RE-IMAGINING MEDICINE COMMENTARY

Digital medicine’s march on chronic disease

Joseph C Kvedar, Alexander L Fogel, Eric Elenko & Daphne Zohar Digital medicine offers the possibility of continuous monitoring, behavior modification and personalized interventions at low cost, potentially easing the burden of chronic disease in cost-constrained healthcare systems.

hronic disease affects approximately half surgeries—successfully addressed ­leading well as 86% of healthcare costs3–5. The United Cof all adult Americans, accounting for at causes of morbidity and mortality of the time States has the highest disease burden of any least seven of the ten leading causes of death (Table 1)1. In contrast, the most pressing issues developed country6. Trends in the above data and 86% of all healthcare spending. The US facing healthcare in the twenty-first century are expected to worsen in the near future. The healthcare system is ill-equipped to handle our are chronic diseases (e.g., respiratory disor- growth in chronic disease prevalence means epidemic of chronic disease. This is because ders, heart disease and diabetes), and many are that, despite increases in average life span, we most chronic disorders develop outside preventable (e.g., through smoking cessation may be experiencing a decrease in average healthcare settings, and patients with these and diet; Table 1; Fig. 1)2. The increase in the health span (the period of a person’s life spent conditions require continuous intervention prevalence of chronic disease is the primary in generally good health)7. to make the behavioral and lifestyle changes contributor to skyrocketing healthcare costs Why are we continuing to lose ground needed to effectively manage disease. Digital (Table 2), which have been such a focal point on chronic disease? Simply put, the bulk of medicine, which enables broad scaling of fre- of discussion in recent months. chronic disease development and management quent, high-touch, personalized, behavioral An unintended consequence of our twen- occurs beyond the reach of the healthcare sys- interventions at low cost, may thus become tieth-century success is that our modern tem. Patients need intervention before devel- an essential component in preventing and healthcare system was born, developed and oping disease, and those with chronic disease managing chronic disorders. Here, we sum- structured with acute diseases in mind. Our need ongoing and consistent support from Nature America, Inc. All rights reserved. America, Inc. © 201 6 Nature marize some key research advances, define the healthcare system is therefore ill-equipped multiple layers of providers to bring about marketplace and describe the opportunity for to prevent, manage and contain costs for behavior change. Continuous ­intervention— digital medicine in chronic disease. chronic disease. Why? Acute care is by defi- in-person provider visits, telemedicine, phone npg nition episodic, its solutions are general calls, e-mails, texts and apps—has the poten- The mismatch of health system and rather than personalized for each patient, tial to improve prevention and management disease burden and its interventions happen within health- efforts. The history of medical progress in the twen- care settings. Prevention and management of Continuous intervention has historically tieth century was dominated by advance- chronic disease do not fit well into this para- been impossible because of financial con- ments in the treatment of acute conditions. digm. Effective solutions for chronic disease, siderations. Fee-for-service reimbursement, These developments—which included better which often have behavioral components, a model suited to acute care, has historically medical sanitation, antibiotics, vaccines and require frequent, personalized interventions rewarded actions over outcomes, and implic- that affect patient actions outside healthcare itly encourages volume over value. In-person Joseph C. Kvedar is in the Department of settings. A 15-minute visit with a physician interventions have received reimbursement Dermatology, Massachusetts General Hospital, every few months, general recommendations preference over digital ones. Reimbursement Boston, Massachusetts, USA, Harvard to lose weight and exercise, and a lifetime of for preventative care has been spotty. The onus Medical School, Boston, Massachusetts, USA, post-diagnosis pharmacologic treatment are of preventing and managing chronic disease and Partners Connected Health, Partners not enough to solve our epidemic of chronic has largely fallen on the patient. And, histori- Healthcare, Boston, Massachusetts, USA; disease. cally, almost no one has been incentivized to Alexander L. Fogel is at Stanford University The mismatch between what our current control costs. Graduate School of Business and the Stanford healthcare system can deliver and what it It’s therefore unlikely that chronic disease University School of Medicine, Stanford, needs to deliver is now of extreme propor- will be prevented or effectively managed California, USA; Eric Elenko and Daphne tions. Today, at least seven of the ten leading in twentieth-century fashion with a pill, an Zohar are at PureTech Health, Boston, causes of death are chronic disease (Table 2), injection or surgery. We already know that Massachusetts, USA. and patients with chronic disease account for the most effective and cost-effective strate- e-mail: [email protected] half of all Americans (117 million people) as gies for chronic disease are the behaviors that

