Prescription Digital Therapeutics Materials

THE ROLE OF PRESCRIPTION DIGITAL THERAPEUTICS IN MEDICAL PRACTICE

STEVEN MALEN, PharmD, MBA

Dr. Steven Malen graduated with a dual degree: Doctor of Pharmacy (PharmD) and Master of Business Administration (MBA) from the University of Rhode Island. Over his career, he has worked as a clinical pharmacist in the retail, specialty, and compounding sectors. He specialized and taught on topics from vaccines to veterinary compounding.

Topic Overview

This course introduces clinicians to prescription digital therapeutics (PDTs), including their integration into clinical practice. The course reviews PDT definitions, research and development, and clinical trial progress. With digital health technologies revolutionizing medicine through smart devices and data- driven interventions, PDTs aim to manage and treat chronic conditions and mental or behavioral disorders via behavior modification. Pharmacy professionals may notice a shift from wellness apps to medical interventions. Pharmacists and pharmacy technicians can provide meaningful guidance to patients and other members of an interprofessional healthcare team.

Accreditation Statement

RxCe.com LLC is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education.

Universal Activity Number (UAN): The ACPE Universal Activity Number assigned to this activity is 

Pharmacist  0669-0000-24-056-H01-P

Pharmacy Technician  0669-0000-24-057-H01-T

Credits: 2 contact hour(s) (0.2 CEU(s)) of continuing education credit

Type of Activity: Knowledge

Media: Internet/Home study Fee Information: $6.99

Estimated time to complete activity: 2 contact hour(s) (0.2 CEU(s)), including Course Test and course evaluation

Release Date: May 21, 2024 Expiration Date: May 21, 2027

Target Audience: This educational activity is for pharmacists and pharmacy technicians

How to Earn Credit: From May 21, 2024, through May 21, 2027, participants must:

Read the “learning objectives” and “author and planning team disclosures;”

Study the section entitled “Educational Activity;” and

Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

Credit for this course will be uploaded to CPE Monitor®.

Learning Objectives: Upon completion of this educational activity, participants should be able to:

Define prescription digital therapies (PDTs) and distinguish them from non-prescription devices

Identify the uses of PDTs in healthcare

Identify how to integrate PDTs into patient care and management

Disclosures

The following individuals were involved in developing this activity: Steven Malen, PharmD, MBA, and Pamela Sardo, PharmD, BS. Pamela Sardo and Steven Malen have no conflicts of interest or financial relationships regarding the subject matter. There are no financial relationships or commercial or financial support relevant to this activity to report or disclose by RxCe.com or any of the individuals involved in the development of this activity.

© RxCe.com LLC 2024: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.

Educational Activity

The Role of Prescription Digital Therapeutics in Medical Practice Introduction

Prescription digital therapeutics are a part of telehealth and are being integrated into clinical practice. Digital therapeutics can be prescription or non-prescription. Prescription digital therapeutics may help close treatment gaps when used to treat and manage chronic medical conditions and mental or behavioral disorders. Prescription digital therapeutics in the clinical setting require knowledge of government regulations and familiarity with the available applications and products. Pharmacy teams may contribute to integrating prescription digital therapeutics into practice and collaborating with other healthcare professionals.

Definition of Prescription Digital Therapeutics

Sepah, et al. (2015) were the first researchers to use the term “digital therapeutics.”1,2 Digital therapeutics is encompassed within digital medicine, which is part of the larger digital health system.3 Sepah, et al., said digital therapeutics are “evidence-based behavioral treatments delivered online.”1,2 Thereafter, the Digital Therapeutics Alliance and Digital Medicine Society added their definition of digital therapeutics, stating they are medical interventions delivered directly to a patient that uses evidence-based, clinically evaluated software to treat, manage, and prevent various diseases and disorders, some of which may require a prescription.4

Digital therapeutics are delivered on smartphones, tablets, or other analytical devices.1-5 They are comparable to software as a medical device (SaMD) since they use software for medical purposes like SaMDs.1,7 However, SaMDs are standalone software medical products; they do not include hardware.7 In contrast, for digital therapeutics to work, they need a hardware component for data collection, storage, and processing.8 What may be

confusing here is that the Food and Drug Administration (FDA) refers to SaMDs as medical “devices,”7 but this may be a bit of a misnomer since there is no hardware. Nevertheless, digital therapeutics are regulated under the SaMD framework, as discussed below.4

With a digital therapeutic’s hardware component in place, the software program transmits diverse personal health data to be stored on the hardware platform.8 Devices have evolved from simple data collectors to deep learning, artificial intelligence (AI), and machine learning (ML) programs that can evaluate the data.8.9

The software and hardware components comprise the “internet of medical things” that supports data transfer over networks, and this may not require human interaction when AI is used to evaluate the data. The “Internet of Medical Things” is mainly a smart device with sensors and integrated circuits that collect, transmit, and store biological signals, or data input, from a patient.8

Digital products make different claims and carry distinct levels of risk. This can lead to the product being characterized as prescription or non- prescription.6 The FDA regulates both forms, but prescription digital therapeutics (PDTs), by definition, require a licensed healthcare professional to prescribe the product.6 Prescriptions are typically required for devices that treat serious diseases, are higher-risk devices, and need a trained clinician to evaluate the data. The clinician monitors the patient and follows up to determine an appropriate response and treatment.6 For example, reSET-O® is a PDT intended to be used with buprenorphine to treat patients with an opioid use disorder.6,10 It provides behavioral therapy to patients with opioid use disorder.10 The therapy is a series of interactive lessons using cognitive behavioral therapy and skill-building exercises. Therapy lessons are delivered by text or audio and may include videos, animations, and graphics.10 By comparison, Natural Cycles is a non-prescription software application.6 This app lets women track their menstrual cycles using digital apps and devices.6

PDTs Versus Traditional Therapeutics

Unlike traditional medications, PDTs provide therapeutic interventions through software applications on computers or mobile devices, where the treatment's effectiveness is largely determined by its content and application method.1 Pharmacotherapy's efficacy is influenced by complex physiological factors. In contrast, digital therapeutics’ efficacy is more likely to be impacted by population characteristics, social and cultural factors, and a patient’s cognitive abilities; e.g., young patients are more likely to use or be familiar with digital devices than older adults.1

Their use in clinical settings with traditional medications may help close treatment gaps when treating chronic medical conditions and behavioral disorders.

