The Pharmacovigilance of Digital Therapeutics (DTX): Developing A New Safety Framework

Abstract

Digital therapeutics (DTx) are one of the novel and outstanding advancements in the health care, changed the way we treat and manage health conditions by using software as a form of medicine. From managing chronic diseases to supporting mental health, these tools offer new possibilities for personalized and accessible care. But just like traditional medicines, digital therapeutics must be safe, effective, and reliable. That’s where pharmacovigilance comes in the process of monitoring and managing potential risks or adverse effects. However, tracking the safety of digital tools is different from monitoring drugs. It involves keeping an eye on software errors, data privacy concerns, unexpected user experiences, and clinical outcomes that may not be immediately obvious. As DTx continue to evolve, so must the systems that ensure their safety. In this review article we have discussed how pharmacovigilance is adapting to the digital age, highlighting the need for smarter monitoring, updated regulations, and stronger collaboration between developers, clinicians, and regulators to protect patients and build trust in this growing field.

Keywords

Introduction

A new class of treatment known as digital therapeutics (DTx) has emerged because of the rapid advancement of drug technology in the digital age^[1]. It is an evidence based remedial intervention supported by high-quality software programs to help, manage, or treat a medical disease or disorders^[2]. DTx utilizes technology like Artificial Intelligence (AI) and behavioural science to promote patient engagement, improve adherence to treatments, and provide real-time data for more accurate and personalized treatments^[3]. DTx does not require preclinical testing, which is necessary for pharmaceuticals, because it is software^[4].  Clinical evidence supports the development of the DTx operations to target particular medical conditions, especially significant habitual conditions^[5]. Many available DTx was primarily developed for neuropsychiatric conditions which can be treated through behavioural change^[5]. Due to the need for remote case operation during the COVID-19 lockdowns, home blood pressure (BP) monitoring and related digital results have recently become very popular^[6]. Type 2 diabetes, hypertension, asthma, coronary obstructive pulmonary disease (COPD), anxiety, and depression can all be treated with digital therapeutics (DTx). Most individuals with type 2 diabetes reside in emerging countries such as China and India. Therefore, the healthcare system's decision to abandon digital technologies may be a catalyst for improving public health in general. They make it possible for patients to stay in regular communication with health care providers (HCPs), which keeps them inspired and assists them in taking certain actions when necessary^[7].

Since last two decades, digital revolution has been drastically transforming many sectors of society specially the healthcare sector, due to the escalating amount of patient’s health data generated and difficulty data archiving and analysis.

History of DTx

In 1995, Dr. Joseph Kvedar from Boston, USA, introduced the "one to many models of care," a concept that uses digital technology to deliver care outside of traditional hospital or doctor's office settings. Dr. Tom Ferguson in 1999 give the term “E?patient”⁸. As early as 2000, there was evidence in the literature that the usage of digital technology improved health outcomes^[8].

Application of DTx

The main indications for which DTx was created were neuropsychiatric and chronic conditions that can be managed by behavioral modification. DTx is designed to be used in therapeutic situations outside of research and development^[5]. The application of DTx for treating chronic diseases such as diabetes, hypertension, asthma has been executed through web platforms^[9], mobile applications^[10], AI^[11], and even automated phone calls for patient convenience^[12]. Especially effective for psychosis^[13] or similarly related mental illnesses^[1]. The finest results from DTx are usually obtained when combined with another form of traditional therapy^[14]. Additionally, when DTx is contrasted with traditional drug-based therapy, the dangers may be fewer^[15]. Products from DTx are marketed as state-of-the-art software intended to manage, treat, or prevent medical conditions^[16,17]. The software has been divided into further subtypes like mobile applications^[18], web applications^[19,20], virtual reality (VR)^[21], AI^[22,23], video games^[24] and approved devices, among others. Numerous illness categories, including psychiatric^[25,26], cardiovascular^[27], metabolic^[28], gastrointestinal^[29], neurodevelopmental^[30], neurological^[31,32], and others, can benefit from DTx. The results could be impacted by DTx, and self-measure metrics could lead to inconsistent reporting.

Digital Therapeutics for Various Diseases

Irritable Bowel Syndrome (IBS)

The extensive condition known as Irritable Bowel Syndrome (IBS) is typified by abnormal bowel patterns and abdominal pain^[33]. According to current estimates, 4.1% of people globally suffer from IBS, with the biggest prevalences occurring in the US, UK, and Canada, where rates range from 4.4% to 4.8% of the population. Psychological factors include anxiety, hypervigilance, catastrophizing, and symptom-specific safety behaviours in addition to gastrointestinal (GI) symptoms.

