Identifying medical wearables and sensor technologies that deliver data on clinical endpoints

During Phase I and Phase II clinical trials, we often try to remove any variability that might influence or alter the properties of a drug being tested – e.g. smoking or the ingestion of grapefruit or alcohol. We put so much effort into creating a perfect testing environment that we may forget that a clinical research unit does not resemble the natural environment for our subjects. In addition to learning whether the drug has been able to decrease symptoms, we want to know if it is able to make the patient's life more ‘liveable’. For example, in a patient with Huntington's disease, the state of disease may be measured using a 10‐m walking test in the clinic 1. However, the real measure that physicians want to know is, can the patient do this at home and are they able to do it multiple times a day, so that they can, for example, go to the bathroom whenever needed. Another issue that needs to be taken into account during clinical trials is the Hawthorne effect 2: the patient might try harder, just because they are being closely monitored by a doctor. One way to address these limitations is the use of medical wearables and sensor technologies, advances in which have opened up new opportunities in the healthcare industry in recent years, especially in the field of clinical trials.

Technological advancements

There are a number of ways that one can imagine how wearable electronics could improve clinical trials, given that the medical biosensors of today are a far cry from previous remote patient monitoring (RPM) systems, such as Holter monitors. They include everything from consumer‐driven devices, such as Fitbit wristbands (https://www.fitbit.com/flex) and the Apple Watch (http://www.apple.com/watch), to those developed specifically for clinicians, such as the wrist‐worn sensor from Empatica (https://www.empatica.com), designed to measure the onset of seizures accurately, or Preventice’s (http://www.preventicesolutions.com), a wearable that monitors arrhythmias outside of the hospital. Even Google has jumped into the wearables market, with their announcement, in June 2015, that it is developing a wrist‐worn sensor that measures pulse, activity level and skin temperature continuously for clinical research 3. It will also be able to take an electrocardiogram (ECG) and record environmental information, such as light and noise levels. In addition to wearable electronics, there are additional emerging biosensors that are likely to prove useful in clinical studies, such as hand‐held electrocardiograph monitors; Proteus (http://www.proteus.com), a Food and Drug Administration (FDA)‐approved ingestible biosensor to monitor drug compliance; body patches that capture physiological responses; and smart inhalers with Bluetooth capabilities. These technologies provide investigators with measurements that used to be confined to short‐term sampling in a clinical laboratory or medical facility.

Thus far, there are only a limited number of clinical trials using wearables and biosensors but this is expected to increase rapidly in the future. One of these trials involves GlaxoSmithKline, working with McLaren Applied Technologies to follow the movements of patients with amyotrophic lateral sclerosis (https://clinicaltrials.gov/ct2/show/NCT02447952). The biometric data are stored in the device, made by Finnish medical technology company Mega Electronics. The data are downloaded automatically via a Bluetooth connection when a patient gets near their wireless router, and are then sent over the internet to a secure server at Glaxo. Currently, the data collected are mostly related to activity, sleep and heart rate. Another clinical trial employed the Equivital LifeMonitor, a soft sensor belt worn across the body, and a mobile app or docking station to which vital data (ECG, respiratory rate, heart rate, temperature, activity, body position, calorific expenditure, oxygen consumption, sleep data) can be transmitted and collected 4. Another wireless health sensor, Scanadu Scout, measures heart rate, blood pressure, blood oxygen level and temperature when placed on the temple. It is currently undergoing its first clinical trial, and is being tested on people selected from among those who invested in a crowdfunding campaign (https://clinicaltrials.gov/ct2/show/NCT02134145).

In 2014, UK‐based CamNtech received FDA approval for two of its devices – MotionWatch and PRO‐Diary. Both are wrist‐worn devices that contain tri‐axis accelerometer sensors to measure the wearer's level of physical activity. PRO‐Diary also has electronic patient reported outcomes (ePRO) capabilities. Other companies working to bring biosensor devices to market include MC10, which markets Biostamp, a sensor that can monitor temperature, movement and heart rate. Because Biostamp is affixed to the skin, wearing it for too long can cause contact dermatitis. So, despite being waterproof and having a long battery life, patients must remember to remove and replace the device once a week. HQ, Inc. offers CorTemp, an ingestible core body temperature sensor that wirelessly transmits core body temperature as it travels through the digestive tract. The National Football League uses the CorTemp to help prevent heat exhaustion among its players (https://spinoff.nasa.gov/Spinoff2006/hm_1.html). Microchips Biotech sponsored the first clinical trial of an implantable microchip‐based drug delivery device capable of storing and releasing precise doses of a drug on demand or at scheduled intervals for up to 16 years (http://microchipsbiotech.com/news‐pr‐item.php?news=6).