Prescription digital therapeutics and traditional pharmacotherapy differ in development, distribution, and management.1 Prescription digital therapeutics have lower development costs and shorter timelines, with direct- to-patient distribution models that bypass traditional pharmaceutical supply chains. Unlike pharmacotherapy, PDTs reportedly have fewer side effects and offer higher medication adherence rates due to their software-based applications and ease of use.1

Prescription digital therapeutics face challenges not found with traditional pharmacotherapy, which include ensuring digital accessibility, user education on digital platforms, and safeguarding patient data.1 Ultimately, PDTs' success hinges on patient engagement and the capacity to adapt through updates, contrasting with the static nature of pharmacological treatments. Table 1 illustrates some reported distinctions between traditional pharmacotherapy and digital therapeutics.

Table 1

Traditional Pharmacotherapy Compared to Digital Therapeutics*

* Adapted from Wang, et al. (2023)1 and Haga, et al. (2014)11

Regulating Prescription Digital Therapeutics

Early attempts by the FDA to regulate digital therapeutics were challenging because of the rapid proliferation of consumer healthcare apps and the diversity of digital products.6 In response to the evolving landscape, the FDA's 2013 Mobile Medical Applications guidance, updated in 2019, and subsequent guidance documents aimed to clarify the regulation of software- run digital products using the risk-based approach provided by the 21st Century Cures Act of 2016.6,12-14 This act refined the definition of medical devices to exclude certain types of software, aligning with the FDA's approach and clarifying which types of software and functions would fall under regulatory scrutiny.6

Digital products make different claims and carry distinct levels of risk. This can lead to the product being characterized as prescription or non- prescription.6 The FDA regulates both forms, but prescription digital therapeutics (PDTs), by definition, require a licensed healthcare professional

to prescribe the product.6 Prescriptions are typically required for devices that treat serious diseases, are higher-risk devices, and need a trained clinician to evaluate the data. The clinician monitors the patient and follows up to determine an appropriate response and treatment.6

When deciding to regulate a PDT, the FDA focuses on the software function. Examples of software functions that the FDA regulates as a medical device include the following:13

Software functions that transform a mobile platform into a regulated medical device, such as a sensor or lead that is connected to a mobile platform to measure and display the electrical signal produced by the heart (electrocardiogram or ECG), or an attachment to the mobile platform to measure blood oxygen saturation for diagnosis of specific disease or condition

Software functions that connect to an existing device type for purposes of controlling its operation, function, or energy source, such as wireless remote controls or synchronization devices for computed tomography (CT) or X-ray machines, or software that calibrates hearing aids and assesses the electroacoustic frequency and sound intensity characteristics emanating from a hearing aid, master hearing aid, group hearing aid, or group auditory trainer.

Software functions that are used in active patient monitoring or to analyze patient-specific medical device data, such as acquiring or processing physiological signals that connect to bedside (or cardiac) monitors for active patient monitoring or software intended for healthcare professional management of heart failure patients that analyzes patient-specific medical information (e.g., daily heart rate, SpO2, blood pressure, or other output from wearable product) to predict heart failure hospitalization

Additional Resource: A more comprehensive list of software functions that the FDA will regulate may be found on the FDA’s website at Examples of Device Software Functions the FDA Regulates, at the following link: https://www.fda.gov/medical-devices/device-software-functions-including- mobile-medical-applications/examples-device-software-functions-fda- regulates

The FDA may decide not to regulate a product. The FDA’s website, Examples of Software Functions That Are NOT Medical Devices, provides a sample of software functions that the agency does not regulate.14 Reviewing these may help one understand the types of software programs the agency does not regulate.

SaMD Framework Used to Regulate PDTs

Currently, the FDA regulates PDTs under the SaMD framework.4,7 New products are reviewed under the de novo pathway, a regulatory pathway that begins with classifying the device based on its potential risk to patients. A Class I device is low risk, a Class II has moderate risk, and a Class III is high risk.4,6 New products must provide reasonable assurance of safety and effectiveness before the FDA approves them.4 Subsequent devices of the same type are cleared by the FDA through the 510(k) premarket notification process.4 This means that a new product must be “approved” by the FDA, while a subsequent, similar product is “cleared.”4 For example, reSET-O®, a prescription opioid use disorder product, was cleared for marketing because it was substantially equivalent to its predicate or previous version reSET.10

Class I and some Class II devices do not require clinical testing. The manufacturer must only show that its medical device is substantially equivalent to a legally marketed product.15 For example, the Natural Cycles app, a non-prescription menstruation tracker, was approved under the de

novo pathway as a Class II device, while Clue was authorized under 510(k) using Natural Cycles as a predicate device.6

New PDTs must go through research and development just like pharmaceuticals.4 Premarket clinical studies are used to demonstrate a new product’s effectiveness and safety for a specific therapeutic indication before FDA approval.4 However, digital therapeutics do not go through the extensive preclinical and clinical trial requirements drug manufacturers must do when seeking FDA approval for a new drug.4 The FDA guidance on the evidentiary standards needed to approve a new PDT is limited.4

