Points of View The use of wearable devices in drug development

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Yasuhiko Nakatsuka, Senior Researcher, National Institute of Biomedical Innovation Policy

1. Introduction

With the rapid spread of mobile technologies such as smartphones, various devices and applications are being developed and utilized in the medical and healthcare fields. The "Strategy for Health and Medical ^Care1)" approved by the Cabinet on March 27, 2020 plans to enhance and strengthen health and medical services utilizing the Internet of Things (IoT), in which sensors and other devices embedded in various objects around us are connected to the Internet and can communicate with each other, as a specific measure. The plan is to enhance health and medical services using the Internet of Things (IoT). Wearable sensors and home-installed IoT devices are expected to provide a means of understanding the status of individuals in their daily lives in more real-time, and to provide personalized health and medical services. In addition, the "Basic Policies for Economic and Fiscal Management and Reform 2020: Overcoming the Crisis and Moving Toward a New ^Future2) " approved by the Cabinet on July 17, 2020, calls for accelerating the use of data in the medical and long-term care fields and the shift to online services in order to ensure a full response to infectious diseases, disasters, emergency situations, and other contingencies. The policy also includes the promotion of data health reform, including the expansion of PHRs. It is assumed that data acquired by IoT devices will be used as part of PHRs in the future, and this is likely to become increasingly important.

Therefore, this paper investigates the use of wearable devices that can acquire healthcare data such as vital signs and step counts in IoT devices in clinical trials of pharmaceuticals. In anticipation of future expansion of the scope of use, we would like to introduce some examples of what kinds of items can be measured.

What are wearable devices?

Wearable devices are computer terminals that can be worn on the arms, legs, head, or other parts of the body while walking around. In other words, unlike PCs and smartphones, wearable devices can be used without the wearer's awareness. There are various types of wearable devices, from the most standard wristwatch type such as the Apple watch ^Ⓡ to eyeglasses, caps, rings, headphones, pendants, and so on. These wearable devices are often used to record users' activities and manage their health, as they can acquire information such as body movements and heart rate through sensors.

For example, Apple ^WatchⓇ, which has the No. ¹³ market share in Japan for wristwatch and wristband types, can currently measure a variety of biometric data, including activity level, number of steps, sleep, heart rate, blood oxygen saturation, maximum oxygen uptake, and electrocardiogram. In particular, the electrocardiogram received approval from the Pharmaceuticals and Medical Devices Agency (PMDA) on September 4, 2020 for manufacturing and marketing of medical devices as the "Home Electrocardiograph Program" and the "Home Heart Rate Monitor Program," and is now available in ^Japan4). Quantitative measurement is becoming possible for a variety of items that were previously difficult to quantify or measure, such as activity level, sleep, subjective symptoms like pain and itchiness, and mental status. There have been an increasing number of reports of research findings and clinical trials using data acquired by wearable devices, mainly from overseas.

3) Status of Wearable Devices in Clinical Trials

We conducted a survey using ClinicalTrials.gov to determine the extent to which wearable devices are being used in clinical trials of pharmaceuticals.

The following conditions were selected for this survey.

The above conditions were used to identify trials that utilize data obtained from wearable devices when developing drugs.

3-1 Survey result: "Number of trials conducted per year

Figure 1 shows the number of trials using wearable devices in clinical trials of pharmaceuticals on an annual basis.

One trial was initiated in 2016 and remained flat in 2017 and 2018, but increased significantly in 2019 and in 2021, with 14 trials conducted as of May 31, 2021, exceeding the number of trials conducted the previous year. It can also be seen that the number of trials using wearable device data as an Outcome measure for clinical trials is also increasing each year, albeit slightly.

3-2 Results "Phase of Implementation

Figure 2 shows in which phases wearable devices are used in clinical trials of pharmaceuticals.

The most common use of wearable devices was in Phase 4, but it can also be seen that many wearable devices are used in Phases 2 and 3, which are required for drug application.

3-3 Survey Result "Implementing Entity

Figure 3 shows the number of clinical trials conducted by entity. The largest number of cases was 20 in Other, followed by Industry and Other/Industry. The main use of wearable devices in the industry was in Phase 2 and 3, which are the later stages of drug development, and the Outcome Indicators also included physical activity tracking, Many of the outcome measures also included physical activity tracking. In some cases, wearable devices were used to detect symptoms in trials for Parkinson's disease patients.

3-4 Study Results "Country of Conduct

Figure 4 shows the number of clinical trials conducted by country. The U.S. had an outstandingly large number of trials (31), while the other countries had one or two trials each. In Japan, there was one trial, a Kyoto University-led study of Alzheimer's disease. The trial measured physical activity parameters with a wearable device as an exploratory outcome measure.

In the U.S., it is mandatory to pre-register a clinical trial on ClinicalTrials.gov in order to file a drug application with the FDA. This may be the reason why the number of registrations is higher in the U.S. than in other countries. Another factor may be the state of national guidance and systems. Since around 2015, the U.S. FDA has successively issued the following guidance as new findings related to drug development using the IoT.

