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Beyond the Current Standard of Care for Pediatric ADHD: A New Era of Digital Therapeutics

Authors

Madison Preib, MPH1; Philip L. Cyr, MPH1,2; Joseph Honcz3;
and Robert L. Findling, MBA, MD 4

Affiliations
1Precision Xtract, Boston, MA; 2College of Health and Human Services, University of North Carolina, Charlotte, NC; 3Precision for Value, New York, NY, ; 4Johns Hopkins University, Baltimore, MD; 5Kennedy Krieger Institute, Baltimore, MD

As the most common neurodevelopment disorder of childhood, attention-deficit/hyperactivity disorder (ADHD) places a significant burden on the US health care system.1-5 In today’s changing medical climate, there is growing pressure to improve patient outcomes while reducing health care costs.3 This commentary discusses a new treatment class known as digital therapeutics, which may prove to be a useful tool in the treatment of chronic conditions such as ADHD.6

Defining ADHD

ADHD is characterized by an inability to focus, hyperactivity, and impulsive behaviors with onset during childhood.2,6,7 Prevalence estimates of ADHD are variable, with conservative rates around 5% in adults and children worldwide8 and 8%-11% in children in the United States.1,9-11 ADHD is more prevalent in men than women and may be associated with lower socioeconomic status and geographic location in the United States.10,11 Symptoms of ADHD are chronic and can profoundly affect academic achievement, well-being, quality of life, and social interactions along with increased caregiver burden and decreased quality of life for parents and siblings of children with ADHD.1,3,12-14 An estimated one-third of children and adolescents with ADHD also suffer from difficult-to-treat, concomitant disorders such as oppositional defiant disorder, depression, and generalized anxiety disorder.1,14  According to the American Psychiatric Association’s Diagnostic and Statistical Manual, Fifth Edition, a diagnosis of ADHD is made for children displaying 6 or more symptoms of inattention and/or hyperactivity-impulsivity beginning before age 12, present in multiple settings (eg, school and home) for at least 6 months, and after other psychiatric disorders have been ruled out.2 There are three types of ADHD, depending on which symptoms an individual displays: predominantly inattentive, predominately hyperactive-impulsive, or combined presentation. Current guidelines recommend a multimodal approach to ADHD treatment that includes behavioral therapy and/or pharmacotherapy aimed at reducing core symptoms and associated behaviors.1-3,12 Treatment regimens for ADHD are usually long-term and often time-consuming resulting in a high burden for patients, providers, and parents.12 The chronic nature of ADHD, family burden, and high prevalence of co-occurring disorders results in patient suffering as well as a significant burden to society and the health care system.3,10,13

Direct and Indirect Cost of ADHD

Children and adolescents with ADHD have higher health care resource utilization than their peers due to necessary evaluation, treatment, and health care visits to manage the condition. Children with impulsive behavior associated with ADHD also have more injuries and visits to the emergency room.4 In 2013, direct US health care expenditures for ADHD were estimated to total $23 billion,5 with direct incremental health care cost estimates of ADHD ranging from $621 to $2720 per-person.4 In addition to increased health care costs, children and adolescents with ADHD are at higher risk of falling behind academically without proper interventions, resulting in significant additional education costs.4,5 The annual indirect costs of ADHD to society, including health care, education, and reduced family productivity and lost income due to caregiving for childhood ADHD, range from $38 billion to $72 billion.4 While the economic and health care burden of pediatric ADHD is significant, there is still need for improved ADHD management.

Unmet Need in ADHD Management 

The management of pediatric ADHD has been well studied,1 however, there is an opportunity for updated clinical guidelines to inform best practices to reflect changes in the ADHD treatment landscape over the past decade. The American Academy of Pediatrics last released clinical practice guidelines in 2011, while the American Academy of Child & Adolescent Psychiatry has not released practice parameters for children and adolescents with ADHD since 2007.1,15 The Cleveland Clinic Journal of Medicine recently released clinical guidelines in 2017, noting a changing medical climate after passage of the Affordable Care Act and a call to treat ADHD better and more cost effectively.3 The guidelines also state that despite concerns of overdiagnosis and overtreatment, many children and adolescents still receive no or insufficient treatment.3 The current standards of care for pediatric ADHD include pharmacotherapy and behavioral therapy1,3,15; however, the barriers to current treatment, such as lack of access or poor adherence due to side effects, show the need for improved treatment options.10,12,16,17

Behavioral Therapy

Evidence-based behavioral therapy is often considered a first line of treatment for children with ADHD.1-3 Behavioral therapy is used more commonly in younger children (especially preschoolers) than adolescents.10 Parents can be educated to administer behavioral therapy practices at home; professional therapy can be implemented and teachers can use behavioral therapy to improve classroom behavior.1-3 Although the benefits of behavioral therapy have been well established,1,12 there are still barriers to access, including time commitment, cost, and access to pediatric mental health care providers, especially in rural regions1,10,12,16,17.