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Table 1 Leading causes of mortality in 1900 and 2013 1900 2013 Percent of Percent of Disease Chronic or acute Annual deaths total deaths Disease Chronic or acute Annual deaths total deaths Influenza and pneumonia Acute 40,362 12 Heart disease Chronic 611,105 24 Tuberculosis Acute 38,820 11 Cancer Chronic 584,881 23 Diarrhea and enteritis Acute 28,491 8 Chronic lower respiratory Chronic 149,205 6 diseases (COPD) Heart disease Acute/chronic 27,427 8 Accidents (unintentional Acute 130,557 5 injuries) Stroke (cerebrovascular Chronic 21,353 6 Stroke (cerebrovascular Chronic 128,978 5 diseases) diseases) Nephritis, nephrotic syn- Acute/chronic 17,699 5 Alzheimer’s disease Chronic 84,767 3 drome and nephrosis Accidents (unintentional Acute 14,429 4 Diabetes Chronic 75,578 3 injuries) Cancer Acute/chronic 12,769 4 Influenza and Pneumonia Acute 56,979 2 Senilitya Acute/chronic 10,015 3 Nephritis, nephrotic syndrome Chronic 47,112 2 and nephrosis Diphtheria Acute 8,056 2 Intentional self-harm (suicide) Acute/chronicb 41,149 2 All other causes Acute/chronic 123,796 36 All other causes Acute/chronic 686,682 26 aThe disease names used in 1900 records are not the same as those used in 2013. In 1900 records, ‘senility’ likely referred to Alzheimer’s disease. b>90% of suicides occur in patients with serious mental illnesses, which are chronic conditions; we believe that describing suicide as an acute condition is misleading (it is most often the end result of a long chronic process).

prevent disease development in the first place, ­implementation of digital therapeutics. The In the twenty-first century, cellphone owner- such as weight loss, exercise and smoking ces- first is the enactment of the Affordable Care ship has increased to 90% from 53%, smart- sation. For chronic disease management, these Act (ACA), which altered reimbursement and phone ownership has increased to 68% from same behaviors play a large role as well, as do patient incentives. Reimbursement incentives 0% and broadband internet penetration in other behavioral factors like medication adher- are shifting away from volume and toward American households has increased to 70% ence. Although these solutions sound simple, value, and many healthcare systems are now from 3% (refs. 11,12). Software applica- they have proven remarkably difficult for our financially responsible (‘at-risk’) for deliver- tions that are now commonplace on mobile healthcare system to deliver. ing quality outcomes at reduced costs. This phones—geolocation tracking, SMS and MMS The time is now to re-examine the twentieth-­ trend has accelerated rapidly: 40% of private messaging, mobile internet access, streaming century paradigms for healthcare, and to payments are currently value-based and 50% video, smartphone apps and connections to develop treatment and prevention paradigms of Medicare payments are anticipated to be IoT devices—were almost inconceivable at for the twenty-first century. We can leverage value-based by 2018 (refs. 8,9). To better the start of the century. Not only do Americans technology to expand the parameters of an manage at-risk contracts, healthcare systems spend more time accessing devices, but they Nature America, Inc. All rights reserved. America, Inc. © 201 6 Nature effective therapeutic. For diseases with behav- are looking for ways to prevent and manage can provide data to and be engaged by digital ioral components, interventions such as coach- chronic disease. Additionally, the ACA’s indi- therapeutics in ways that were unimaginable in ing, cognitive behavioral therapy and support vidual mandate has contributed to the growth the twentieth century. npg groups can be very effective. Traditionally, in high-deductible health insurance plans, Below we review how digital medicine is these therapies have been difficult to obtain in which now comprise nearly one quarter of all being applied to several important chronic our healthcare system, they have been difficult commercial plans10. Patients thus increasingly diseases. to scale, and it has been a struggle to standard- demand high-­quality, low-cost solutions like ize payments and incentives for such services. digital therapeutics. The diabetes epidemic Now, with the advent of wearable technology, The second factor is the growing interest of Diabetes is the seventh leading cause of death the Internet of Things (IoT), mobile computing employers in managing employee healthcare in the United States5. The disease affects platforms, value-based care and new incentives costs. In the twenty-first century, premiums for 9.5% of the US population—29.1 million for patients, employers, payers and healthcare employer-sponsored healthcare, which covers Americans—and >95% of diabetic patients systems, we can envision delivering these behav- 147 million people, have increased by 123%, have type 2 diabetes, which is strongly asso- ioral interventions to whole populations in the whereas wages have increased by only 43%9. ciated with behavioral factors such as a high- same way we fluorinate our drinking water and From an employer’s perspective, healthcare is calorie diet and physical inactivity13. Diabetes deliver vaccines on a large scale. Patients can becoming an increasingly large component of costs the healthcare system $245 billion annu- now be reached before, during and after chronic the cost of an employee. Employers are now ally, $176 billion of which are in direct medi- disease development, interventions can be deliv- more willing to play an active role in reduc- cal costs2. Medical management of diabetic ered continuously, and deployment can occur ing their employees’ healthcare costs, which patients includes behavioral change recom- either inside or outside the healthcare system. includes preventative therapies and chronic mendations for diet, exercise and smoking This is the promise of digital medicine. disease management that digital therapeutics cessation, oral antidiabetic agents, insulin can deliver at low cost. therapy and prevention of complications asso- Why now? The third factor is the explosion in technolog- ciated with diabetes, such as cardiovascular risk A combination of three factors has made ical progress, cell phone and smartphone own- factor management14. To successfully man- the time ripe for the development and ership, and broadband Internet penetration. age diabetes, patients must adopt a number

