By Joseph Constance
Wearable devices and apps stand to significantly impact the data available from clinical trials. Wearables and apps help generate sets of longitudinal biometric data that can provide novel insights into the long-term, real-world impact of drugs.
But the devices and apps bring some challenges too — accessing the raw data from wearables, validating the data, processing and analyzing extensive amounts of wearable data, and data security issues.
“Generally speaking, there is no requirement for FDA validation or approval of devices used in research studies, including clinical trials,” Mark Pletcher, MD, MPH, a general internal medicine physician and professor of epidemiology and biostatistics at the University of California at San Francisco, said in an email.
As per standard research ethics and the “Common Rule” — the Federal Policy for the Protection of Human Subjects — research subjects may be asked to perform a wide range of tasks during the course of a research study, including using apps and devices of any sort, as long as the benefit overall outweighs the risks posed to participants, as governed by Institutional Review Boards, which provide oversight to research studies, adds Pletcher.
“However, if you’re talking about clinical trials conducted for a regulatory purpose (e.g., seeking approval from FDA for a new drug), then there may well be requirements from FDA for validation or approval of a device if the measurements from that device are going to be used for the FDA approval,” he continued.
Generally, consumer mobile health apps are not marketed as clinical support medical devices that fall under 21 U.S.C. § 321 (h). When a mobile health application counts as “software as a medical device” (SaMD under 21 U.S.C. § 321(h)), it requires an Investigational Device Exemption (IDE) under 21 C.F.R. § 812. This further requires an analysis of device in a trial for significant risk, nonsignificant risk, or exempt status.
A Fundamental Change
Wearables and apps have the potential to fundamentally improve how outcomes are measured by providing a continuous stream of objective data. This data is consistent across geographies and can be available in near real-time, allowing for compliance monitoring and management in a timely fashion.
A Growing Interest
Kaiser Associates conducted a study for Intel, which estimated that up to 70% of clinical trials would incorporate wearable sensors by 2025. Benefits for sponsors and patients are spurring the use of wearable devices. Wearables are good at collecting new and objective data while also lowering costs and improving the effectiveness of the trials. Pulling data from wearables also offers opportunities to undertake more observational studies. This can lead to new interventional studies that optimize patient care through new treatments and protocols.
Also fueling the use of wearable devices is how patients are taking a more active role in their own healthcare. As we become more proactive in our care strategies and our own treatment plans, our health outcomes stand a good chance at improving, and the costs of any treatment could decline.
Wearables also offer a better perspective of a patient’s response to treatment by providing their ongoing health status and response to the trial drug that is objective.
ClinicalTrials.gov lists 1124 studies with the word “wearable” in their descriptions, which includes wearable devices for medical use, and testing other medical devices using wearable technology. Examples include:
- Wearable Devices for Secondary Prevention of Ischemic Stroke.
- Wearable Real-Time Feedback System to Improve Gait and Posture in Parkinson’s disease.
- Atrial Fibrillation Detection Using Garmin Wearable Technology.
Litmus Health, a provider of real-world data, examined nearly 200 brands and manufacturers of wearable devices and published an extensive report analyzing remote monitoring and the use of wearable devices and sensors in clinical trials. The analysis includes transparency scores, measured in low/medium/high, to provide researchers with an overall sense of how challenging it may be to incorporate the wearable into a study. The devices reviewed include:
- ActiGraph, GT9X Link.
- ActiGraph, WGT3X-BT.
- Apple Watch Series 4 GPS.
- Atlas Shape.
- Empatica E4.
- Fitbit Ionic.
- Garmin Vivomove HR.
- Huawei Band 3 PRO.
- Polar A370.
- Samsung Gear Fit2 PRO.
- Spire Health Tag.
- Strive Apex HR.
- VitalConnect VitalPatch.
- Withings Steel HR.
Connected health, including wearable devices and mobile health technology, is an opportunity to generate patient-centric data. Drug makers, CROs, and their partners have been investing in wearable technology and analytics to give trial sponsors a continuous real-time patient view, as opposed to isolated snapshots.
The two main consumer activity trackers on the market today, the Fitbit and Apple Watch, can monitor vital signs, including heart rate, respiratory data, and movement levels. Industry experts say there is growing excitement around wearables. Apple, through the open source framework ResearchKit, offers the ability to build apps. Apple is continuing to invest in ResearchKit for the creation of mobile applications that support medical researchers by gathering robust and meaningful data.