Pathophysiology of IBS

The best way to understand IBS is from a biopsychosocial standpoint. The biopsychosocial approach recognizes that complex interactions between a person's environment, neurophysiology, and psychological characteristics result in IBS symptoms. a two-way dialogue that connects the brain's emotional and cognitive regions to digestive processes. The enteric and the central nervous system exchange information. The gut microbes interact with this network through immunological, endocrine, and neurological signalling pathways, according to mounting evidence. Immune function, intestinal permeability, microbial diversity, and gut motility are all impacted by modifications in gut–brain connections.

Brain–Gut Behavioural Therapy (BGBT) in IBS

The use of brain-gut behaviour therapy as a global treatment paradigm for IBS is being supported by increasing clinical data. Cognitive behavioural therapy (CBT), gut-directed hypnotherapy (GDH), self-management programs, mindfulness-based therapies, and psychodynamic interpersonal therapy are the five evidence-based categories into which BGBTs are separated.

Digital Therapeutics in Irritable Bowel Syndrome

The availability of digital therapies via smartphone apps and the internet is growing. For instance, Mindset Health in Cremorne, Australia, developed the evidence-based smartphone app Nerva, which offers three months of self-directed hypnosis for the treatment of IBS symptoms. Improvements in IBS symptoms that were statistically and clinically significant were found through a retrospective study of the app. Diaphragmatic breathing exercises, daily 15-minute sessions, and instruction on the gut-brain axis are all part of the strategy. Digital Therapeutics for IBS 229, a trial that randomized patients to either waitlist control (n = 59) or prompt therapy with Zemedy (n = 62), evaluated the app in February 2024. (n = 59)^[33].

Diabetes

One of the biggest public health issues is diabetes mellitus (DM), which affects 476 million people worldwide and has increased by 129.7% in the past 20 years ^[34]. By 2025, the World Health Organization's (WHO) Global Action Plan for the Prevention and Control of Noncommunicable Diseases is expected to have cost the world economy $2.1 trillion. The worldwide economic burden of diabetes mellitus is expected to reach $2.5 trillion by 2030 due to the rise in the prevalence of the disease rather than the rise in healthcare costs per person.

Digital therapeutics in diabetes      

By addressing the undermanaged areas of diabetes, such as self-care, medication adherence, and routine clinical monitoring of glycaemic control, DTx models for the treatment of prediabetes, type I DM (T1DM), and type 2DM offer efficient disease management. All people under 45 should have regular monitoring, according to the American Diabetes Association, and those with risk factors for prediabetes and type 2 diabetes (T2DM) should be screened. In this regard, it is advised to use technology-assisted therapies to avoid type 2 diabetes. Mobile applications for insulin titration and dose optimization form the basis of the majority of DTx products. In order to enable efficient, individualized diabetes management, these applications assist patients and healthcare providers in reviewing, analyzing, and evaluating patient data^[35]. Additionally, certain apps (like BlueStar® Rx) offer customized digital coaching and insights to maximize treatment regimens ^[36]. In contrast to Go Dose, which is exclusively suitable for the rapid-acting insulin Humalog, Insulia® works with any brand of basal insulin, including Basaglar, Toujeo, Levemir, Tresiba, and Lantus.

Non-alcoholic Fatty Liver Disease (NAFLD)

Since there is currently no approved treatment for non-alcoholic fatty liver disease (NAFLD), the illness's rising incidence globally is especially concerning. The buildup of fat in more than 5% of hepatocytes is a metabolic disorder called non-alcoholic fatty liver disease (NAFLD)^[37]. Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular risk, renal involvement, a high tumor incidence, and a high mortality rate^[38]. Although it has been demonstrated that lifestyle interventions benefit patients with non-alcoholic fatty liver disease (NAFLD), concerns regarding the therapies' success rate and the patients' capacity to maintain a healthy lifestyle must be addressed ^[39].

Digital Therapeutics For NAFLD

The use of DTx to treat NAFLD is currently in its early stages of investigation. As a first practical investigation of DTx for patients with NAFLD, some have carried out web-based remote lifestyle treatments, such as nutrition, exercise, and health education. Online exercise management's impact on NAFLD patients was demonstrated by prospective exercise intervention research conducted in Germany. After completing an 8-week online course, each participant finished a 12-week follow-up survey ^[40].

The team also developed a communication module. The module offered chat rooms for patients to interact with one another and have more access to equal support, while also facilitating communication with doctors so that patients could receive professional advice. The results showed that peak oxygen demand increased by 2.4 mL/kg/min while body weight decreased by 1.0 kg. Patients with non-alcoholic fatty liver disease (NAFLD) participated in a 6-month structured mobile technology intervention trial that focused on nutrition and exercise ^[41]. Based on the concepts of carbohydrate diet control or the Mediterranean diet, the researchers created a weekly meal plan for the patients.