In addition, the DRAFT GUIDANCE on "Use of Electronic Records and ElectronicSignatures in Clinical Investigations Under 21CFR Part 11 -Questions and Answers" was ⁸⁾ was published in ^June8), which presented the regulator's approach to the use of mobile technologies, such as wearable sensors, in clinical trials.

In Japan, the Ministry of Health, Labour and Welfare (MHLW) published the "Guidelines for the Safety Management of Medical Information Systems, Fifth Edition" in May ²⁰¹⁷⁹⁾, but it does not specifically address the handling in clinical trials, so the issuance of guidance such as the one mentioned above will encourage more active use of wearable sensors and other mobile technologies in clinical trials. Therefore, it is anticipated that the issuance of the above-mentioned guidance will further stimulate the use of wearable sensors, etc. in clinical trials.

3-5 Findings "Target Diseases

The diseases covered in the clinical trials conducted with the wearable devices are listed in Table 1. Parkinson's disease and heart failure were the most common diseases tested in 5 trials each; type 2 diabetes, orthostatic hypotension, angina pectoris, cognitive impairment, and Alzheimer's disease were tested in 2 trials each. Wearable devices were also utilized in trials of rare diseases such as Angelman syndrome, Rett syndrome, and muscular dystrophy, although in smaller numbers. Angelman syndrome and Rett syndrome are rare diseases of the nervous system, and developmental disorders are recognized as symptoms. In addition, symptoms such as hand movements are also observed, and it is assumed that wearable devices are being used to quantify these symptoms. It is expected to be used as a biomarker to detect such symptoms in the future. It was also observed that the devices are being actively utilized in cognitive disorders, Alzheimer's disease, bipolar disorder, and other psychiatric disorders, including Parkinson's disease, which is the most common.

3-6 Survey result "Application of wearable devices

The most common applications of wearable devices were physical activity (number of steps, activity intensity) and sleep duration data. In particular, physical activity data was utilized mainly in cardiovascular studies such as heart failure, orthostatic hypotension, and angina pectoris.

A device called ^BioStamp10) was used in a study of mild cognitive impairment, and it is expected to be used as a tool for generating new research findings from heart rate, myoelectric activity, activity level, etc. Vital data during exercise, which is acquired by a close-fitting flexible sensor, can be collected from the subject's daily life. The device is expected to be utilized as a tool for generating new research findings based on heart rate, myoelectric activity, activity volume, and other data. At the time of writing (June 2, 2021), this device has not been certified as a medical device. In addition, the Personal KinetiGraph ( ^PKG® ) exercise recording system has been used in some trials for Parkinson's disease ^patients11). This device was developed by Global Kinetics, a US company, and will be a device that can measure objective data to distinguish motor patterns consistent with tremor, motor sluggishness, dyskinesia, and immobility.

Clinical trials using wearable devices are often intended to measure routine data that cannot be obtained in hospitals, and such applications are not expected to lead to a reduction in the frequency of testing in regular clinical trials. In the future, when the accuracy of measurement devices improves to the point where they can replace current tests, there will be an advantage in reducing the frequency of visits to hospitals.

4. expansion of measurement range and improvement of measurement accuracy

The main applications of wearable devices in clinical trials were to measure activity (e.g., number of steps taken) and sleep duration. Various companies are developing wearable devices, and progress is remarkable in expanding the range of measurement and improving the accuracy of acquired data. The following are examples currently in the development stage.

Wristwatch type

Movano, Inc. of the United States is developing a new wristwatch-type device that enables noninvasive and continuous monitoring of blood glucose ^levels12). This device is reported to be capable of measuring blood glucose levels by irradiating millimeter waves to the skin and receiving and analyzing the reflected waves with an antenna.

Similarly, as a non-invasive blood glucose measurement device, Quantum Operation Inc. of Japan has also developed a smartwatch that measures blood glucose levels without the use of ^needles13). The company is also developing other wristwatch-type SpO2 sensors/heartbeat, respiration, and body movement sensors. By using IoT sensors to detect vitals related to respiratory diseases, this device is expected to be used for screening of people with apnea syndrome, prevention of interstitial pneumonia caused by side effects of anticancer drugs, and prevention of the spread and severity of COVID-19 infection. The device is also in preparation for a medical device application in Japan.

Patch type

Recon Health, a joint venture established by XCO Tech of Canada and Atlazo of the U.S., has announced a new patch device that enables remote monitoring of vital ^signs14). The patch incorporates a clinical-grade, all-in-one multi-sensor that measures respiratory rate, heart rate, heart rate variability, body temperature, and activity level, in addition to blood oxygen saturation. In the future, additional features will include blood pressure, ECG (electrocardiogram), heart rate analysis, and cognitive analysis via cough and voice. Doctors and nurses can use objective patient data for telemedicine appointments and digital medical services. It is envisioned that medical data on cardiovascular, respiratory, and neurodegenerative diseases of patients at home can be reviewed and analyzed to help in the clinical diagnosis and treatment of chronic health conditions.