Breakthrough Devices Program

The FDA also provides a voluntary program called the Breakthrough Devices Program.16 This program applies to certain medical devices and device-led combination products that provide more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions.16,17 The Breakthrough Devices Program may also apply to certain devices that benefit populations impacted by health and/or healthcare disparities.15,17 The Breakthrough Devices Program is intended to incentivize innovation.17 The FDA awards this designation early in development to speed up a product’s availability. The product’s benefits and risks may not be fully evaluated, and full judgment on the product's efficacy and safety is shaped by the postmarket evidence collected.17 This designation also qualifies a device for supplemental Medicare reimbursement.17

Breakthrough designation automatically qualifies a device for supplemental Medicare reimbursement.17 This is because, in 2020, CMS waived the long-standing requirement that devices demonstrate "substantial clinical improvement" for beneficiaries before supplemental Medicare reimbursement can occur.17

Clinical Trials and Evidence for PDTs

Some Class II and all Class III devices require clinical testing.15,18 Randomized clinical trials (RCTs) are used to evaluate digital therapeutics, similar to the process for drug products.18

The CONVOKE Clinical Trial

An example of a digital therapeutic clinical trial is the CONVOKE trial. CONVOKE is a randomized, multicenter trial evaluating the efficacy and safety of a PDT developed for schizophrenia patients.19 The objective of CONVOKE is to evaluate the efficacy of two PDTs in addition to a stable dose of standard- of-care therapy for the treatment of negative symptoms of schizophrenia in late adolescents and adults.19 Both PDTs use a smartphone app that attempts to provide intervention and treatment strategies.19 The trial is evaluating whether either PDT, used as an adjunct to standard pharmacological therapy, will result in better outcomes in schizophrenic patients compared to pharmacological therapy alone.19

Concerns with PDT Clinical Trials

There is an ongoing need to navigate ethical considerations, ensure data security, and maintain a user-centered design to enhance patient care's accessibility and effectiveness.20 A group of experts evaluated twenty FDA- authorized PDTs. The review revealed significant gaps in the evidence base supporting these technologies. The authors published that most clinical studies were conducted as a postmarket analysis.20 They rated this approach as having lower evidence standards than premarket studies. Furthermore, they identified a notable lack of diversity in the study's participants.20 The authors also reported that over half of the studies failed to report a participant’s race, and over 80% omitted ethnicity data. Additionally, many studies required English proficiency and imposed age restrictions on participants. These findings underscore the urgent need for more thorough and inclusive clinical research to bolster confidence in PDTs, thereby

facilitating better clinical and coverage decisions,19 and the need for rigorous evaluation of PDTs.21

Clinical Conditions and PDT Products

The number of mobile apps emerging in digital health is growing rapidly. Phan, et al. (2023) reported that the FDA approved or cleared approximately twenty-three digital therapeutics through the de novo or 510(k) premarket pathways.22 Some of these products required a prescription, while others were authorized by the FDA for use in the United States without a prescription.22 The prescription devices treat, manage, or prevent many diseases and conditions, such as psychiatric disorders, substance use disorders, chronic pain, neurological diseases, cardiovascular diseases, respiratory diseases, and endocrinological diseases (e.g., diabetes).1,22

More recently, the range of applications has expanded to include treatments for irritable bowel syndrome, migraines, post-surgery recovery for hip and knee replacements, and ear diseases.1 The United States has led the charge in PDT commercialization, with many products receiving clearance from the FDA.1

FDA-Approved PDTs

Prescription digital therapeutics are part of the emergence of telehealth, and products have been approved to manage medical conditions.1 For example, in 2010, a diabetes management app by WellDoc, Inc., called BlueStar, was the first mobile prescription therapeutic to be given FDA approval in the United States.21,23 This smartphone device was designed to help type II diabetes patients self-manage their condition.23 On April 7, 2020, WellDoc, Inc., received authorization to premarket BlueStar® Rx, which was found to be substantially equivalent to its predicate BlueStar.23 BlueStar Rx requires a prescription from a healthcare provider for Type I and Type II diabetes patients aged 18 years and older. It may appear on an app store as BlueStar Diabetes. BlueStar Rx is intended to provide secure capture, storage,

and transmission of blood glucose test data and transmit that information to the patient to aid in diabetes self-management. BlueStar Rx provides motivational, behavioral, and educational coaching messages to the patient based on real-time blood glucose values and trends. It operates on mobile phones or personal computers. The healthcare provider titrates the insulin dose for the patient based on the patient’s specific parameters.

In addition to chronic disease states, PDTs have been approved for managing mental or behavioral disorders, including substance use disorders, sleep disorders, schizophrenia, ADHD, and chronic pain.1, In 2017, Pear’s reSET therapy was the first FDA-approved PDT for a mental or behavioral disorder, specifically as a monotherapy for the treatment of substance use disorders in patients 18 and older.24 Pear’s reSET therapy was followed by a subsequent version reSET-O®.10 reSET-O is used in combination with a buprenorphine-based medication and is indicated for patients 18 and older with an opioid use disorder.10 Both app versions are available. As mentioned above, the reSET therapy apps use CBT-based tools that track substance use, cravings, and triggers (e.g., social pressure and loneliness).10 This PDT requires a physician’s prescription. These apps are designed for patients in outpatient therapy for the indicated use disorder.24 Treating clinicians such as psychologists or psychiatrists may log on to a dashboard to access a patient’s data and monitor the patient’s progress. reSET applications have a label similar to a drug container label.24 The reSET label has instructions for clinicians describing how to use the device in therapeutic practice.24

Why would clinicians want to integrate PDTs into their practices? Prescription digital therapeutics may help increase healthcare access, adherence to treatment plans, encourage patients to manage their healthcare, and improve outcomes.1,30 Available PDTs and nonprescription digital therapeutics are numerous, possibly in the thousands.30 They utilize technologies such as smartphone apps that can track a patient’s mood, deliver meditation sessions, and provide other therapies, on-demand.30

Patients are the primary beneficiaries of PDTs. Patients provide feedback on efficacy, usability, and outcomes, which guide the refinement of PDT solutions to meet their specific needs.3,31,32 Ultimately, digital therapeutics enable patients to participate in managing their healthcare.3,32 Table 2 provides examples of current FDA-authorized PDTs.

