With the adoption of digital health technologies, sponsors, CROs, and other stakeholders are discovering how technologies such as wearable devices can enable patient-centric measurement of health markers and that frequent and continuous monitoring beyond the clinic can offer more precise and accurate assessments than traditional observational models.

However, the lack of clear regulatory guidelines and standardization has limited the use of digital health technologies to generate endpoints in clinical research.

Marie McCarthy, Senior Director of Product Innovation at ICON plc and Manpreet Sidhu, Executive Principal and Global Head of ICON’s Health Economics and Outcomes Research practice, discuss some of the lingering challenges the industry faces with widespread adoption of digital health technology, the data that can be leveraged from wearables, and where advances are being made. –KB
 

Contract Pharma: What are some of the lingering challenges the industry faces with widespread adoption of digital health technology?

Marie McCarthy: In an increasingly digital world, data is abundant, vast, and complex. These factors make collection, management and analysis challenging. The volume and diversity of data is contributing to concerns about high levels of delays and inefficiencies. Additional challenges include patient acceptance, privacy and security issues, and regulatory acceptance. In a recent webinar hosted by ICON, 40 percent of participants reported that regulatory authorities are the biggest barrier to the adoption of digital endpoints as there is no formal guidance with respect to the use of digital endpoints in a studies, though the FDA’s guidance (2009) on PRO endpoints can be used as a foundation. The lack of clear guidelines and standardization across countries and regions has led to cautious use of digital health technologies to generate digital endpoints in clinical research.

In addition, even though digital devices can be used in clinical trials, it does not necessarily mean they should be. Sponsors need to take the patient’s voice into consideration when deciding on study objectives by selecting digital endpoints that are meaningful to patients. Then, once the appropriate digital endpoint is identified, sponsors can consider the type of wearable or sensor that can provide meaningful data. In some instances, endpoints may be focused on assessing improvement in everyday function, while in others, it will be about measuring stability or deterioration in a condition.

CP: Where are advances being made?

MM: We’ve begun to witness some of the benefits of incorporating digital health technologies during the COVID-19 pandemic. The acceleration of their adoption is a combination of factors, including the growing availability of suitable technology and the increased adoption of these devices as part of standard care, in addition to telehealth visits and advice from regulators with respect to virtual visits. The FDA COVID-19-related guidance documents for clinical studies speaks to the evaluation of alternative methods, such virtual visits where in-person visits are no longer feasible.

However, the use and adoption in drug development clinical trials is still in its infancy, partially due to a lack of definitive regulatory guidance. There are some collaborations such as the Clinical Trials Transformation initiatives (CTTI) which include members from industry, regulators and patients that have developed guidance documents for those interested in using devices in clinical trials. This includes:

●      Prioritize the patient – Sponsors should select measures with the patient in mind and capture insights that are not only clinically meaningful but are meaningful the patient

●      Select the device – The process of device selection involves device identification, patient acceptance testing, and technical usability and feasibility testing.

●      Manage operational excellence – Overlooking operational excellence can severely jeopardize the endpoint. Therefore, sponsors will need to look at the end-to-end process holistically and implement risk contingency, including logistics, data management, patient engagement, compliance and sites.

CP: What are the regulatory hurdles around HTAs?

Manpreet Sidhu: The requirements for global Health Technology Assessment (HTA)/reimbursement considerations are continuing to evolve in response to the current pandemic. HTA boards in most countries initially slowed or delayed their appraisal timelines during the early days of the pandemic, although most are now ‘back in business’, even if operating virtually. Also, some HTA boards have stated that they plan to prioritize certain products for appraisal before others. While very few of these bodies have been explicit about their criteria for prioritization, we can glean something from those that have.

The National Institute for Health and Care Excellence (NICE) in the UK, the Dental and Pharmaceutical Benefits Agency (TLV) in Sweden, and Haute Autorité de santé (HAS) in France are all fast-tracking assessment of products related to COVID-19. Additionally, HAS has clarified that it will prioritize interventions in oncology, pediatrics or any medication in a serious disease with unmet need, and products for temporary use and requests for early care funding. It is also likely to evaluate indication extensions according to a simplified procedure.

