In the intricate landscape of clinical development, proving the efficacy of medical interventions based on clinical outcome assessments (COAs) has long stood out as a complex and costly task.
Key Takeaways
- The traditional clinical outcome assessments (COAs) used in drug development are facing challenges in terms of dependability and cost-effectiveness, leading to a decline in drug success rates.
- The adoption of digital health technologies (DHTs), such as wearable devices, in clinical research is on the rise, with approximately 2.2% of clinical trials in high-income countries incorporating wearables since 2020.
- Wearable DHTs offer advantages such as more meaningful data collection, improved patient engagement, objective real-time data, and reduced reliance on self-reported information.
These assessments, vital for gauging the success of new treatments, have been a cornerstone of the research process for decades. Yet, the lack of significant evolution since their inception raises questions about their dependability in today’s demanding development landscape, which has seen a steady decline in drug success rates.
Introducing hybrid and remote research designs and the growing recognition of patient-centric approaches in R&D decision-making and regulatory approvals have heightened the demand for precise and reliable measurement techniques that seamlessly integrate into patients’ daily routines.
Pharmaceutical companies are increasingly interested in exploring the benefits and feasibility of incorporating digital health technologies (DHTs), such as wearable devices, into their research initiatives. This strategic shift promises to obtain more meaningful, objective data that authentically mirrors a patient’s real-life experiences.
Adoption of Wearable Endpoints
The use of wearable DHTs, such as actigraphy, in clinical research programs has increased steadily since 2014 (Figure 1). Overall, approximately 2.2% of clinical trials in high-income countries have incorporated wearables since the start of 2020.1
Adoption is highest in development programs that struggle to assess ‘function in daily life’ for patients using traditional COAs, such as neurology, pulmonology, cardiology, and rheumatology.
Advantages of Wearable DHTs
Wearable devices bring more meaningful data collection and improved patient engagement to clinical trials, ultimately enhancing the efficiency of development programs. They support objective, continuous, and real-time data collection, reducing the reliance on patients’ self-reported information and enabling researchers to capture fluctuations and trends that may have been missed in sporadic measurements.
Wearables enable remote monitoring, thereby decreasing the necessity for frequent in-person site visits. Longitudinal data can be gathered over an extended period, offering a better grasp of an individual’s condition and the effectiveness of treatment.
These wearables can also capture diverse data, encompassing physiological, movement, and sleep metrics. This can provide a more profound understanding of the multifaceted factors influencing a patient's health, which may change in response to a new treatment.
With their capacity for real-time, objective data collection and continuous monitoring, wearable devices stand as conduits that effortlessly capture patients’ experiences, unburdened by the recall biases that can plague traditional approaches. They collect data that allow novel insights while helping sponsors complete trials faster and with fewer participants.
Moreover, ongoing enhancements continually broaden the scope of these devices into new areas of disease and metrics. They provide direct access to raw sensor data, incorporate traceability functionalities, and boast extended battery life to spare participants the inconvenience of frequent recharging.
For instance, recent advancements encompass the integration of PPG sensors for heart rate monitoring, microphones capable of detecting coughs, temperature sensors, and barometers to identify movements characterized by vertical changes, such as falls. There is also a heightened emphasis on maximizing patient comfort during continuous wear. This is reflected in the use of more pliable and softer materials against the skin, all while ensuring the devices maintain close contact with the wrist to gather data accurately.
Regulatory Outlook
The need to assess physical activity and functioning in clinical development has been recognized by both the FDA and EMA across several conditions, including cardiovascular and pulmonary disease, rheumatoid arthritis, amyotrophic lateral sclerosis (ALS), and cancer.2-6
A significant leap forward was highlighted through Bellerophon’s pivotal trial of its inhaled treatment for pulmonary fibrosis. With FDA approval, a wearable device was used as a primary endpoint to measure moderate-to-vigorous physical activity. Although the drug’s outcome was unfavorable, it marked a substantial regulatory endorsement for digital endpoints within clinical development.