Table 2

Examples of FDA-authorized PDTs

Challenges and Barriers to Using Digital Therapeutics

Some digital therapeutics are readily available to the public through digital and mobile devices. This has given rise to the concept of “digital self- care.”33 Many clinicians see the benefits of involving patients in their wellness regimens, disease management, and treatment; however, these technologies raise questions regarding a patient’s ability to interpret health data, report it to a primary care provider, and appreciate if a device functions properly.32 There are only a few studies on this important topic, and these questions will likely be addressed over time.33

Digital Therapeutics and the Clinician-Patient Relationship

What is certain is that with mobile digital therapeutics, the traditional clinician-patient relationship will change as the patient takes on

responsibilities that were previously within the clinician’s domain.33 For example, it is the clinician, possessing training and expertise, who reviews and interprets a patient’s health data gathered in the clinical setting. However, with digital technologies, sensing, measuring, visualizing, and recording bodily phenomena may take place outside the clinical setting.33 This may give the patient more reporting responsibilities.22,33 Should or can a clinician rely on the patient’s self-report? How will this impact the management of a patient’s chronic medical condition?

Safety and Efficacy of Digital Therapeutics

Concerns exist about the safety and efficacy of PDTs.19 Long-term adverse effects remain largely unknown and will likely surface over time. Additionally, PDTs hold promise for enhancing the collection and analysis of real-world data. They necessitate rigorous scientific methods to ensure the collection of high-quality data. It is also critical to approach PDTs with caution. They should not replace conventional treatments and management by a licensed clinician, especially since outcomes are still being studied.34 For example, in one case, a female patient was advised to download a mobile health app to help with counting carbohydrates.35 She recently had diabetic ketoacidosis, triggered by low insulin levels.35 After starting to use the app, the patient experienced severe and avoidable hypoglycemia.35 The app had recommended she take more than twice the correct amount of insulin.35

Integrating PDTs into clinical practice demands a balanced approach, supplementing rather than supplanting established treatments and ensuring that when PDTs are prescribed, they are done with a full understanding of their merits and limitations.

Related to safety and efficacy, questions of whether digital devices and software will function properly and how updates to the software will be handled will need to be answered.22 A digital therapeutic device may not function as planned.33 This could be due to a software program malfunction, which may cause a manufacturer to recall a product.36 A patient may not

realize a software or device malfunction and continue using the product. This could compromise data the patient is reporting to a healthcare provider.

Many applications are regularly updated and made available to patients. Discrepancies in updates could occur. Moreover, as software is updated, how will regulators and users know if it has become completely different from its initial design?22

Systemic Barriers to Using PDTs in Clinical Practice

There are systemic barriers to using PDTs.30 A broader digital health system is needed to transition into digital health.30 Integrating PDTs into clinical practice requires technological and infrastructural changes to the digital health system. Patient engagement is also needed.30 It could be that the pandemic set the beginning stages of developing this system in motion, but more is needed.30 More effort is needed to create the systems, improve technology and infrastructure, and foster patient trust and engagement in PDTs. Engaging patients with PDTs requires overcoming obstacles such as digital literacy, accessibility issues, and the personal preference for traditional face-to-face interactions.37

Adequate Knowledge About PDT Technologies

Most clinicians do not discuss PDTs and nonprescription digital therapeutics with patients.30 This could be because of a general lack of knowledge about the available products. From a technological standpoint, digital therapeutics for healthcare interventions vary in quality, and there is a lack of familiarity with some technologies among clinicians.30 This could be partly due to the absence or paucity of digital health curricula in professional education.36 Also, pharmacy staff may want to familiarize themselves with new technologies but are hindered by time constraints in a busy pharmacy setting.30

Patients also lack familiarity with technologies, or they may not have the literacy to use digital devices. Some patients may not have a mobile phone with advanced capabilities. Researchers have published limitations in access to digital health for elderly or low-income patients.5,31,32

PDTs and Patient Privacy Concerns

Privacy, security, and data governance in PDTs are paramount concerns due to the sensitive nature of the health data involved.1,5,6,30 These new technologies differ from traditional therapies because they rely on software applications that store and share sensitive patient medical information.22 The storage and access of sensitive patient medical information remains a concern since patient confidentiality must be preserved.22

Clear policies for data handling, storage, and sharing are necessary. Developers must implement stringent security measures, including encryption, access controls, and regular security audits, to prevent unauthorized access and data breaches. Additionally, privacy policies must be transparent, providing patients with clear information on how their data is used and shared. Ensuring compliance with regulatory bodies and adopting best practices in data governance will reinforce the safety and effectiveness of PDTs, fostering trust and reliability in these healthcare innovations.

PDTs and Health Insurance

Health insurance companies have been reluctant to cover digital therapeutics under their health plans because many therapeutics lack sufficient evidence that they are effective.38 Lumbreras, et al. (2024) reported that insurance companies had more questions than answers about these new products and how they could be integrated into health benefits.38 This reluctance to cover digital therapeutics was especially true before the COVID-

19 pandemic.30 However, when the Centers for Medicare and Medicaid Services and private healthcare insurance expanded coverage for telehealth under the public health emergency declaration, healthcare providers, such as mental health clinicians and pharmacists, transitioned to teleconferencing and expanded their use of smartphones and other apps.30-32

Pharmacy Role in PDTs

Pharmacists should engage with patients when digital therapeutics are prescribed.39-41 Pharmacists’ involvement and use of digital therapeutics (e.g., mobile apps) have been positive.42 Moreover, the pharmacist should lead the healthcare team when digital therapeutics are prescribed since pharmacist- led healthcare models in patients with chronic conditions have been shown to improve health outcomes.43,44

After a therapeutic device is prescribed, a pharmacist may be involved in accessing and reviewing data from the digital therapeutic to assist the healthcare team in evaluating the effectiveness of the therapy, treatment adherence by the patient, and recommendations on modification of treatment plans if needed.39 Patients will have questions about digital therapeutic devices. The pharmacist is well-positioned to answer patient questions about prescriptions and renewals, as well as questions about the operations and functions of a device.39 This will require pharmacists to understand and be familiar with the devices and how they work. Pharmacists and pharmacy staff must also be vigilant and review a patient's prescription and nonprescription

apps to prevent adverse effects.45 This is similar to their role when they review a patient’s over-the-counter drugs and prescription medications.