Digital Therapeutics for Allergic Diseases

By offering a more thorough understanding of allergic disorders and their triggers, high-quality eHealth technologies can help improve disease control in the field of allergic illnesses ^[42].  A considerable percentage of people worldwide suffer from pollen allergies, which are predicted to become more common ^[43,44]. For people with pollen allergies, pollen forecasts can be quite helpful in avoiding allergens ^[45]. According on user input, using traditional aerobiology methods to offer correct information presents issues ^[42]. It is mostly caused by variables that might change from year to year and from person to person, such as regional differences in allergen content, pollen loads, and pollen allergy symptoms.^[46].

Advanced forecasting models have been incorporated into mobile applications like "Pollen" and "Pollen-News," which provide a variety of pollen-related information, such as flowering start dates, season countdowns, forecast maps, botanical details, pollen dispersal models, and push notification services for patients.^[42]. The healthcare system seamlessly incorporates TM and emerging technologies, providing a wide range of services with cutting-edge characteristics. According to a position paper published by the American College of Allergy, Asthma and Immunology (ACAAI), TM significantly improved the health of individuals who lived in isolated or rural locations⁴⁷. Furthermore, the EAACI Task Force published a position paper detailing over 130 mobile applications for allergies ^[48]. Authorized healthcare practitioners can access eHealth records, which are digital archives of patients' test results, diagnoses, treatments, and medical histories. The Allergy Monitor platform made it easier and more uniform to assess the severity of the condition ^[49].

Hypertension

Globally, hypertension is prevalent and the primary avoidable risk factor for cardiovascular disease ^[50,51]. Despite the availability of several pharmaceutical treatment options, blood pressure regulation is frequently not at its best ^[51]. Apps that are widely available and promise to help with medication adherence or hypertension control ^[52]. Data about the use of digital therapies in the treatment of hypertension is somewhat scarce ^[6]. Information and communications technology (ICT), or digital technologies, are used to help health and health-related sectors. This is known as digital technologies for health ^[53]. Digital therapeutics employs ICT to save, retrieve, share, and exchange health-related data to aid in the prevention, diagnosis, treatment, and monitoring of hypertension ^[54]. The broad availability of smartphones and tablets makes this possible.

The patient, medical personnel providing treatment, and gadgets that gather medical data (such as a smartphone, tablet, or connected blood pressure monitor) and possibly additional environmental data (such as temperature, humidity, and air pollution) are all included on the Internet of Medical Things. Stakeholders involved in patient care, such as the patient, the hospital, clinic, or healthcare provider, and pertinent medical experts (such as a doctor, nurse, or pharmacist), have access to all this information.

Certain processes to lower blood pressure are part of effective digital therapies for hypertension. The reducing effects of digital therapeutic interventions in hypertensive patients can be attributed to a variety of possible processes. These include eating a balanced diet, consuming less salt and more potassium, getting more exercise, losing weight, controlling alcohol consumption, managing stress, and maintaining proper sleep hygiene ^[55,56]. Among the lifestyle changes suggested by the guidelines, cutting back on salt consumption is crucial for lowering blood pressure, especially in Asian patients who suffer from hypertension ^[55].

A digital treatments intervention (the HERB system; CureApp, Inc.) created especially to encourage lifestyle changes ^[57]. Users of the app customized their profiles by adding information about their age, sex, lifestyle, social background, and behavioural habits. It includes reminders to check blood pressure, take medication, and exercise, as well as alerts when doctor's appointments are due, records of blood pressure, blood pressure control, and drug use, education modules, health evaluations, and the ability to interact with doctors remotely ^[58]. Systolic and diastolic blood pressure changes from baseline were the main outcome measure for the 480 individuals who were enrolled and monitored for six months. In terms of salt reduction, digital therapy approaches may work in concert with diuretics or renin-angiotensin system inhibitors.

Furthermore, to further lower risk, digital therapies modules that target other cardiometabolic risk factors—like obesity, diabetes, and hyperlipidaemia—could be combined to those that target hypertension. A tablet-based illness self-monitoring system is another strategy that has been demonstrated in a smaller trial to dramatically lower blood pressure when compared to standard therapy ^[59]. Despite the evidence's mixed quality, there is mounting proof that mHealth app treatments can effectively cure hypertension. According to a new meta-analysis, individuals with hypertension who utilized smartphone applications saw drops in blood pressure and improvements in drug adherence ^[60]. It has a thermometer, a barometer, and a high sensitivity actigraphy that can identify the wearer's subtle body motions in three different directions.^[61]. Blood pressure and intracuff pressure waveform data are recorded by the system and forwarded to a data centre for analysis. The results are communicated to the patient's doctor.