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of other behaviors that take place outside the company developed a machine-learning algo- WellDoc, which was co-founded by healthcare setting, such as frequent blood sugar rithm, powered by four patient data streams: University of Maryland endocrinologist monitoring, medication adherence and the self-reported motivation, continuous activ- Suzanne Sysko Clough, recognized the clas- self-injection of insulin. Unfortunately, only ity data, rudimentary location data and local sic problem of a chronic condition managed 16% of diabetic patients report fully adhering weather data. Patient readiness to change was by an acute care–focused healthcare system. to these behaviors15. periodically assessed, and personalized mes- Diabetic patients are largely left to manage Compounding the enormous present bur- sages were automatically delivered to each their complex condition on their own, and den of diabetes in the United States is the even patient. many of the most important interventions greater potential for diabetes in the future. TTM proved to be a powerful intervention, are performed by the patient in their home. Prediabetes, a condition in which patients are at producing an average 1% drop in hemoglo- Instead of following the typical protocol high risk for developing diabetes, affects 32% of bin A1c (HbA1c) for engaged patients. These of having patients test their blood sugar at Americans (86 million people)13. Prediabetes results are comparable to the average effect regular intervals during the day, the BlueStar is associated with the same behavioral factors of oral antidiabetic agents like metformin, smartphone-based app guides each patient as diabetes, and guidelines for preventing dia- thiazolidinediones and sulfonylureas, but in learning the optimal time to test blood betes in prediabetic patients include diet and with zero possibility of adverse events. In sugar. In this way, it provides patients with exercise, smoking cessation, and in some cases, addition to producing a drop in HbA1c, a more accurate picture of how blood sugar the addition of the oral antidiabetic agent met- TTM produced a noticeable improvement in fluctuates throughout the day in response formin (Glucophage)16. physical activity, which has additional health to environmental stimuli. The BlueStar ran- Multiple digital medicine companies have benefits. Developing and deploying TTM cost domized clinical trial demonstrated a statisti- developed solutions to address the epidemic on the order of a few million dollars, not the cally significant 1.2 point increase in HbA1c of diabetes and prediabetes. Below, we exam- billions that are standard for a pharmaceuti- levels compared with the standard of care17. ine in more detail the offerings from Partners cal product, illustrating the power of digital On the strength of these results, as well as Connected Health—a Boston-based institu- medicine. The Apple Watch has a built-in a successful equivalence claim to predicate tion centered on innovation in healthcare reminder system that provides a haptic pulse, devices, BlueStar obtained US Food and Drug delivery where J.C.K. currently serves as vice urging individuals to stand hourly. This and Administration (FDA) clearance. Currently, president—and companies, such as WellDoc other hardware and software approaches in BlueStar is available by physician prescription (St. Paul, MN, USA), Omada Health (San development could be synergistic with the only and is distributed through pharmacies. Francisco), Glooko (Palo Alto, CA, USA) and TTM approach. Podimetrics (Cambridge, MA, USA). Prevent. Modeled after the Diabetes BlueStar. Most diabetics manage their blood Prevention Program (DPP)18, Omada Health Text2Move. The Text2Move (TTM) study has glucose levels by checking their insulin lev- (San Francisco) developed Prevent, a 16-week, been one of the most successful programs at els periodically throughout the day, and then online, interactive behavioral intervention pro- Partners Connected Health. The goal of the self-administering insulin when necessary. gram designed to reduce the development of study was to understand whether automated, However, only 55% of type 2 diabetics report diabetes in prediabetic patients through weight personalized, targeted and motivational text receiving diabetes education, and following loss and increased physical activity. messages could boost activity levels among their initial diagnosis, their face-time with Peer-reviewed studies conducted by Nature America, Inc. All rights reserved. America, Inc. © 201 6 Nature type 2 diabetics to improve outcomes and physicians is typically limited to 15-minute Omada indicate that, across all prediabetic reduce healthcare spending. To do this, the appointments every few months15. patients who started the program, the average

npg All other causes 100 100 Cancer Chronic/

acute Nephritis, nephrotic syndrome hoi/ct ct Chronic Acute Chronic/acute 90 90 and nephrosis Heart disease

80 80 Acute Diphtheria 70 70 Accidents (unintentional injuries) 60 60 Diarrhea and enteritis 50 50 Tuberculosis Chronic In uenza and pneumonia 40 40 Senility (likely Alzheimer’s disease) Stroke (cerebrovascular 30 30 diseases) cent of total deaths 20 20 Chronic lower Per repiratory diseases (COPD) 10 10 Intentional self-harm (suicide) Diabetes 0 0 1900 2013

Figure 1 The shift from acute to chronic disease. Leading causes of mortality in 1900 versus 2013 (refs. 1,2). The disease names used in 1900 records are not the same as those used in 2013. For example, in 1900 records, ‘senility’ likely referred to Alzheimer’s disease. In 2013 data, >90% of suicides occur in patients with serious mental illness, which are chronic conditions; we believe that describing suicide as an acute condition is misleading (it is most often the end result of a long chronic process).