Integrating PDTs into pharmacy practice also presents an expanded responsibility for pharmacy technicians. Pharmacy technicians should become familiar with digital therapeutic devices and how they work to help them identify potential adverse events. This may help the technician with order entry for digital therapies. In addition, if a potential adverse event is suspected, the pharmacy technician should immediately notify the pharmacist. It will also significantly impact pharmacy technicians’ role in order entry and processing, management of equipment and supplies, patient safety, quality assurance, and adherence to federal requirements.

As the healthcare landscape evolves to include PDTs, questions will arise, particularly whether the prescription process will involve direct patient downloads of mobile apps and how the pharmacy team will engage in this new model. Furthermore, the critical aspects of patient safety and error prevention strategies will need to be reimagined for a digital setting, including new protocols for ensuring the correct patient receives the appropriate digital therapy and the implementation of digital equivalents to barcode usage for inventory separation. Additionally, executing event reporting and root-cause analysis will adapt to digital product integrity issues and software-related incidents.

Pharmacists and pharmacy technicians should be aware that some PDTs are prescription only, but some can be self-downloaded as a wellness or self-care option

Begin to ask patients if they are using any devices as part of their treatment

Ask identified PDT users if they are using the PDT daily as an adherence check

Refer PDT mobile application clinical questions to the pharmacist

Determine a place to enter the use of newly identified PDT in the pharmacy profiles

The Future of PDTs

Prescription digital therapeutics are here to stay, and government regulations will change as technology is studied and evolves.46 Since this is the case, what will digital healthcare look like in the coming years? How will AI-driven PDTs impact healthcare outcomes? Will pharmacists and pharmacy staff be an integral part of PDTs, or will they be bypassed by direct developers to patient products and downloads?

Future Directions in PDT Regulation

The Access to Prescription Digital Therapeutics Act of 2022 is a bipartisan bill introduced in the Senate, adding prescription digital therapeutics to the list of services and products eligible for coverage under Medicare and Medicaid. The bill also directs CMS to establish payment methodologies and product-specific Healthcare Common Procedure Coding System codes for prescription digital therapeutics.4 In addition, the FDA has established the Digital Health Center of Excellence, which is a strategic effort to address digital health regulation more comprehensively moving forward.6

Artificial Intelligence and Machine Learning

The rapid evolution of software as a medical device presents a significant opportunity for PDTs to advance.6 This includes incorporating AI and ML.47 Artificial intelligence and ML systems can be “locked,” which means they cannot adapt or continually learn from their environment.47 Alternatively, AI and ML systems could use “continual learning” or “lifelong learning” software and algorithms.47 Continual learning software and algorithms can be updated by incorporating new data and retaining previously learned knowledge using complex mathematical equations.47 The new data may include post-FDA approval and real-world data that could be learned by the program, leading to improved health outcomes.47 As technologies evolve, particularly with the integration of adaptive AI and ML, PDTs can become more personalized and improve patient care.47

Continual learning software comes with some risks that scientists and developers must address.47 New data adapted into the software may have errors, such as a patient reporting incorrect data. This could be a patient providing incorrect or incomplete personal data or a clinician entering incomplete or inaccurate symptoms or diagnosis in a patient’s electronic health records.47 A system may receive biased data. For example, if an AI and ML system were developed using data from multiracial patients, but then post- approval data is collected disproportionately from a single racial patient population. When this occurs, the outcomes for other racial groups can deteriorate.47 This type of error is referred to as a “domain shift.”47 To mitigate this outcome, digital therapeutic device trials should monitor and report participant diversity.46 Reports should include race, ethnicity, sex, and socioeconomic status. Companies may need to adjust trial recruitment strategies to ensure the trial represents all patient populations.46

Finally, there is a risk that new information could interfere with previously learned information. This is referred to as catastrophic forgetting. If prior knowledge is overwritten, the performance of the system will deteriorate.47

Will PDTs Cause Pharmacy Teams to be Bypassed

A concern with PDTs is that pharmacy teams may be removed from the process.40,47 This concern is not exclusive to the pharmacist in a healthcare team.47 This could occur with downloadable technologies to an app on a device without a prescription.47 A patient may visit an app store or an online portal.47 Bypassing the pharmacy in the PDT process creates a critical gap in the traditional healthcare delivery model, especially concerning patient safety and the necessary checks and balances inherent in the pharmacy system.

Summary

Digital therapeutics are medical interventions delivered directly to a patient. They are evidence-based, clinically evaluated software used to treat,

manage, and prevent various diseases and disorders, some of which may require a prescription. Unlike traditional medications, PDTs provide therapeutic interventions through software applications on computers or mobile devices, where the treatment's effectiveness is largely determined by its content and application method. The FDA regulates PDTs under the SaMD framework.

The number of mobile apps emerging in digital health is growing rapidly. Prescription devices treat, manage, or prevent many diseases and conditions, such as psychiatric disorders, substance use disorders, chronic pain, neurological diseases, cardiovascular diseases, respiratory diseases, and endocrinological diseases (e.g., diabetes). More recently, the range of applications has expanded to include treatments for irritable bowel syndrome, migraines, post-surgery recovery for hip and knee replacements, and ear diseases. Concerns exist about the safety and efficacy of PDTs. Long-term adverse effects remain largely unknown and will likely surface over time. There are systemic barriers to using PDTs.