Digital Therapeutics in Urology

The area of mobile health apps is expanding and presents new opportunities for providing healthcare services ^[62]. There are over 172 applications available in the Google Play Store and Apple App Store that remind users when and how to perform Kegel exercises. An Android smartphone app was created to teach users how to track and control their own symptoms of an overactive bladder. The app featured monthly, three-day symptom logs, Kegel and bladder training exercises, and medication reminders ^[63,64]. This app featured monthly, three-day symptom logs, Kegel and bladder training exercises, and medication reminders. Most participants reported symptom relief within a week after beginning treatment, according to smartphone applications that evaluate the management and natural course of urinary tract infections (UTIs)^[65]. A wearable device called Dfree predicts when a user's bladder is full and notifies them when it's time to use the restroom. It has been demonstrated that Dfree and other urology smartphone apps are potential digital therapies that provide a practical way to treat problems with bladder control.

A smart toilet system is a technical advancement that monitors and analyses a user's urine and faeces by integrating multiple sensors and gadgets into a conventional toilet ^[66]. An Internet of Things-based smart toilet that detects and prevents urinary tract infections at home. Utilizing machine learning techniques, the gadget predicted the likelihood of a urinary tract infection and integrated many sensors to monitor significant biomarkers in urine ^[66]. Recent research indicates that smart toilet systems have the potential to completely transform the detection and treatment of a range of urological problems and provide a comfortable, non-invasive way to monitor patients with chronic urological conditions like interstitial cystitis or bladder cancer ^[67,68].

Digital Therapeutics for Anxiety and Depression

Anxiety and depression present significant obstacles for both individuals and healthcare providers worldwide. According to WHO research, 264 million people worldwide suffer from depression and anxiety disorders ^[69], and seven billion dollars are lost annually in the USA alone due to depression ^[70]. Traditional psychological therapies have been the most common interventions for treating anxiety and depression ^[71]. However, traditional psychological therapies are not easily accessible to everyone who could benefit from them ^[72].

Prior studies have demonstrated that depressive individuals favored psychological therapies over psychiatric medication, and those who did not receive their preferred therapy type had poorer functioning alliance ratings ^[73]. Digital mental health services might assist enhance access to mental health treatment ^[74]. The Unified Protocol for Transdiagnostic Treatment of Anxiety and Depressive Disorders (UP) is a well-regarded method in the field of mental health ^[75].

Multiple studies have tested digital therapeutics to remedy psychiatric symptoms and to manage anxiety or depression ^[76]. In essence, the Dario behavioural health platform is a transdiagnostic, modular tool that provides emotion-focused treatment for a variety of mental health issues ^[75]. The platform may be utilized with the help of a qualified coach or as a self-directed intervention. It was created using the UP paradigm for drug abuse, stress, anger, depression, and anxiety ^[75]. Each program's framework consists of app sessions that include breathing exercises, textual skills, conceptual films, and tools for tracking progress. This study tracks user cohorts with anxiety and depression scores based on their answers to the Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) ^[75]. Emerging technologies such as artificial intelligence, in particular machine learning, could be used to personalize anti-depressant therapies based on patient data in the future ^[77]. 

Governance And Security of Data

Data rights and cybersecurity considerations are prerequisites for the widespread use of DTx^[78]. Risks of illegal access and manipulation of these goods and underlying data might jeopardize patient care and product confidence when DTx transfers information online. In October 2018, the FDA published draft recommendations on cybersecurity in SaMD and networked medical devices ^[79]. Payment criteria for DTx are also being created currently because SaMDs are still being evaluated for therapeutic efficacy and cost-effectiveness ^[80]. Although they have not yet issued codes for the use of DTx as a stand-alone treatment, the Centres for Medicare and Medicaid Services (CMS) have also offered some limited recommendations. Additionally, SaMDs are not covered by any specific Medicare benefit group. Therefore, DTx's access to patient demographics is further limited as they are now ineligible for new Medicare Coverage of Innovative Technology policies ^[81]. The safety and effectiveness of algorithms in various patients is another technological problem, especially for DTx based on artificial intelligence (AI). For instance, social determinants of health and other biases that impact healthcare algorithms performance might not always be captured by training datasets ^[82].

CONCLUSION

The research shows that digital therapies particularly smartphone CBT works equally well as standard face-to-face treatments in beating patient’s symptoms. Both treatment methods lowered patients' symptoms, but digital therapeutics had a small advantage by letting participants join in and saw fewer symptoms. Underprivileged communities value digital treatments for treating diseases more effectively and at lower cost with services tailored to each person's needs. The study requires more research to improve patient cooperation and long-term participation while showing the importance of interactive platforms for effective digital treatment delivery. Modern digital health solutions should expand treatment based on evidence that shows they make it better and simpler to reach for everyone.

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