CP: How are HTAs being used in response to the pandemic?

MS: As we come to the close of 2020, there is a significant push for approvals of vaccines and antivirals as governments begin to open up economies while preparing for future waves. Moving forward, we predict that HTA bodies will pivot, in the short term, toward assessing the evidence of antibodies, antivirals and vaccines. There will also be a clear focus on therapies that can free up resources that are in short supply, such as ICU (intensive care unit) beds and ventilators.

For sponsors with products in classes that can be fast tracked, there should be a focus on demonstrating value within mainstream and unusual scenarios. For products in classes that are currently deprioritized, sponsors should use this time to fill data gaps with real-world data (RWD), expert opinions, and indirect treatment comparisons that will strengthen their case when the time comes. This will be especially important as health systems will have been depleted of financial resources and potentially will need to apply more stringent assessments.

In view of the current pandemic and the impact on national health care budgets, as well as the economy globally and at a country level, the assessment of therapies to ensure ascertainment of value for the health care setting, and the patient, will continue to be a focus for authorities, therefore the requirement for evidence to support this value should be prioritized.

CP: What data can be leveraged from wearables, and is it considered reliable?

MM: There is increased interest in the use and value of digital endpoints in clinical studies, as illustrated by the FDA’s agreement to use a physical activity endpoint (MVPA) measured by an acitgraphy device as the primary endpoint in a pivotal Phase 3 cardiovascular study. 

There is also a growing array of devices available to researchers. While the Apple Watch, Fitbit or Galaxy Watch3 were not initially developed for research use, they can still produce useful information with respect to an individual’s physical behaviors as they go about their daily lives. Increasingly, these devices are gaining credibility among the scientific community and are being used in clinical studies to track changes in physical activity and sleep patterns. Engagement by these companies with the FDA Precertification (Pre Cert) program has helped affirm their suitability as research tools. For these companies it is likely that FDA clearance of their electrocardiogram application, designed to detect signs of atrial fibrillation (AFib), has strengthened this credibility.

The incorporation of photoplethysmography (ppg) sensors along with the standard accelerometers in these wearables is transforming them from mere fitness trackers into biosensors with the capability of measuring a large number of physiological parameters including blood oxygenation – an important parameter for respiratory diseases, including Covid-19.

As the adoption of wearables grows, more sponsors, CROs, and other stakeholders are demonstrating how digital health technologies can enable patient-centric measurement of health markers, such as physical activity, sleep, heart rate, medication adherence and respiration patterns/rate. Frequent and continuous monitoring — beyond the walls of the clinic — can offer more precise and accurate assessments than traditional observational models.

Further, digital health technologies can capture new measurements that would have been unimaginable previously. For example, a team at Johns Hopkins conducted an observational study requiring subjects to perform five cognitive tasks on a smartphone application, then merged the task data to form a validated mobile Parkinson’s disease (PD) score. Using a novel machine-learning approach, they demonstrated how this score complements standard PD measures by providing frequent, objective, real-world assessments that could enhance the clinical care and evaluation of therapeutics.

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Marie McCarthy is part of the multidisciplinary Innovation Team at ICON plc. Seen as a key Entrepreneur within the organization she has specific responsibility for developing solutions in the direct to patient paradigm. Her focus is primarily on the use of wearables and sensors in clinical trials, with particular emphasis on the potential these devices have to monitor the physical behaviors of the digital patient. Prior to ICON, Marie was EU Sales and Marketing Manager with Philips Respironics, building awareness of the value of Actigraphy endpoints among Clinicians and Researchers.

Manpreet Sidhu has over 20 years of experience in health economics, including strategic evidence generation planning, project management, systematic reviews, economic modeling, strategic market access, and dossier development.  She leads ICON’s Health Economics and Outcomes Research practice which delivers innovative tailored solutions to help clients generate HEOR evidence, meet specific HTA challenges with early advice and submissions, support market access and bolster arguments for product reimbursement.