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participant lost 4.7% and 4.2% of baseline is also a primary contributor to other leading To date, the Propeller system has been body weight after 1 and 2 years, respectively19. causes of death, including cancer, heart disease, deployed with commercial partners, which Patients also reduced their HbA1c levels by stroke and diabetes. The annual economic costs include payers, employers and healthcare sys- an average of 0.38% and 0.43% after 1 and 2 of smoking are nearly $290 billion, $133 billion tems. Additionally, Propeller has developed years, respectively19. These results are compa- of which is in direct medical care24. Although a public-private partnership with the city of rable to the original DPP results, and Omada’s efforts to reduce the prevalence of smoking Louisville, Kentucky, which has a high preva- programs are now recognized by the Centers have had success, nearly 18% of the adult pop- lence of chronic respiratory diseases. for Disease Control (Atlanta)18,20. Omada’s ulation still smokes2. However, nearly 70% of products are not FDA approved and do not smokers report wanting to quit, and >40% of SmartQuit. 2Morrow developed and clini- reach patients through the traditional health- smokers make an attempt to quit each year24. cally validated the SmartQuit smartphone app care system. Instead, Omada markets its prod- Chronic respiratory diseases have behavioral for smoking cessation. To date, of the >400 uct to large employers as a means to stimulate components, both in disease development and smoking cessation apps, SmartQuit is the only employee weight loss, reduce the incidence of in management. Many cases are due to smoking app-based smoking cessation therapy that has chronic disease in the employer’s workforce or secondhand smoke, and smoking cessation demonstrated effectiveness in randomized and reduce employee healthcare costs. or avoidance are integral components of treat- clinical trials. ment plans. Successful management of chronic The company provides an eight-day pre-quit Glooko software. Glooko has developed an respiratory diseases also requires behavioral program followed by 6 months of automated FDA-cleared software platform that not only interventions, such as proper inhaler use, medi- support, which includes video tutorials and can automatically download data from >50 dia- cation management, and diet and exercise. in-app rewards, such as badges. Patients track betes devices, including insulin pumps, blood Digital medicine for the epidemic of chronic their progress and receive automated feedback, glucose meters and wearable devices, but also respiratory disease is now emerging. Below, we with encouragement and reminders. Patients allows patients to manually download informa- describe in detail four companies, Propeller can also customize their program to be used in tion on diet and other lifestyle factors. Glooko Health (Madison, WI, USA), 2Morrow conjunction with nicotine replacement therapy. software analyzes trends and provides feed- (Kirkland, WA, USA), LifeMap Solutions (San SmartQuit is based on the Acceptance and back to optimize treatment. The system can Jose, CA, USA) and Claritas Mindsciences Commitment Theory of behavior change, send data to patients through a smartphone (Worcester, MA, USA), that have applied digi- which has been shown to outperform other app, and data can be automatically shared with tal medicine tools to such disorders. smoking cessation approaches, such as providers by a population health management cognitive behavioral therapy and the US platform. Glooko systems are sold directly to Propeller. Propeller Health has designed the Clinical Practice Guidelines, across multiple patients and clinics, and can also be distributed Propeller system for COPD and asthma patients digital and in-p­erson platforms25. The app by payers and health systems. with the goals of increasing medication adher- has been found to be two to three times more ence, predicting disease exacerbations, and effective than unaided smoking cessation, with RTM System. Podimetrics is developing the reducing the frequency and severity of symp- pilot trials demonstrating a 13% overall quit RTM System, a solution for early detection of toms. Propeller’s solution combines sensors rate and a 15% quit rate in some subgroups25. diabetic foot ulcers, which cost the healthcare attached to patients’ inhalers, a patient-facing It also increased quit rates by 62–88% compared system $9–13 billion annually21. The RTM smartphone app, a physician-facing website and with the National Cancer Institute’s QuitGuide Nature America, Inc. All rights reserved. America, Inc. © 201 6 Nature System is a connected, at-home, temperature- data from a network of air-quality sensors, such smartphone app25. monitoring foot mat that detects local tem- as those used by the Environmental Protection A lite version of the SmartQuit app is freely perature changes in the foot that signal ulcer Agency. Propeller monitors the use of both con- available on iOS and Android devices, and npg development. The device can send data to troller and rescue inhalers, and tracks patient the full version is available through employ- patients and providers, and enables providers trends over time. By combining these data ers, health insurance plans, some state-level to access tools for clinical support and popula- streams, Propeller aims to provide patients and departments of public health or through an tion health management. Podimetrics systems providers with frequent, personalized feedback in-app purchase. are currently available through payer and pro- on the connections between environmental fac- vider pilot testing. tors and patient behavioral factors in chronic COPD Navigator and Asthma Health. respiratory disease. LifeMap Solutions has developed smartphone Chronic respiratory diseases and smoking The Propeller system has four FDA clear- apps for COPD and asthma management that cessation ances, which include FDA-granted claims that combine patient data, care guidelines and Fourteen percent of the US population suf- its system can be used to increase medication behavioral science techniques in an effort to fers from chronic respiratory diseases, includ- adherence, predict exacerbations, and reduce improve outcomes and reduce cost. The goals ing chronic obstructive pulmonary disease the frequency of symptoms and exacerbations of the apps are to log patient symptoms and (COPD) and asthma. Chronic respiratory in asthma and COPD. It has been cleared for events, provide medication reminders and diseases cause 150,000 deaths annually, and use with GlaxoSmithKline’s (London) Diskus identify patterns in environmental factors and their economic cost exceeds $105 billion, dry powder inhaler, Boehringer Ingelheim’s patient behaviors that correspond with exac- $80 billion of which is in the form of direct (Ingelheim, Germany) Respimat and other erbations. LifeMap apps are freely available to medical care2,22,23. medications using pressurized metered-dose patients, and can be obtained through partner- Cigarette smoking is a primary contributor inhalers. Although Propeller Health has yet to ships with employers, payers and healthcare to respiratory disorders, such as COPD and publish results on efficacy and cost in peer- systems. asthma. Over all, it is responsible for nearly reviewed medical journals, the company has 500,000 deaths in the United States each year, indicated that it is conducting randomized CravingToQuit. Claritas MindSciences comprising 20% of all deaths nationwide. It trials. developed CravingToQuit, a digital smoking