What is certain is that with mobile digital therapeutics, the traditional clinician-patient relationship will change as the patient. Pharmacists should engage with patients when digital therapeutics are prescribed. Pharmacists’ involvement and use of digital therapeutics (e.g., mobile apps) have been positive. Moreover, the pharmacist should lead the healthcare team when digital therapeutics are prescribed since pharmacist-led healthcare models in patients with chronic conditions have been shown to improve health outcomes. Integrating PDTs into pharmacy practice also presents an expanded responsibility for pharmacy technicians.

Course Test

According to the Digital Therapeutics Alliance and Digital Medicine Society, digital therapeutics are medical interventions used to treat, manage, and prevent diseases and disorders that

do not require a prescription.

are evidence-based, clinically evaluated software that may require a prescription.

that do not require clinical trials or a prescription.

are standalone software medical products that do not include hardware

Pear’s reSET-O therapy is FDA-approved

to treat substance use disorders in patients 18 and older

as a CBT monotherapy.

to treat drug misuse in adolescents.

for patients 18 and older with an opioid use disorder.

Which of the following is accurate regarding the CONVOKE study?

The objective of CONVOKE is to evaluate the efficacy of four prescription digital therapeutics (PDTs)

CONVOKE evaluates PDT in addition to a variable dose of therapy for the treatment of migraine

Information about a downloadable CONVOKE mobile app is available through a discount drug card

It is a randomized, multicenter trial to evaluate the efficacy and safety of PDTs and standard of care

Which PDT option below is correctly paired with its intended therapeutic area?

Somryst-substance use disorder

Pear reSET-PTSD, panic disorder

Freespira-chronic low back pain

EndeavorRx-Attention-Deficit/ Hyperactivity Disorder (ADHD)

A barrier to the use of PDTs in the clinical setting includes

a lack of knowledge and familiarity with available PDT products.

a lack of difference or variance between PDT products.

the fact that patients know more about technology than healthcare providers.

the fact that medical software programs cannot be regulated.

Which of the following statements accurately describes digital therapeutics in healthcare?

Mobile apps available to the public have given rise to the concept of digital self-care.

Mobile digital therapeutics will have NO impact on the traditional clinician-patient relationship.

Digital therapeutics are superior to traditional treatments because they do not malfunction.

The integration of digital therapeutics into clinical practice will replace established pharmacotherapy treatments

The Access to Prescription Digital Therapeutics Act of 2022 is a bipartisan bill introduced in the Senate that would

establish the Digital Health Center of Excellence.

add PDTs to the list of services and products eligible for coverage under Medicare and Medicaid.

require all future PDTs be regulated as Software as a Medical Devices (SaMDs).

make patient self-care illegal.

“Domain shift” is a term used to describe post-approval data that is collected

from a broad spectrum of races, ethnicities, genders, and socioeconomic statuses.

on a healthcare facility's computer domain, not the developer’s.

disproportionately from a single racial patient population, causing the outcomes for other racial groups to deteriorate.

to ensure digital interventions do not have software malfunctions.

What are some considerations for pharmacy teams as PDTs are integrated into the pharmacy setting?

changes in patient safety and error prevention strategies are not expected

all patients are appropriate for digital therapy because the applications are online

the execution of adverse event reporting and root-cause analysis will adapt to encompass digital product integrity

new pharmacy staff responsibilities are unlikely because of strong compliance with the software

A patient comes to the pharmacy counter with a new prescription for an opioid use disorder. The patient shared that she is using the reSET-O app. She also mentioned that she did not need to fill her buprenorphine prescription now that she has the app. What should the pharmacist advise the patient?

The reSET-O therapy app uses a CBT-based tool, so you don’t need the prescription.

The reSET-O therapy is used in combination with a buprenorphine- based medication.

They need to download their doctor’s contact information on the app.

The reSET-O app is indicated for substance use disorders, not an opioid use disorder.

References

Wang C, Lee C, Shin H. Digital therapeutics from bench to bedside. NPJ Digit Med. 2023;6(1):38. Published 2023 Mar 10. doi:10.1038/s41746- 023-00777-z

Sepah SC, Jiang L, Peters AL. Long-term outcomes of a Web-based diabetes prevention program: 2-year results of a single-arm longitudinal study. J Med Internet Res. 2015;17(4):e92. Published 2015 Apr 10. doi:10.2196/jmir.4052

Dang A, Arora D, Rane P. Role of digital therapeutics and the changing future of healthcare. J Family Med Prim Care. 2020;9(5):2207-2213. Published 2020 May 31. doi:10.4103/jfmpc.jfmpc_105_20

Salsabili M, Tesell M, Alcusky M, et al. Prescription digital therapeutics: Applying Medicaid experience to value assessment and formulary management. J Manag Care Spec Pharm. 2023;29(6):685-691. doi:10.18553/jmcp.2023.29.6.685

Brezing CA, Brixner DI. The Rise of Prescription Digital Therapeutics in Behavioral Health. Adv Ther. 2022;39(12):5301-5306. doi:10.1007/s12325-022-02320-0

Watson A, Chapman R, Shafai G, Maricich YA. FDA regulations and prescription digital therapeutics: Evolving with the technologies they regulate. Front Digit Health. 2023;5:1086219. Published 2023 Apr 17. doi:10.3389/fdgth.2023.1086219

Food and Drug Administration. Software as a Medical Device (SaMD). FDA. December 4, 2018. https://www.fda.gov/medical-devices/digital- health-center-excellence/software-medical-device-samd. Accessed May 10, 2024.