In addition to the wristwatch and patch type, the following other forms have also been developed.

EEG type

Korean company iMediSync is developing an EEG (electroencephalogram) brain mapping device, ^iSync-WaveTM. ^{15)iSyncWaveTM} is a portable, gel-free EEG brain mapping device that can be used both in the clinic and at home. It is expected to lead to early detection of neuropsychiatric disorders such as dementia, Parkinson's disease, traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), attention deficit/hyperactivity disorder (ADHD), and depression.

Acoustic

An Australian company, Noisy Guts, is developing an acoustic belt for noninvasive diagnosis of the ^bowel16). Early diagnosis and intervention of irritable bowel syndrome is important to prevent complications such as the development of bowel cancer. Current diagnostic methods for irritable bowel syndrome require invasive tests such as colonoscopy. The use of this acoustic belt will provide a new, accurate, non-invasive approach for the diagnosis of irritable bowel syndrome and screening for inflammatory bowel disease by recording bowel noise over time and combining it with other data such as heart rate, skin temperature, and skin electrical response (sweating).

In terms of data reliability, a study has been ^reported17) that showed a correlation between data acquired by wearable devices and results of clinical laboratory tests in hospitals. In this study, subjects wearing a smartwatch that monitored heart rate, step count, and skin electrical activity underwent concurrent hospital blood tests (red blood cell count, white blood cell count, blood oxygen level, blood glucose level, etc.) and heart rate tests. As a result, the researchers reported that the vital sign data collected from the smartwatch showed a more stable and accurate heart rate than the hospital readings. They also reported that vital sign data collected from the smartwatch was able to predict some laboratory values with less error than was done using vital sign data obtained in the hospital.

5. challenges in using wearable devices in clinical trials

The use of wearable devices allows for the collection of more objective data that is independent of the subject's or patient's interpretation, memory, and judgment (without bias), and allows for the continuous and timely collection of data related to biological responses in daily life (exercise, sleep, seizures, etc.), which have been difficult to collect during medical examinations and tests, The data can be collected and visualized in a continuous and timely manner. Furthermore, real-time support for subjects and patients can be provided through mutual communication between wearable devices and medical institutions that can check seizure and medication status, etc. However, there are some challenges in utilizing such a wide variety of data in drug development.

The most important issue is how to develop and establish evaluation indices using wearable devices, etc., and how to proceed with the validation of these devices. When using wearable devices as indices for clinical trials, it is important to guarantee measurement accuracy in accordance with the purpose of their use. If a device has been approved as a medical device, it is assumed that its measurement accuracy is known in many cases, making it easier to use in clinical trials. In recent years, the number of wearable devices that have obtained approval has been increasing. However, the accuracy of each device, or even the same device, differs depending on the data item, so sufficient verification according to the purpose of use is necessary when utilizing these devices.

6. summary

The government is promoting reform of the healthcare system to reduce healthcare costs while ensuring the quality of care. Already in Europe and the U.S., a new concept called "health tech" has emerged to solve various issues in the medical field by utilizing AI and IoT. One element of health tech is wearable devices, and in the U.S., research and development of wearable devices by companies involved in health tech is progressing. In the future, the Corona Disaster is likely to trigger an increasing interest in health management and disease prevention through wearable devices such as the Apple ^WatchⓇ.

In addition to being able to record daily physical condition for use in health management by medical professionals, including not only the patient but also caregivers, wearable devices are also expected to be used as an auxiliary tool for physicians to grasp the health condition of patients and make decisions on lifestyle guidance and therapeutic intervention. In addition, even in situations where hospital visits are restricted and prescription management is difficult due to disasters or infectious disease pandemics, the use of wearable devices to monitor health status will enable efforts to prevent chronic diseases and mental illnesses from becoming more severe.

In order to develop new indicators for clinical development in the future, the performance of the device itself is naturally important, but it will also be important to develop ideas on what items can be measured with what sensors and the algorithms to achieve this. In developing and establishing such new evaluation indices and promoting device validation, it will be important to establish common evaluation indices in cooperation with academic societies and regulatory authorities, etc., so that evaluation indices will not be created in a chaotic manner. This joint effort will not only lead to increased efficiency for individual pharmaceutical companies, but also to greater convenience for the healthcare professionals and patients who will ultimately use the devices, as they will be able to use a common set of indicators.

Although there are various issues involved in the use of wearable devices, there are various possibilities for the creation of new value through the use of this technology, and some cases have already been introduced into the clinical development of pharmaceutical products. The environment surrounding wearable devices is evolving on a daily basis, and the ability to quickly catch up with the latest technology and information and quickly incorporate it will make the difference in competitiveness within the pharmaceutical industry.

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