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Table 2 Selected chronic diseases and their digital medicines2–5,14,22,23,25,28–31,35,36,45,46 Total cost (direct, Disease Prevalence (%) Annual deaths indirect; $ billions) Digital medicine product Obesity 34.9 300,000 147 (142.1, 4.9) Omada, Noom, Rise, Canary Health, Lantern, RecoveryRecord, EcoFusion, MedTep, Zipongo Prediabetes 32.0 NA NA (44, NA) Omada, Noom, Canary Health, Blue Mesa Health, Personal Medicine Plus Hypertension 26.7 61,762 118.6 (91.4, 27.2) Omada, Noom, Personal Medicine Plus, Withings Hyperlipidemia 21.9 NA 38.5 (NA,NA) Omada, Noom Smoking-related 17.8 480,000 300 (170, 156) SmartQuit, QuitGuide, Chrono Therapeutics, Click Therapeutics, Quit diseases Genius, Claritas MindSciences Chronic pain (includes 15.0a NA 592 (280.5, 311.5)b Jojnts, Reflexion Health, Canary Health, RespondWell arthritis) COPD and asthma 13.7 149,205 105.9 (79.5, 26.4) Propeller Health, LifeMap, MedTep Diabetes 9.5 75,578 245 (176, 69) Omada, Noom, Canary Health, EcoFusion, Podimetrics, WellDoc, Glooko, Dexcom Alcoholism 7.0 88,000 223.5 (24.6, 198.9) Pear Therapeutics, The Alcohol Tracker, A-CHESS Coronary artery disease 5.3 NA 129.6 (46.8, 82.8) EcoFusion, MedTep Serious mental illness 4.2 41,149c 317.6 (100.1, 217.5) Ginger.io, Lantern, Recovery Record, MedTep Digital medicine matched with diseases only if specifically mentioned by the product or company. NA, not available. aMedian of range estimates. bMean of range estimate. cThe vast majority of suicide deaths are due to serious mental illness