Pharmacotherapy

Pharmacotherapy is the most commonly used treatment for ADHD10 and includes FDA-approved stimulants (eg, amphetamine, methylphenidate) and nonstimulant medications (eg, atomoxetine, guanfacine, clonidine); with more evidence supporting the use of stimulants over nonstimulants.1,3 Pharmacotherapy for ADHD is generally well-tolerated, but there are concerns about adverse events and unfavorable side effects that may result in poor parental perception of stimulants.12,16,17  Common adverse events reported for simulant therapy for ADHD (occurring in ≥5% of users) include decreased appetite, headache, anxiety, nervousness, insomnia, abdominal pain, and dizziness; while common adverse events reported in ≥5% of users of nonstimulant medication include nausea, vomiting, fatigue, decreased appetite, and somnolence.16-21 Optimizing medication doses may be challenging with ADHD pharmacotherapy, with several agents requiring several-weeks-long titration period and multiple follow-up visits with health care providers.16,17 While the short- and long-term efficacy of pharmacotherapy for ADHD have been proven,1-3 adherence is essential for effective treatment.3,16,17 

Rates of inconsistent pharmacotherapy use or discontinuation of ADHD medication were recently estimated to be between 13.2% to 64% within the first year.3,22,23 Another study estimated that 95% of teenagers discontinue pharmacotherapy before age 21,24 indicating adherence and discontinuation could be more prominent issues for adolescents than children with ADHD.3 Treatment nonadherence is often associated with a parent’s perception that the medication is not working, combined with the potential for diversion and abuse in stimulant medications, may lead to poor parental perception of stimulant medications.3,16,17,25 As such, the prescribing information of psychostimulants include boxed warnings about the potential abuse and dependence.18-20 Adverse events, challenges associated with dose optimization, poor adherence, discontinuation, and parental concerns about effectiveness and abuse of pharmacotherapy indicate that there is an opportunity for new treatment options to better manage ADHD symptoms.

Digital Medicine and Therapeutics

Recent advances in health care include emerging treatments that leverage information science, computer science, and technology to improve health as part of the digital medicine era.24 Digital medicine aims to improve access to therapy, reduce treatment/diagnosis costs, increase quality of care, and make medicine more personalized for patients, through products such as wearable devices or software.6,26 Prescription digital therapeutics are a subset of digital medicine, defined by the Digital Therapeutics Alliance as evidence-based therapeutic interventions driven by quality software programs meeting high standards of safety, effectiveness, and value.6 Digital therapeutics need to be distinguished from the broad health and well-being market, as digital therapeutics are required to show proven efficacy and safety through randomized clinical trials regulated by the FDA; they will also be considered prescription medical therapies and be given under physician supervision. This differentiation is important for patients, providers, advocacy groups, developers, regulators, and investors to ensure that digital therapeutics meet high standards of safety and effectiveness. Patients and providers are beginning to have access to digital therapeutics across a wide range of physical and mental disorders, including neurodevelopmental disorders like ADHD. 

Treating ADHD With Digital Therapeutics

There are many potential benefits to managing neurodevelopmental disorders with digital medicine and therapeutics. These new therapies could provide highly personalized care with immediate collection and analysis of patient outcomes data for providers that is not available from pharmacotherapy or behavioral therapy. Access to treatment is increased as digital therapy can be implemented at home, on multiple platforms (ie, mobile devices, websites, tablets), and on a regular basis without requiring face-to-face interaction with a health care provider. In addition, the stigma associated with delivery of traditional therapies is reduced by allowing privacy through treatment administration at home.6 Children and adolescents who are working through the complex management of life with ADHD could potentially benefit greatly from digital medicine and therapeutic interventions.

One area of digital medicine currently under research is the use of remote monitoring technology (RMT) to improve medication adherence and self-management of individuals with ADHD. Patients with ADHD could track their symptoms and medication use through a mobile application, with regularly scheduled reminders from the application.27 Ideally, providers would have real-time access to the patient’s data to monitor treatment outcomes ultimately reducing in-person health care visits. A recent study examined the feasibility of RMT for remotely monitoring medication adherence in patients with ADHD during the 4 to 6 week pharmacotherapy titration period.27 The study found that patients, parents, and health care providers were receptive to using RMT in the treatment of ADHD, but the potential utility was thought to be highest for ongoing management and support of ADHD rather than during the distinct titration period.27 

In addition to improving symptom and medication tracking with digital medicine, digital therapeutics could also provide novel treatment options for children and adolescents with ADHD.28-31 These software-based therapies can be implemented through a computer or mobile application in an interactive platform that is appealing to patients.6 Based on cognitive neuroscience research, the development of digital therapeutics for ADHD links implicated brain systems with specifically targeted interventions aimed at improving cognitive deficits.30 Digital therapeutics can be embedded with algorithms that continuously adapt to the patients’ cognitive control ability, provide feedback, progress, and compliance.21 Digital therapeutics hold the potential to improve the ADHD treatment landscape; however, any product developed would need to be carefully regulated and monitored to ensure safety and efficacy.