As part of the Apple Watch launch, the Research Kit technology was introduced (http://researchkit.org). With the Research Kit, iPhone and Apple Watch consumers can download clinical apps for diabetes, asthma or Parkinson's disease, and allow their data to be collected and anonymized. The Apple Watch biosensors can measure heart rate, balance, sleep pattern, gait, activity level, speech impairment and hearing. In conjunction with the iPhone, additional data can be collected, such as inhaler usage and peak flow values. Research Kit has also helped with patient recruiting efforts. For example, it has been reported that, with Research Kit, Stanford University enrolled 11 000 applicants for a cardiovascular study in just 24 hours 5. Although digital informed consent is not a common practice yet, Research Kit allows for this approach, better enabling clinical studies to be performed in patients' homes rather than at a clinical research unit.

Challenges

Wearable technologies offer companies the potential for a deep well of data during clinical trials. In addition, the use of electronics may reduce or eliminate the Hawthorne effect. With wearable devices and biosensors, new standards to measure disease severity and progression may emerge, and subjective questionnaires can be complemented with tools that measure how well the patient really is. For example, with current technological equipment, one can track specific behavioural characteristics that are important to psychiatric conditions, such as sleep patterns and how often the patient leaves the house. However, more data do not necessarily translate into beneficial data. One of the biggest challenges in sensor data analysis is displaying large amounts of data in a meaningful way. Without an appropriate analytical platform, the data value from wearable sensors may be unrealized.

Typical wearable systems involve one or more sensors which produce analogue or digital data, a data acquisition unit which may collect and convert sensor data, a processing unit which may receive the raw data from a transceiver on the sensor (such as Bluetooth) and may retransmit processed data through a transceiver (such as a wireless connection to an internet router), and analytical software to process and display the data for evaluation 6. The packaging of these components may vary and their data‐processing location may also vary. Some components may be worn, while others are packaged with a communication device such as a Bluetooth or internet router, and analytical software may be located on a remote server (‘in the cloud’). With ingestible biosensors for success, each component (ingestible biosensor, radiofrequency identification relay and patient/clinician interface) must be accepted and used effectively. Ingestible biosensors must also meet stringent security requirements for protecting patient information. Data transmitted and stored on remote servers allow wearable sensors to be upgraded without the need for user installation of software in their monitoring devices. Other technologies involve using cellular communications such as smart phones to both process and transmit data to a server for analysis. Data may be collected in real time or at scheduled intervals, or be proximity based. Multiple sensors may be deployed in a Wireless Body Area Network (WBAN) or Wireless Body Sensor Network (WBSN).

Limitations

One issue that arises with wearable biosensors is that wireless transmissions from the sensor and/or other components pose a security risk for interception and insertion of rogue data if not protected by encryption and other security methods. In 2007, Former US Vice President Dick Cheney's embedded heart defibrillator's wireless feature was turned off, for fear of an assassination attempt by terrorists hacking into the defibrillator and sending a shock signal. More mundane, but also important, is the worry about loss of consumer privacy through interception of health and personal data.

Despite rapid developments in sensor and battery technology, missed communications, battery life, normal wear and tear, and comfort issues remain. Some sensor technologies are deployed with redundant sensors to prevent a single sensor failure. That does not necessarily solve the problem as some missed communications are due to a network being congested or not available (sensors or control units are out of range of a router). Advancements in reduced sensor size and power consumption, along with better algorithms for data collection, have eased battery limitations but more improvements are needed. In normal wear and tear, factors such as drops, water, sweat, bending, excessive heat and vibrations can damage or destroy sensors and components. Even something as simple as exposure to sunscreen or body lotion can destroy electronic components. Ultraviolet light exposure from sunlight can cause splitting of chemical bonds in polymers used in sensors. Some of these issues may be resolved with the use of more flexible components (e.g. batteries) and better waterproofing.

Comfort and cultural acceptance for the wearer also cause some limitations. Armband sensors which fit under clothes may be preferred over waistbands or wristbands. Cameras or audio‐recorders that may be part of the wearable devices may not be acceptable in some public places. Another limitation is that devices may require routine charging or periodic calibration, and technical installation on even the simplest devices can be difficult for some patient populations. Certain patients suffering from cognitive impairment and/or memory problems (e.g. those with Alzheimer's disease) may not use the sensor properly, or may remove/damage the sensor because they cannot recall the purpose of the 'foreign object' that is fitted to them (even though they originally agreed to wear it).

Summary

The advances in sensor technology and microelectronics have opened new opportunities in the healthcare industry, especially in the field of clinical trials. For example, while a patient's general practitioner may not need to know the daily heart rate and caloric output, these data would be helpful for investigators of a new drug targeting obesity. While, in the past, more measurements would have directly increased the burden for the test subject, the use of wearable medical devices which can be worn for a prolonged period offers the data without the need for the subject to be bothered over and over again. They also make it possible to have uniform measurement equipment among subjects, without much effort. Thus, although there are some limitations, it seems clear that as the potential for wearable electronics in clinical trial data capture is realized, their use will be expanded and integrated into normal practice.

Competing Interest

There are no competing interests to declare.

Mombers, C. , Legako, K. , and Gilchrist, A. (2016) Identifying medical wearables and sensor technologies that deliver data on clinical endpoints. Br J Clin Pharmacol, 81: 196–198. doi: 10.1111/bcp.12818.