cessation program delivered through a smart- But in terms of clinical practice, it seems likely target for ­intervention: cognitive interference phone app in conjunction with an online that digital medicine tools will have their most (efficiently managing two or more information community and video support groups. immediate benefits in psychiatric conditions, streams real-time). In addition to evidence that CravingToQuit is a digitally delivered version where social stigma or lack of access to skilled measuring a patient’s cognitive interference of the Mindfulness Training approach, an in- therapists represent barriers to patient care. susceptibility has the potential to provide a person version of which was found by one study Below, we describe two companies, Jintronix sensitive biomarker of neurological function, to be more than twice as effective for smoking (Seattle) and Akili Interactive Labs (Boston), there is clinical evidence that directly improv- cessation as another leading smoking cessation that are applying digital medicine approaches to ing the ability to process cognitive interference approach26. The program is delivered over the chronic neurological disease, and MoodGYM, results in more general improvement in cogni- course of three weeks, and can be purchased which is a program developed in Australia. tive domains, which has been demonstrated in either directly by patients or through employers. elderly subjects in a sham-controlled study31. Jintronix. Requiring a computer fitted with In a pilot study, Akili showed that Project EVO Chronic neurological and psychiatric Microsoft Kinect for Windows, the Jintronix improved attention and other aspects of cogni- conditions package provides physical and occupational tion (e.g., working memory) in children with Chronic neurological and psychiatric condi- therapy at home for patients undergoing ADHD, as measured by objective tests32. The Nature America, Inc. All rights reserved. America, Inc. © 201 6 Nature tions represent some of the most challeng- rehabilitation for stroke and other conditions. company plans on carrying out a pivotal study ing and costly problems facing the healthcare The system uses motion tracking and visual for pediatric ADHD in 2016 and currently has system today. Alzheimer’s disease affects feedback to reinforce physical rehabilitation clinical trials in several chronic neurological npg 5.3 million people in the United States alone exercises, which are presented in the forms and psychiatric illnesses, including autism, and is responsible for nearly 85,000 deaths each of games designed to be enjoyable. This is the Alzheimer’s disease and depression. year5,27. Chronic pediatric neurological condi- first time that Microsoft’s Kinect, which was tions include attention deficit hyperactivity originally designed purely as an entertainment MoodGYM. A software program developed disorder (ADHD), which has been diagnosed games platform, used a product that received by Australian National University (Canberra, in up to 11% of US children aged 4–17 and FDA clearance for a healthcare-related use. Australia), MoodGym is one example of digi- autism spectrum disorder, which is estimated Injecting a gaming component to make the tally delivered cognitive behavioral therapy to affect up to 1.5% of children in the United exercise enjoyable engenders compliance, (CBT) programs. CBT is a mainstay of psy- States28,29. Furthermore, ~800,000 individuals which is particularly important for an at-home chiatry and has been used to treat depression, in the United States will suffer from stroke each therapy. anxiety and other conditions. The technique year30. Current treatment options, including involves changing a patient’s thought pro- medications, often have limited efficacy and/ Cognitive Engine and Project EVO. Akili cesses and behaviors, and has historically or problematic adverse events. Other current Interactive Labs is developing therapeutic and been delivered in person by a skilled psy- alternatives include interventions that are more cognitive monitoring tools delivered through chologist. The techniques used in CBT can costly and time-intensive interactions with a a mobile action video game-like interface for be delivered digitally and a meta-study has therapist (e.g., applied behavioral analysis for several chronic disorders where cognition is suggested that Internet-delivered CBT may autism). negatively affected. The company’s goal is to be as effective as in-person therapy33. A chal- Apple’s (Cupertino, CA, USA) Research Kit get FDA clearance for its therapeutic prod- lenge that online CBT faces is compliance and set of apps for the iPhone is already being tested ucts after completion of the required pivotal motivating the patient to engage with the as a tool for gathering information and moni- clinical studies. The company’s main prod- exercise, particularly given that lack of moti- toring patients with chronic conditions, one of uct, Project EVO, is based on measuring and vation is often a characteristic of depression. which is the mPower app for Parkinson’s disease. improving a new functional neurological Including a degree of human contact and