There are several digital therapeutics in various stages of development targeting ADHD treatment.28-31 The first, NeuroTracker (CogniSens Inc.), uses a three-dimensional multiple object tracking (3D-MOT) task to train attention in children with various neurodevelopmental conditions, including ADHD and autism.28 A recent trial of 129 Canadian students with a diagnosed neurodevelopmental condition (Autism Spectrum Disorder, ADHD, intellectual disability, language disorder, learning disorder, or other) ranging from age 6 to 18 measured the efficacy of NeuroTracker using Conners Continuous Performance Test (CPT-3).28 Participants were randomized to a treatment group (3D-MOT: NeuroTracker), an active control group (visual strategy/math-based game), or treatment-as-usual group. The results showed that post-training, CPT-3 performance significantly improved from baseline for participants in the treatment group only.28 Currently, NeuroTracker is used widely by professional athletes to improve attention and focus; however, this study shows the future promise of treatment for neurodevelopmental conditions.

A second digital therapeutic currently under development is a brain-computer interface (BCI) attention-training program licensed by Atentiv Inc.29 This BCI-based attention-training program consists of a headband with mounted dry electroencephalography sensors that transmit EEG readings to a computer through Bluetooth-enabled protocol during the computer-training activity.29 A small study, recently completed in Singapore, measured the efficacy of the BCI-attention training program in 17 children with ADHD. Parents completed the 18-question ADHD Rating Scale before and after treatment. Following the BCI-attention training program, parent-rated inattentive and hyperactive-impulsive symptoms on the ADHD Rating Scale showed significant improvement.29 There is still need to test the efficacy and safety of BCI-attention training programs with wearable EEG sensors in a large, randomized trial.

Another promising example of a digital therapeutic for treating ADHD farther along in the development process is AKL-T01 (Akili Interactive Labs, Inc), an investigational medical device and a potential prescription digital therapy for the treatment of children with ADHD.30,31 AKL-T01 software is designed to deploy sensory and motor stimuli to target and activate the prefrontal cortex, the area of the brain known to play a key role in cognitive function, through an interactive software-based therapy.30 This home-based therapy is administered for approximately 25 minutes a day, 5 days a week aimed at improving cognitive deficits common with ADHD, such as inattention and inhibition.30 In a multicenter, randomized, active-control trial in the United States (STARS-ADHD), AKL-T01 users (n=180) showed statistically significant improvement in the Test of Variables of Attention: Attention Performance Index (T.O.V.A. API: an objective measurement of attention and inhibitory control used to evaluate treatment for ADHD) compared with the active control group (n=168).31 Based on the positive results of this study, AKL-T01 is currently seeking FDA clearance for an indication to treat inattention and inhibitory control in pediatric patients with ADHD. If cleared, this digital therapeutic could be used in conjunction with current standards of care, as an alternative therapy for patients who experience adverse side effects of pharmacotherapy, in patients who do not have access to behavioral therapy, or for patients whose ADHD symptoms are not controlled with current treatment options.30 As digital therapeutics gain recognition in the ADHD management landscape, patients, parents, health care providers, and even payers stand to benefit. 

Conclusion

The potential to use digital therapeutics for treating ADHD, among numerous other neurocognitive disorders, appears to be very promising. For providers, digital therapeutics present the possibility of novel treatment options for conditions previously untreated or undertreated. The ability to prescribe digital therapeutics as monotherapy or in conjunction with current therapies shows promise to improve patient outcomes with unprecedented access to real-time patient data. Patients may eventually realize benefit from digital therapeutics through increased access to care, personalized treatment plans, and reduced stigma associated with certain traditional therapies. There is also potential for digital therapeutics to provide cost offsets or savings for payers who are responsible for providing coverage to patients suffering from chronic conditions. As the health care landscape continues to evolve, digital therapeutics may one day play a pivotal role in improving health outcomes for patients and reducing health care costs.

 

Disclosures: Robert L Findling, MBA, MD, receives or has received research support, acted as a consultant, and/or served on a speaker’s bureau for Aevi, Akili, Alcobra, Allergan, Amerex, American Academy of Child & Adolescent Psychiatry, American Psychiatric Press, Arbor, Bracket, Daiichi-Sankyo, Epharma Solutions, Forest, Genentech, Insys, Ironshore, KemPharm, Lundbeck, Merck, NIH, Neurim, Noven, Nuvelution, Otsuka, PCORI, Pfizer, Physicians Postgraduate Press, Roche, Sage, Shire, Sunovion, Supernus Pharmaceuticals, Syneurx, Teva, TouchPoint, Tris, and Validus. 

Precision Xtract and Precision for Value, part of Precision Value and Health, perform value and access consulting services and have provided those to entities developing digital therapeutics. Philip Cyr, MPH, is vice president of evidence strategy, generation, and communication at Precision Xtract. Joseph Honcz is the vice president of payer access solutions at Precision for Value. Madison Preib, MPH, is a research scientist at Precision Xtract.

Funding provided by Akili Interactive Labs, Inc.

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