Wearable quantified physical activity has also been incorporated into an EMA-qualified clinical endpoint for COPD and accepted into the FDA COA qualification programs for chronic heart failure and sarcopenia. Additionally, wearable-qualified walking and mobility outcomes have been proposed as key clinical endpoints for neurology, pulmonology, and rheumatology development programs.7
The momentum behind the adoption of DHTs is set to gain more traction, particularly as the demand for decentralized clinical trials (DCTs) continues to grow. The FDA and EMA have issued guidelines outlining the integration of DHTs in clinical research.8,9 A significant milestone was also reached in June 2022 when the FDA incorporated DHTs into the strategic framework of its five-year action plan for the ALS Act.
Barriers to Broader Adoption in Trials
Although the potential of DHTs is unquestionable, the pace of their integration into clinical trials has been gradual and cautious. Overall, the percentage of clinical trials reporting the use of wearables as primary or second endpoints on clinicaltrial.com is less than 1%.
The healthcare industry’s inherent aversion to risk often deters changes to the status quo, potentially slowing the adoption of novel endpoints. The complex landscape, characterized by frequent trial setbacks, fosters hesitancy among decision-makers when embracing new technologies, as there is apprehension that any failures could be attributed to these changes.
While wearable devices might not independently guarantee more successful drugs, their integration can substantially enhance the efficiency and effectiveness of drug evaluations, delivering invaluable insights across the clinical trials lifecycle. This dynamic is one that industry sponsors cannot afford to overlook, even amid the uncertainty surrounding adoption.
Optimizing the Integration of Wearables
Sponsors seeking to incorporate wearable-derived measures in their clinical programs should carefully evaluate the following factors. These considerations will play a pivotal role in optimizing the utility of wearable data, safeguarding data integrity, and fostering productive interactions with payers and regulatory bodies.
Begin With the End in Mind
Study sponsors will want to craft an overall strategy for the use of wearable data in their clinical programs. Often, especially in the early days, sponsors venture into wearable technology adoption in isolated pilot studies and trials without a well-defined strategy for its role in supporting the broader clinical development plan. The absence of such a plan can result in inadequate design of data collection and analysis of these pilot studies.
Endorsement by the regulatory authorities necessitates substantial evidence generation, which is time-consuming. Program leaders are strongly advised to proactively consider the overall evidence generation plan and strategize the deployment of DHT in early-phase trials. For large companies with multiple assets in the same indication, the sponsor could consider and form the strategy around the indication or therapeutic area, not necessarily the assets.
Longevity of the Data
Clinical development is a long game. Ensuring the longevity and consistency of the data collected over several years is paramount. Such long-term consideration poses a dilemma to the technology industry, which thrives on agility and rapid change.
It could prove detrimental to a multi-year clinical trial if the technology, be it hardware or software, undergoes significant changes during the study period or between early and later phases. The recent FDA DHT guidance8 stated that the sponsors should assess all DHT platform updates to ensure data integrity and satisfaction of regulatory requirements.Thus, researchers should opt for platforms prioritizing stability and backward compatibility over constant updates, even if it means some delay in adopting the latest technology, which may or may not offer substantial benefits to the research.
Raw Data Retention
Raw data retention is vital to maximizing data value throughout clinical development programs and longer. Raw data here refers to the original sensor data collected at a high frequency (multiple data points per second).
This is the ultimate source data that can be processed to derive digital clinical measures using various algorithms akin to the individual item scores for patient-reported outcomes (PROs) or Clinician-Reported Outcomes (ClinROs). Unlike PROs and ClinROs, wearable data algorithms are complex and significantly impact the accuracy and reliability of the derived digital measures.
Algorithm development is the most active area of research in digital health science, evolving with the rapid advancements in data science. Retaining raw sensor data allows the adoption of improved and new health metrics while meeting regulatory requirements on data integrity, verification, and validation.
Pay Attention to Statistical Analysis
Sponsors should diligently evaluate the resources and methodologies necessary for analyzing the gathered wearable data. Sensor data inherently differs from the discrete data points associated with traditional endpoints, demanding special consideration and innovative approaches for analysis.
