEAR Therapeutics’ prescription digital therapeutics use mobile applications as an adjunct to outpatient treatments for diseases in therapeutic areas such as psychiatric and neurological diseases. The app, called “reSET-O app”, increases retention of patients in an outpatient treatment program and is a prescription cognitive behavioral therapy (CBT). While I was unable to locate a similar product in development for urology patients, the reSET-O app provides a clear roadmap for the improved care of a huge number of patients with urological conditions. CBT and other psychotherapeutic interventions have been demonstrated to improve the quality of life and reduce negative effects in patients with cancer: it can treat anxiety and depression as well as persistent fatigue and insomnia caused by prostate, bladder, or renal cancers ( ; ). CBT can also help as an adjunctive treatment for patients with sexual dysfunction ( ). The impact of CBT on the quality of life in patients with prostate cancer was demonstrated by a randomized controlled trial where, after 10 weeks of cognitive behavioral stress management, awareness of disease, change of mood, and communication all significantly improved ( ). The realm of CBT is not limited to the 2.0 generation of devices. In November 2021, the first virtual reality digital therapeutic was approved by the FDA in the United States of America. The therapeutic called EaseVRx is an immersive virtually reality system that also uses CBT as well as other behavioral therapies to help with pain reduction in adults with chronic low back pain. The device allows provision of proven and effective “virtual care” to patients. The application of such innovations allows for gamification of therapy and encourages better compliance with treatment regimens. The uptake of virtual reality will likely increase as the cost of devices capable of creating or displaying ultrarealistic environments becomes attainable to more and more. The immersive experience in therapy is not dissimilar to the simulated environment used in urological training, where surgeons can learn how to act, react, and prepare for unfamiliar situations and ultimately gain mastery of them. Similarly, patients can prepare for how they might feel, or act, and prepare to learn about stoma care, for instance, before they wake up after surgery, experiencing the physiological trauma of radical surgery and under the residual effects of anesthesia and sedatives. These are very real concerns for patients and can help patients be more fully informed prior to various therapies and also help them prepare for their rehabilitation.


The use of AI in software treatments is driving personalization and increasing engagement. AI-enabled therapeutics can provide a diagnosis and/or truly personalize care by tailoring the treatment for that patient. It can also anticipate patient needs and challenges based on the individual’s behavior. This allows for a much more efficient and effective care plan that can be updated as the individual’s needs change. Much of the technology required is miniaturized and made sufficiently desirable, and includes functional devices to smartphones and watches, to digital personal assistants and wearable sensors. For example, Clickotine, a digital therapeutics platform helps smokers quit using customized plans and medically proven strategies to overcome cravings and also provide supports to cease using tobacco. The application also requires various device permissions, which allows it to not just track user behavior but make recommendations based on defined rules—for example, if the user had mentioned getting nicotine cravings when they would consume coffee or if in a bar, the app would provide a message of support to the user when they entered a geofenced area or they made a purchase of a coffee using their smart device. Again, while I was unable to find a company focused on patients with urological conditions, the technology and expertise exist and has manifested a functional and available application, which can help countless urology patients who may need to quit tobacco, reduce caffeine intake or who need to reduce fluid intake after a certain time.


Barriers to adoption


Digital therapeutics have demonstrated that they offer meaningful and significant solutions to disparate and often poorly addressed elements of healthcare. As alluded to above, digital therapeutics have yet to become mainstream, not just in urology but all of healthcare. This is due to multiple barriers which are currently retarding greater adoption.


Reimbursement for digital therapies is similar to most new adjunctive treatments, subject to the vagaries of payers and insurance companies. Each reserves the right to cover a therapy but, in general, demonstrating safety, efficacy and demonstrating utility in the at-risk group are the most basic of hurdles to be crossed. In general, if a digital therapy aims to replace another proven intervention, pharmaceutical or otherwise, the barriers are higher. But digital therapies that help monitor, or are adjunctive therapies, or those which complement or improve compliance or efficacy are often considered more palatable. As payment models across the globe are in flux and more advocate for outcomes-based pricing models, digital therapeutics may offer a very attractive proposition to developers of all sorts of therapeutics. They will not only offer a method to potentially augment other therapies, but also are well positioned to provide hard data on the impact on health-related quality of life, offering insights into improved patient function even before the patient’s next scheduled visit. This, coupled with the relatively low development cost and relatively shorter development time, will help incentivize their development and incorporation into the treatment protocol for all novel therapies, pharmacological or otherwise.


There are hundreds of thousands of “apps” on various application marketplaces (including Android’s Google Play Store, and Apple’s App Store for iOS), which claim a health-related purpose. Consumers can become disillusioned or lack confidence in a legitimate application because they may first seek an application to help self-manage before they attend their physician. They may come to associate such applications as low value, or invasive, and may even be deterred by the somewhat extensive list of permissions that applications utilize—particularly those asking to access your storage, your contacts and messages, your location and GPS tracking settings, or those requesting network control and the ability to wake your device from sleep among others. While each of these may have a legitimate and benign purpose in a legitimate prescription digital therapeutic, patients who are also consumers of digital products may be wary and reluctant to share this information. The FDA requires all medical device companies to identify and mitigate cybersecurity risks as part of premarket submissions, but best practice standards are rapidly evolving ( ).


The use of AI weaves in another layer of complexity, which may hinder the adoption of digital therapeutics employing such methods. There have been notable examples of the limitations of AI-derived tools to discriminate along the lines of data it was exposed to during its training: the data used in many training datasets, and in particular clinical data available for use in medicine, are often biased by those for whom data are available in an electronic format. This tends to favor those from western nations and those from areas where health systems have been using electronic medical records for longer. This could lead to biased decisions and inequitable delivery of healthcare. Some have proposed a checklist for AI models: as with regulatory labeling for other therapeutics, digital therapeutics employing AI and similar methods should include a labeling requirement that makes it clear how such algorithms and tools were trained, as well as clear descriptions of the cohort demographics and social determinants of health ( ).


As with all novel devices, whether endoscopic, laparoscopic, robotic, or other disruptive innovations in medicine or industry, reluctance and resistance to change can be expected. Urologists are also well placed to help improve patient experience and the quality of life by acting as early adopters and vigilant gatekeepers for this next wave of innovation.



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Mar 12, 2023 | Posted by in UROLOGY | Comments Off on Digital therapeutics

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