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encouragement of the user could increase products to measure physiology. The com- ­recommendations for medication taking, compliance. pany has produced a blood pressure monitor which includes prescription fulfillment, dos- that is placed on the wrist as well as one that is age, timing, d­ uration and other relevant fac- Chronic cardiovascular conditions placed on the arm. In both cases, the data are tors—are of major concern in chronic disease, Cardiovascular disease is one of the leading sent to an app and displayed using an app on as 83% of all prescriptions are filled by patients causes of death in the United States, and is a mobile device such as a phone. The data can with chronic conditions, and the average often associated with other chronic diseases also be stored so that a patient can later share patient with one or more chronic diseases fills (e.g., obesity). The sequelae of cardiovascu- it with a physician. Both blood pressure moni- >20 prescriptions per year7. Multiple studies lar disease can include debilitating events, toring devices have received FDA clearance. have demonstrated that 50% of medications such as stroke, that then lead to other chronic prescribed for chronic disease are not taken problems. Being able to monitor a patient on No-burden monitoring as directed, and between 20% and 30% of all a frequent or continuous basis to alert him or One intriguing direction of monitoring for prescriptions are never filled34. Annually, her of a change in a key physiological param- cardiovascular and other chronic conditions is medication nonadherence is responsible for eter (e.g., blood pressure or heart rate) could ‘no-burden’ monitoring that is used passively 125,000 deaths, 10% of all hospitalizations help prevent an acute cardiovascular event. by smartphone or other devices. An ideal no- and $100–289 billion in healthcare costs34–36. Recording a patient’s data over time with a burden application is compatible with devices Nondigital approaches to increase medi- granular data set will also allow a physician a patient already owns and uses regularly, and cation adherence are generally resource to understand if a treatment intervention is once downloaded, is ready to function without intensive or ineffective. The most reliable effective. As artificial intelligence approaches any further action by the patient. Although put- method is directly observed therapy, in which become more sophisticated, it could be pos- ting on a wearable or opening an app every day healthcare providers watch patients take each sible to start to automate sifting through requires minimal effort, even a small amount dose of medication. The method is time and the data to make a conclusion, which will of required effort can be burdensome enough resource intensive, and virtually impossible to be key to making the data actionable from that many patients use them less consistently scale up to address the epidemic of chronic the viewpoint of a physician who only has a over time or discontinue their use altogether. disease. Indirect methods include patient short amount of time to spend with a patient. Furthermore, sensor diversity, data quality, surveys, monitoring of patient pill diaries, Several different sensors are available for mea- data format, device cost and limited durability pill counts and monitoring prescription refill suring physiology, and a subset are useful for of wearable devices each represent substantial rates. Historically, indirect methods have been heart-rate monitoring. obstacles to large-scale adoption and routine reactive, and they do not proactively attempt Below, focusing on medical applications, use of meaningful longitudinal health moni- to increase adherence. we discuss three examples of companies pro- toring. Now, digital medicines are working to ducing digital tools for blood pressure and There are some early examples of no-burden increase adherence and compliance in chronic heart monitoring. What the companies have monitoring approaches including some aca- disease. Below, we discuss in more detail the in common is the use of a physical device in demic work around an app that is downloaded offerings from Proteus Health (Redwood City, conjunction with an app. to a phone and could potentially accurately CA, USA), MediSafe (Boston), Mango Health measure heart rate passively without the need (San Francisco) and Memotext (Bethesda, AliveCor Mobile ECG. AliveCor (San for a separate device. Another example, Sonde MD, USA). Nature America, Inc. All rights reserved. America, Inc. © 201 6 Nature Francisco) is marketing a mobile electrocardi- Health (Boston) is a digital medicine company ography (ECG) device that works with an app. developing technology for computational Proteus Discover. Proteus Digital Health is The company’s product has received clear- analysis of nonlinguistic features in voice and working to address medication adherence npg ance from the FDA. The app has the ability other sounds that are correlated with subtle through a system that can determine whether to detect atrial fibrillation, which can signifi- changes in neurological and physiological patients have ingested medications. The cantly increase the risk of stroke. To help phy- function. Sonde’s technology enables longi- Proteus system consists of an Ingestible Event sicians better examine the data obtained from tudinal monitoring of mental, emotional and Marker, which is a digital sensor embedded the recordings, the company has established physical health conditions in the background in a pill, and the Proteus Personal Monitor, a provider dashboard, which a physician can on devices that most people already own and which is an externally worn adhesive monitor. access online. AliveCor has also started to try use every day, and without requiring that the The Proteus Discover system can report when to integrate patient data into electronic health content of their speech be stored or analyzed. medication is taken, how medication is taken records (e.g., for Practice Fusion). This approach has potential advantages of and information related to activities of daily being both no-burden and privacy preserv- living such as steps, heart rate and resting time. Wireless blood pressure monitor. Withings ing. No-burden approaches could be crucial Data are sent to patients through a smartphone (Cambridge, MA, USA) is focused on making when longer-term compliance for meaningful app and can also be shared with providers and digital products for physiological monitoring. longitudinal monitoring is required in patients researchers with patient consent. Studies have The company developed and obtained FDA with difficult care regimens. A clear example indicated that the Proteus system is an effica- clearance for a wireless blood pressure cuff is the case in lifelong chronic conditions, such cious and cost-effective alternative to directly used in conjunction with an app to display as heart disease, where objective early indica- observed therapy37,38. blood pressure data. Historic readings are tions of new complications have the potential The Proteus system has received FDA clear- saved and can be stored in the cloud, allowing to allow earlier and less costly interventions. ance, and is currently the only cleared device either the patient or physician to note changes with a claim for general medication adher- from previous readings. Medication adherence and compliance ence. Proteus is also ‘CE-marked’ for use in Similar to Withings, iHealth Lab (Mountain Medication adherence and compli- Europe. The company recently announced a View, CA, USA) sells a number of wireless ance—a patient’s following of providers’ new FDA application for integration of the