Unfortunately, because wearable DHTs are frequently positioned as exploratory endpoints, their analysis often assumes a lower priority within the study team. The constrained bandwidth of the biostatistics team, combined with often limited familiarity with wearable data, often results in the underutilization of wearable-derived endpoints. Study teams are advised to proactively plan for resource allocation and develop a tailored approach to analyze wearable data. Collaboration with specialized technology vendors experienced in handling wearable data can also prove beneficial.
Partnerships are Crucial
A central challenge in advancing novel digital measurements as clinical endpoints revolves around bridging gaps in validation evidence. This obstacle looms large and can be too substantial and costly for any individual technology provider or sponsor to tackle. DHT providers and sponsors are diligently working to bring together their multidisciplinary expertise to unravel the complex intricacies of sensor data analytics and link this to clinically meaningful outcomes. This concerted effort aims to propel the integration of wearables into mainstream clinical development practices.
Currently, we are witnessing the formation of pre-competitive working groups dedicated to collaboratively developing purpose-built DHT instruments while reducing operational and regulatory friction points.
A working group involving several global pharmaceutical sponsors has recently been established to co-develop a fit-for-purpose instrument to measure nocturnal scratch in atopic dermatitis. This partnership approach to digital endpoint development holds strong potential for endorsement by health authorities and marks a pivotal stride forward in amassing the necessary evidence.
Conclusion
In summary, wearable DHTs have enormous potential to bring more meaningful data collection to patient-centric clinical trials. They provide advantages such as objective, real-time data collection, remote monitoring, and diverse metric capture, ultimately enhancing the efficiency of drug development.
While regulatory recognition is growing, barriers to broader adoption persist due to industry hesitancy and aversion to risk. However, sponsors wishing to leverage wearable-derived measures can address these barriers by meticulously planning their strategies, considering data longevity, stability, retention of raw sensor data, and prioritizing statistical analysis. Collaborating with specialized technology partners will also help further accelerate the integration of wearables into development practices.
The momentum behind wearable DHTs is undeniable, and as DCTs gain traction, their role is set to expand. With a strategic approach and a commitment to addressing challenges, sponsors can unlock the full potential of wearable data.
About the Author
Christine Guo, PhD, Chief Scientific Officer, ActiGraph, leads the clinical and data science team at ActiGraph, responsible for the scientific strategy and services supporting ActiGraph‘s leadership in digital medicine. Christine has over 15 years of experience in clinical research and a vision for leveraging technology in clinical trials and practice. Prior to ActiGraph, Christine was Head of Scientific Innovation at Biogen Healthcare Solutions, leading the clinical development and validation of Biogen’s digital medicine products (Software as Medical device) in multiple sclerosis, neuromuscular, and neurodegenerative diseases. Christine brings unique scientific insights by bridging clinical and technical disciplines and is passionate about leveraging data and technology to improve people’s health. Christine holds a B.A. in biological sciences from Peking University and Ph.D. in neuroscience from Stanford University.
References
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- European Medicines Agency. Clinical Investigation of Medicinal Products for Treatment of Rheumatoid Arthritis [Internet]. Available from: https://www.ema.europa.eu/en/clinical-investigation-medicinal-products-treatment-rheumatoid-arthritis#current-effective-version-section
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- European Medicines Agency. Clinical Investigation of Medicinal Products for Treatment of Pulmonary Arterial Hypertension. 2018. Available from: https://www.ema.europa.eu/en/clinical-investigation-medicinal-products-treatment-pulmonary-arterial-hypertension
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- Mobilise-D. [Internet]. Available from: https://mobilise-d.eu/
- FDA. Digital Health Technologies for Remote Data Acquisition in Clinical Investigations [Internet]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/digital-health-technologies-remote-data-acquisition-clinical-investigations
- European Medicines Agency. Questions & Answers on the Qualification of Digital Technology-Based Methodologies to Support the Approval of Medicinal Products [PDF]. Available from: https://www.ema.europa.eu/en/documents/other/questions-answers-qualification-digital-technology-based-methodologies-support-approval-medicinal_en.pdf