Lee HY, Lee KH, Lee KH, et al. Internet of medical things-based real- time digital health service for precision medicine: Empirical studies using MEDBIZ platform. Digit Health. 2023;9:20552076221149659. Published 2023 Jan 9. doi:10.1177/20552076221149659

Benjamens S, Dhunnoo P, Meskó B. The state of artificial intelligence- based FDA-approved medical devices and algorithms: an online database. NPJ Digit Med. 2020;3:118. Published 2020 Sep 11. doi:10.1038/s41746-020-00324-0

Food and Drug Administration. reSET-O. FDA Marketing Approval Letter to Pear Therapeutics, Inc. FDA. May 23, 2019. https://www.accessdata.fda.gov/cdrh_docs/pdf17/K173681.pdf. Accessed May 17, 2024.

Haga SB, Mills R, Moaddeb J. Pharmacogenetic information for patients on drug labels. Pharmgenomics Pers Med. 2014;7:297-305. Published 2014 Oct 3. doi:10.2147/PGPM.S67876

Food and Drug Administration. Policy for Device Software Functions and Mobile Medical Applications. FDA. September 2022. https://www.fda.gov/regulatory-information/search-fda-guidance- documents/policy-device-software-functions-and-mobile-medical- applications. Accessed May 15, 2024.

Food and Drug Administration. Examples of Device Software Functions the FDA Regulates. FDA. https://www.fda.gov/medical-devices/device- software-functions-including-mobile-medical-applications/examples- device-software-functions-fda-regulates. Accessed May 16, 2024.

Food and Drug Administration. Examples of Software Functions That Are NOT Medical Devices. FDA. 09/29/2022. https://www.fda.gov/medical- devices/device-software-functions-including-mobile-medical- applications/examples-software-functions-are-not-medical-devices. Accessed May 16, 2024.

Baltaxe E, Hsieh HW, Roca J, Cano I. The Assessment of Medical Device Software Supporting Health Care Services for Chronic Patients in a Tertiary Hospital: Overarching Study. J Med Internet Res. 2023;25:e40976. Published 2023 Jan 4. doi:10.2196/40976

Food and Drug Administration. Breakthrough Devices Program. FDA. September 2023. https://www.fda.gov/regulatory-information/search- fda-guidance-documents/breakthrough-devices-program. Accessed May 16, 2024.

Moneer O, Rathi VK, Johnston JL, Ross JS, Dhruva SS. Aligning US Agency Policies for Cardiovascular Devices Through the Breakthrough Devices Program. JAMA Cardiol. 2023;8(12):1174-1181. doi:10.1001/jamacardio.2023.3819

Huh KY, Oh J, Lee S, Yu KS. Clinical Evaluation of Digital Therapeutics: Present and Future. Healthc Inform Res. 2022;28(3):188-197. doi:10.4258/hir.2022.28.3.188

Study of Two Digital Therapeutics for the Treatment of Experiential Negative Symptoms of Schizophrenia (CONVOKE). Clinicaltrials.gov. March 15, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05838625. Accessed April 6, 2024.

Kumar A, Ross JS, Patel NA, Rathi V, Redberg RF, Dhruva SS. Studies Of Prescription Digital Therapeutics Often Lack Rigor And Inclusivity. Health Aff (Millwood). 2023;42(11):1559-1567. doi:10.1377/hlthaff.2023.00384

Agarwal P, Mukerji G, Desveaux L, et al. Mobile App for Improved Self- Management of Type 2 Diabetes: Multicenter Pragmatic Randomized Controlled Trial. JMIR Mhealth Uhealth. 2019;7(1):e10321. Published 2019 Jan 10. doi:10.2196/10321

Phan P, Mitragotri S, Zhao Z. Digital therapeutics in the clinic. Bioeng Transl Med. 2023;8(4):e10536. Published 2023 May 3. doi:10.1002/btm2.10536

Food and Drug Administration. BlueStar® Rx. FDA Premarketing Authorization Letter to WellDoc, Inc. FDA. April 7, 2020. https://www.accessdata.fda.gov/cdrh_docs/pdf19/K193654.pdf. Accessed May 18, 2024.

Weir K. The ascent of digital therapies. Monitor Psychol.

2018;49(10):80.

Food and Drug Administration. Somryst. FDA Marketing Approval Letter to Pear Therapeutics, Inc. FDA. September 15, 2023. https://www.accessdata.fda.gov/cdrh_docs/pdf19/K191716.pdf. Accessed May 18, 2024.

Ritterband LM, Thorndike FP, Morin CM, et al. Real-world evidence from users of a behavioral digital therapeutic for chronic insomnia. Behav Res Ther. 2022;153:104084. doi:10.1016/j.brat.2022.104084Shafai G,

Aungst TD. Prescription digital therapeutics: A new frontier for pharmacists and the future of treatment. J Am Pharm Assoc (2003). 2023;63(4):1030-1034. doi:10.1016/j.japh.2023.03.012

Food and Drug Administration. EndeavorRx® FDA Marketing Approval Letter to Akili Interactive Labs Inc. FDA. June 15, 2020. https://www.accessdata.fda.gov/cdrh_docs/pdf20/DEN200026.pdf. Accessed May 18, 2024.

Food and Drug Administration. Freespira® FDA Marketing Approval Letter to Palo Alto Health Sciences, Inc. FDA. August 23, 2018. https://www.accessdata.fda.gov/cdrh_docs/pdf18/K180173.pdf. Accessed May 18, 2024.

Food and Drug Administration. Rejoyn. FDA Marketing Approval Letter to Otsuka Pharmaceutical. FDA. March 30, 2024. https://otsuka- us.com/news/rejoyn-fda-authorized. Accessed May 18, 2024.

