Sharing Clinical Evidence Endpoints

It’s a library with no books, only data. And just certain types of data, at that. Submitted from pharma houses big and small, from every clinical trial phase, these data are not proprietary: They’ve been submitted by researchers sharing a common vision.

Founded in 2019, the Digital Medicine Society (DiMe) houses these data contributions in its Library of Digital Endpoints; 366 endpoint listings so far. They are measurements of patient-specific indicators, like step counts, glycemic variability measurements, time intervals. The technology being assessed is recorded as well: smartphone apps, home spirometers, pedometers, continuous glucose monitors.

Trial results are not listed in the library. What matters is what the researchers measured and if those calculations represent aspects of disease that are clinically relevant and important to the patients who have that particular malady.

This library is one of many resources that stakeholders in biometric monitoring and digital therapeutic technologies can use to see what’s been measured and how it’s been measured. This effort to attain standardization has numerous participants, including FDA, the Clinical Trials Transformation Initiative (CTTI), Digital Therapeutics Alliance (DTA), large pharma, huge tech companies, and more.

Unlike a drug—with apologies for stating the obvious—digital medicine tools have software, hardware, algorithms—it’s possible that different companies contributed to the tool’s components.¹ So relying on existing regulatory frameworks will not work with these tools, the measurers say. Verifying performance against established criteria; validating the algorithm’s performance to accurately capture the metrics; and clinically validating the tool’s output are the three necessary components to reach standardization, proponents say.¹

The DiMe and other like-minded groups believe that health care, while “experiencing a revolution in the use of sensors to collect data on patient behaviors and experience,” cannot benefit yet from the “use and reuse of trustworthy data” because of the continuing “deficits in standards, lexicons, data rights [and more].”² FDA recently established its guidance on fit-for-purpose—does the tool do what it’s supposed to do, in the way that it was designed.

Which of course takes time for FDA to review the data, the technology, the results.

The sense of urgency to reach standardization is real: the estimated number of wearables, ingestibles and other connected sensors now reaches 929 million. Tracxn.com counted 193 types of wearables as of October 2022.^3,4

As for their actual use, any sense of urgency is not readily apparent. While the popularity of the use of digital technologies among physicians, according to an AMA study⁵ of 1,300 physicians, has grown—since 2016, the average number of tools used per physician has climbed from 2.2 in 2016 to 3.8 in 2022—it was just 30% of these physicians who used them in 2022. Physicians like telehealth but are wary of remote technologies. The primary reason: liability.⁵

A 2021 study found that while 15.84% of trials started after the pandemic used what the author called connected digital products, the majority of use was in COVID-focused, observational and non-industry funded trials.⁶

Hence the work to establish standardization. FDA and NIH established a glossary of definitions known as BEST (Biomarkers, Endpoints and Tools); CTTI created a flow chart for researchers to follow when creating a novel endpoint. The DTA, along with CRO Curebase and other stakeholders issued a whitepaper in December spelling out the whys and hows of reaching standardization for digital therapeutic technologies, or DTx.⁷

“A fit-for-purpose DTx evidentiary standard—applying both to products provided via prescription and non-prescription routes—must include the types, quality, timing, and levels of clinical evidence considered to be sufficient for DTx product regulatory, reimbursement, and clinical use purposes,” according to the whitepaper.

Megan Coder

Megan Coder, DTA’s chief policy officer, said her group established 10 criteria that it believes should be incorporated into every DTx product. These include interventions based on software and their clearance or certification by regulatory bodies as proof of all product assertions. She said DTA is working with ISO International to establish standards. “[Standardization] makes it easier for policy makers, makes it easier for them to make decisions.”

And because these therapeutic interventions—that treat, manage, or prevent disease—do work with biometric sensors, “there are integrations there. What happens [in the biometric sensor space] does impact us. It is nice we have collaboration” with DiMe and others, she said.

But there is no standard without knowing what and how to measure, and this is where Pip Griffiths, PhD, comes into the picture. She and her colleagues at DiMe are working with others in the field to determine which questions and answers will lead to clinical relevance.

“What matters is, what do we need to measure; how do we [translate] it into a digital parameter?” Griffiths said.

Pip Griffiths

Griffiths is working to establish the digital parameters for Alzheimer disease. It is not an easy route to get there, considering a possible marker of disease could be specific to that disease, or to something else. What also is taken into consideration are the important points for pharma, regulators, academics, caregivers, let alone the patients themselves. After the deep dive into the published literature for clues, like sleep and memory issues, loss of social abilities, behavioral changes, the broad, the team interviews patients and their caregivers alike to amass qualitative data. Griffiths is using those qualitative answers to establish the digital measures. “Using these algorithms, finding decline, you can start looking at people early on, and then enroll patients at an early stage.” Digital biomarkers, she says, present an opportunity for average citizens to check their brain health regularly… “Right now, people can't be helped early on.”

She and her team are also starting to measure parameters relating to sleep issues across a broad range of disease areas, covering respiratory, neurological and musculoskeletal. “We are trying to be what we call omni-therapeutic.”

Christine Bahls is a freelance writer for medical, clinical trials, and pharma information.

References

1. Coravos, A., Doerr, M., Goldsack, J. et al. Modernizing and designing evaluation frameworks for connected sensor technologies in medicine. npj Digit. Med. 3, 37 (2020).
2. Clay I, Angelopoulos C, Bailey AL, et al. Sensor Data Integration: A New Cross-Industry Collaboration to Articulate Value, Define Needs, and Advance a Framework for Best Practices. J Med Internet Res 2021;23(11):e34493.
3. Liu, S. Number of connected wearable devices worldwide from 2016 to 2022 (in millions). https://www.statista.com/statistics/487291/global-connected-wearable-devices/
4. Tracxn.com https://tracxn.com/d/trending-themes/Startups-in-Wearables-for-Remote-Patient-Monitoring
5. AMA. Digital Health Care 2022 study findings. https://www.ama-assn.org/about/research/ama-digital-health-care-2022-study-findings?utm_content=231720627&utm_medium=social&utm_source=linkedin&hss_channel=lcp-18444986 Updated Sept 28, 2022.
6. Marra C, Gordon WJ, Stern AD. Use of connected digital products in clinical research following the COVID-19 pandemic: a comprehensive analysis of clinical trials. BMJ Open. 2021 Jun 22;11(6):e047341.
7. Digital Therapeutics Alliance. Setting the stage for a fit-for-purpose DTx evidentiary standard. Dtxalliance.comDecember 2022.