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Proteus system with Otsuka Pharmaceutical’s The Memotext system can integrate data from process will still be subject to regulation by the (Chiyoda-Ku, Japan) Abilify (aripiprazole) for electronic medical records, patient wearables Federal Trade Commission (FTC) whose goal the measurement of compliance and physi- and monitors, and payer claims data. Memotext is to protect consumers from unfair and deceit- ologic response in serious mental illness. is available through pilot programs, employers ful practices. Recently, the FTC reprimanded and payers, and is used in conjunction with and levied a large fine against one company for MediSafe. MediSafe has developed a cloud- pharmaceutical companies. making unsubstantiated claims regarding the synced smartphone app to improve medication ability of its main product to improve cognition adherence. The app allows patients to manually Initial success, but challenges remain and fend off age-related cognitive decline41. enter medication schedules, medication doses, Despite initial success in multiple digital medi- Likewise, the FTC reprimanded another com- measurements, provider appointments, diary cine approaches to chronic disease, challenges pany for making unsubstantiated claims for entries and a social support network. MediSafe remain in the areas of patient engagement, improving cognition, including in ADHD42. sends patients reminders of their schedules, regulation and privacy. However, given the enormous number of and allows patients to send medication alerts Patient engagement and motivating patients health-related apps available, the FTC will not and summaries to providers and designated to use the digital medicine products can be a be able to police all of them. For those digital members of their social support network. The challenge. One obstacle is that older patients interventions aimed at chronic disease that do app creates a ‘virtual pillbox’ for patients that and underserved patients—those with the not seek FDA approval, there will be a question includes images of the size and shape of pills. highest rates of chronic disease—are the least of how to judge the quality of the intervention, MediSafe also provides multimedia content rel- technologically savvy members of the popula- especially for consumers who are not familiar evant to patient disease management and edu- tion, and therefore the least likely to be able to with science. cation. The app is freely available to patients use digital medicine products. This is why a Privacy and security are also a major concern on iOS and Android platforms, and MediSafe new breed of ‘no-burden’ approaches may be for digital medicine interventions particularly creates customized versions of the app for cor- beneficial. for those that affect behavior change through porate partners, such as healthcare systems, Given that 60% of patients with chronic intensive monitoring of personal data, such as payers, employers and pharmacies. disease have more than one chronic disease7, location data, movement data and purchase Although MediSafe has yet to publish find- another issue is that digital medicine solu- data. Large amounts of aggregated health data ings in peer-reviewed medical journals, it tions are not available across the board for all could be valuable to third parties, which could does present results of internally conducted chronic conditions; this may complicate the incentivize digital medicine companies to sell research on its website. The company reports development of strategies for driving patient the data to third parties. Individuals may sim- that its 2.5 million users are 86% adherent to engagement. What’s more, although most ply push ‘accept conditions’ when download- prescribed medications, a substantial improve- chronic diseases have a behavioral component, ing an app that includes a provision for use of ment over the 50% national adherence rate there may be limits to how much behavior can the patients’ data, but few people will read the (http://bit.ly/1om8W35). Compared with change, and how many behaviors can change details of the agreement or realize how their control groups, MediSafe patients with hyper- at once. Can we use digital medicines to get data are being used. Digital interventions may lipidemia, hypertension and diabetes achieve patients to stop smoking, lose weight and bet- be subject to the Health Information Portability statistically significant increases in medication ter monitor their blood glucose, all at the and Accountability Act (HIPAA) and inter- adherence of 10.7%, 5.4% and 7.7%, respec- same time? Also, most clinical validation and ventions may need to build in safeguards to be Nature America, Inc. All rights reserved. America, Inc. © 201 6 Nature tively. deployment of digital medicines designed to HIPAA compliant. Hacking of financial insti- affect chronic disease is done with self-selected, tutions that have built highly secure systems Mango Health. Mango Health has developed volunteer patients. It remains to be seen how shows the complexity of guarding against the npg a ‘gamified’ smartphone app for medication well digital medicines work in patients who release of sensitive information. If a series of adherence. The app combines medication have some resistance to using them. Finally, it high-profile hacking incidents were to occur in adherence-promoting features, such as sched- remains to be seen whether the use of digital the digital health space, it could fundamentally ules, reminders, information and alerts, with medicines can be sustained over long peri- undermine trust in the system. That said, the features of video games that encourage adher- ods. Digital medicine products have at most a value of an individual’s health data to a hacker is ence and healthy behaviors. Patients who few years’ track record, and details about total much less clear than that of their bank account adhere to their medication regimen and life- patient retention and long-term outcomes are details, which is probably why there have been style goals earn badges and points, which can sparse. fewer large-scale hacking incidents in health- then be redeemed for gift cards or charitable Regulation is also an issue that will need to care (even so, over 100 million patient health donations. The Mango Health app is avail- be addressed, as discussed previously in this records were stolen in the first six months of able for free to patients, and is also available series40. Because apps that make claims about 2015 alone43). through payers and employers. the diagnosis or treatment of the disease are On the surface, digital medicine for chronic subject to FDA enforcement discretion, apps disease seems low risk, particularly compared Memotext. Memotext has built a digital com- aimed at chronic disease that don’t make direct to traditional drug therapy. However, there are munication platform to increase medication disease claims (e.g., greater medication compli- differences in the safety risk posed by different adherence. The platform uses a combination ance) may find that they are not subject to FDA digital medicine applications. A game to treat of interventions, including text messages, pre- regulation. Depending on the exact claim that a cognitive disorder or to gamify taking medi- recorded phone calls, e-mails, and app-based is being made (e.g., ‘aids in weight loss’ verses cation to increase compliance is relatively low and web-based reminders to encourage medi- ‘treats obesity’), developers of digital medicine risk. On the other hand, apps that are involved cation adherence. One study found that the interventions can choose whether or not to be in monitoring physiological function or whose Memotext system resulted in a statistically sig- subject to FDA regulation. Those interven- output can result in a patient or physician tak- nificant increase in adherence of 31% (ref. 39). tions that do not go through the FDA approval ing life-saving action are much higher risk.

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