Johansen SL, Olmert T, Chaudhary N, Vasan N, Aragam GG. Incorporating Digital Interventions into Mental Health Clinical Practice: a Pilot Survey of How Use Patterns, Barriers, and Opportunities Shifted for Clinicians in the COVID-19 Pandemic. J Technol Behav Sci. Published online May 10, 2022. doi:10.1007/s41347-022-00260-8

Mace RA, Mattos MK, Vranceanu AM. Older adults can use technology: why healthcare professionals must overcome ageism in digital health [published correction appears in Transl Behav Med. 2022 Nov 03;:]. Transl Behav Med. 2022;12(12):1102-1105. doi:10.1093/tbm/ibac070

Bell IH, Thompson A, Valentine L, Adams S, Alvarez-Jimenez M, Nicholas J. Ownership, Use of, and Interest in Digital Mental Health Technologies Among Clinicians and Young People Across a Spectrum of

Clinical Care Needs: Cross-sectional Survey. JMIR Ment Health.

2022;9(5):e30716. Published 2022 May 11. doi:10.2196/30716

Fiske A, Buyx A, Prainsack B. The double-edged sword of digital self- care: Physician perspectives from Northern Germany. Soc Sci Med. 2020;260:113174. doi:10.1016/j.socscimed.2020.113174

Kim HS. Apprehensions about Excessive Belief in Digital Therapeutics: Points of Concern Excluding Merits. J Korean Med Sci. 2020;35(45):e373. Published 2020 Nov 23. doi:10.3346/jkms.2020.35.e373

Case study: Rassi-Cruz M, Valente F, Caniza MV. Digital therapeutics and the need for regulation: how to develop products that are innovative, patient-centric and safe. Diabetol Metab Syndr. 2022;14(1):48. Published 2022 Apr 1. doi:10.1186/s13098-022-00818-

9

Food and Drug Administration. Class 2 Device Recall RelievRx. May 17, 2024.

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfres/res.cfm?id=2 00685. Accessed May 18, 2024.

Baroni MP, Jacob MFA, Rios WR, et al. The state of the art in telerehabilitation for musculoskeletal conditions. Arch Physiother. 2023;13(1):1. Published 2023 Jan 4. doi:10.1186/s40945-022-00155-0

Lumbreras AG, Hurwitz JT, Liang X, et al. Insights into insurance coverage for digital therapeutics: A qualitative study of US payer perspectives. J Manag Care Spec Pharm. 2024;30(4):313-325. doi:10.18553/jmcp.2024.30.4.313

Vatanka P, Lofton JC. Re-envisioning the Pharmacist's Role in the Era of Digital Health—CPhA's Inaugural Digital Health Conference. Journal of Contemporary Pharmacy Practice. 2020;67(2):23–32.

Shafai G, Aungst TD. Prescription digital therapeutics: A new frontier for pharmacists and the future of treatment. J Am Pharm Assoc (2003). 2023;63(4):1030-1034. doi:10.1016/j.japh.2023.03.012

AMCP Partnership Forum: Digital Therapeutics-What Are They and Where Do They Fit in Pharmacy and Medical Benefits?. J Manag Care Spec Pharm. 2020;26(5):674-681. doi:10.18553/jmcp.2020.19418

Park T, Muzumdar J, Kim H. Digital Health Interventions by Clinical Pharmacists: A Systematic Review. Int J Environ Res Public Health. 2022;19(1):532. Published 2022 Jan 4. doi:10.3390/ijerph19010532

Wechkunanukul K, Parajuli DR, Hamiduzzaman M. Utilising digital health to improve medication-related quality of care for hypertensive patients: An integrative literature review. World J Clin Cases. 2020;8(11):2266- 2279. doi:10.12998/wjcc.v8.i11.2266

Dunn SP, Birtcher KK, Beavers CJ, et al. The role of the clinical pharmacist in the care of patients with cardiovascular disease. J Am Coll Cardiol. 2015;66(19):2129-2139. doi:10.1016/j.jacc.2015.09.025

Akbar S, Coiera E, Magrabi F. Safety concerns with consumer-facing mobile health applications and their consequences: a scoping review. J Am Med Inform Assoc. 2020;27(2):330-340. doi:10.1093/jamia/ocz175

Adu-Brimpong J, Pugh J, Darko DA, Shieh L. Examining Diversity in Digital Therapeutics Clinical Trials: Descriptive Analysis. J Med Internet Res. 2023;25:e37447. Published 2023 Aug 2. doi:10.2196/37447

Vokinger KN, Feuerriegel S, Kesselheim AS. Continual learning in medical devices: FDA's action plan and beyond. Lancet Digit Health. 2021;3(6):e337-e338. doi:10.1016/S2589-7500(21)00076-5

Bollmeier SG, Stevenson E, Finnegan P, Griggs SK. Direct to Consumer Telemedicine: Is Healthcare From Home Best?. Mo Med. 2020;117(4):303-309.

DISCLAIMER

The information provided in this course is general in nature, and it is solely designed to provide participants with continuing education credit(s). This course and materials are not meant to substitute for the independent, professional judgment of any participant regarding that participant’s professional practice, including but not limited to patient assessment, diagnosis, treatment, and/or health management. Medical and pharmacy practices, rules, and laws vary from state to state, and this course does not cover the laws of each state; therefore, participants must consult the laws of their state as they relate to their professional practice.

Healthcare professionals, including pharmacists and pharmacy technicians, must consult with their employer, healthcare facility, hospital, or other organization, for guidelines, protocols, and procedures they are to follow. The information provided in this course does not replace those guidelines, protocols, and procedures but is for academic purposes only, and this course’s limited purpose is for the completion of continuing education credits.

Participants are advised and acknowledge that information related to medications, their administration, dosing, contraindications, adverse reactions, interactions, warnings, precautions, or accepted uses are constantly changing, and any person taking this course understands that such person must make an independent review of medication information prior to any patient assessment, diagnosis, treatment and/or health management. Any discussion of off-label use of any medication, device, or procedure is informational only, and such uses are not endorsed hereby.

Nothing contained in this course represents the opinions, views, judgments, or conclusions of RxCe.com LLC. RxCe.com LLC is not liable or responsible to any person for any inaccuracy, error, or omission with respect to this course, or course material.

© RxCe.com LLC 2024: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.