When wearables were first considered for trials, companies turned to early consumer devices. However, some did not meet regulatory requirements. Clinical grade devices such as those offered by Phillips and ActiGraph filled a void. But over the years, consumer devices have improved and are starting to be recognized by the FDA. The Apple Watch Series has FDA clearance for monitoring irregular heart rhythms.
But Wearables Present Challenges
Some challenges to the widespread implementation of mobile apps in clinical research include the need to validate the technology of mobile health apps, and the need to develop a regulatory structure that supports the use of mobile health app technology in research.
In addition, many commercial wearable devices come with their own proprietary algorithms with no clinical validation or access to the raw data on which they were based. Without raw data, it will be hard to illustrate that a clinical trial is measuring real-world data related to patient outcomes. And, without raw data analyses cannot be upgraded as new algorithms are validated, hampering the construction of a real knowledge base that can be harnessed. And there are concerns about security and privacy.
Moreover, adding wearables to a clinical trial could increase costs depending on the number of participants, the type of wearable used, the data you’re trying to obtain from that wearable, and the required infrastructure. Patient adherence rates must be monitored to make sure data is collected as expected. How the data is transferred to other devices, and how information is sent to the trial database for interpretation are additional issues that need to be addressed.
Other issues involve data accuracy and the validation of data, such as determining whether the wearable has been worn at relevant times during the trial without tampering. On the other hand, there are opportunities if drug makers can collaborate on algorithm development and agree on overall industry outcome measures.
When developing wearables and apps, it is important to establish a foundational data strategy. With wearable devices, the amount of collectible data can be overwhelming and not always necessary. Specifically, define which data is to be collected. Establishing a clear data strategy upfront is essential, impacting informed consent, protocols, data security, and other important issues.
For example, a company wishing to use total sleep time as an indirect indicator of activity must define what sleep is; how to display the data; and decide what may be irrelevant, such as number of steps.
In November 2018, the FDA introduced its MyStudies app, which collects real-world evidence through mobile devices. It increases the diversity of information available for clinical trials. Real world data can be collected from such sources as electronic health records, claims and billing activities, and product and disease registries, as well as from patient-generated data in home-use settings, or from data gathered from other sources, such as mobile devices.
In an email, an FDA spokesperson stated that there is a large spectrum of digital health technologies, including apps and wearables, which may be appropriate for use in a clinical investigation, some of which meet the definition of a medical device. When using digital health technologies in clinical trials, it is important to ensure that the digital health technology is fit-for-purpose, i.e., that the level of validation associated with the digital health technology is sufficient to support its use in the clinical investigation.
Sponsors should engage early with the appropriate Center within the FDA responsible for the medical product under investigation to discuss the use of digital health technologies in a specific clinical investigation. Investigational use of medical devices in clinical trials in the US is governed by regulations that address requirements for human subject protection, such as informed consent and oversight by investigational review boards. For certain studies, referred to as significant risk, prior approval of the study by the FDA is also required, according to the spokesperson. More details can be found at the FDA’s Good Clinical Practices resource page.
To support the development of tools (including digital health technologies and questionnaires that may be delivered via mobile platforms) for use in assessing medical products, the FDA has a number of qualification programs (Medical Device Development Tools (MDDT) Qualification Program for CDRH-regulated products, and the Drug Development Tool (DDTT) Qualification Programs) for CBER/CDER-regulated products.
The spokesperson indicated that through these voluntary qualification programs, sponsors may choose to qualify tools for a specific context of use to allow them to be used in multiple clinical investigations where the context of use is the same as the qualified context of use. Lists of qualified tools can be found at the links above. However, please note that the appearance of a tool on a list does not guarantee that it would be appropriate to use it in any specific trial, and the absence of a tool from a list is not meant to imply that it should not be used, the spokesperson said.
With FDA backing, the future, for sure, will involve using broader, real-time patient data in clinical trials. The use of wearable devices and apps can make clinical trials yield fountains of real-world data and change for the better. They offer trial sponsors greater insights and patients a more consistent and convenient experience while encouraging enrolment and participation in the trials themselves.