Digital Biomarkers: Types, Endpoints, Clinical Trials & FDA
Welcome back to?Signals,?the place where we explore the next frontiers of healthcare & technology, inspired by the people we meet on?T Minus 10
This week we are talking about?digital biomarkers. Depending on your level of involvement in healthcare and technology, this might be a relatively new concept to you. But before you start to feel overwhelmed, rest assured this week's Signals will bring you up to speed on one of the most exciting and rapidly-growing areas of development in healthcare today.
Biomarkers are vitally important in healthcare. A biomarker is a?medical signal?that can measure health in an accurate and reproducible way. [1] Thanks to the evolution of digital technologies from wearables and software to sensors and cameras, a category of biomarkers has emerged that is unique to these digital health-enabled tools, appropriately called digital biomarkers. Measures must be objective, quantifiable, and reproducible — and scientific evidence needs to show that the health attribute measured by the device maps consistently and accurately to a clinical outcome. [2]
A 2016 Rock Health report illustrates how digital biomarkers are classified, by novelty in measurement and insight (picture below). [3]
As I was researching this piece I noticed the first wave of excitement and calls for more evidence / collaboration in the biomarkers space seem to hit its height 5 to 7 years ago. Today, the application of biomarkers has already transformed the diagnosis and management of cancers, cardiovascular disease, and immunological and genetic disorders with greater precision, and their use in these fields is now commonplace. [4] And because of their broad utility and flexibility, the biomarker movement is arguably still in its infancy.
In today's issue of Signals we will focus on the opportunities, barriers, and remaining questions inspired by biomarkers as they continue to quantify the invisible spectrum of our everyday lives. The graphic below is a great illustration of the breadth and depth of biomarker applications across our lives, as well as their potential uses in research and data security risks. Simply put, it's a great time to get involved and contribute to this growing field.
Note: For complete definitions and updated guidance please see references below and refer to the FDA–NIH Biomarker Working Group, BEST (Biomarkers, EndpointS, and Other Tools). [5]
Signals
1. Drug development. The team from Digital Medicine Society (DiMe) has put together a treasure trove of education, resources, and insights to advance the capabilities of digital tools in medicine. Their Project Moneyball is a must-read for those hoping to understand the art and science of combining technology and medicine to drive clinical study success. The figure below highlights tech contributions in that process. The authors point out that while digital biomarkers have significant potential to transform drug development, only a few have contributed meaningfully to bring new treatments to market. Taking it a step further, they also identified 5 gaps for pharma sponsors and tech providers to address in the ecosystem of digital biomarkers that is worth understanding if you have a seat at the clinical trials table, so to speak. [6]
2. Case Study: Atrial Fibrillation Endpoints. Taking our lesson from the DiMe piece above, it's helpful to see how different tech providers leverage modular approaches to solve for a similar endpoint. From the operating system to the patient's screen, the image below depicts how 5 product companies built components of their offerings across the product cycle. This 2019 paper published in Nature outlines key considerations for the development and evaluation of digital biomarkers, examining their role in clinical research and routine patient care. [7] If you are at a company that develops software and/or sensor products for commercial use in healthcare and wellness markets, these examples are likely not new to you. At the same time, with each passing headline of a new feature or sensor added to these products, it's easy to forget how much clinical rigor, time, energy, and resources are needed to bring validated measures to market. These are not your average sprint cycles managed by a Product Manager and her team of developers. They are one essential piece of the collaborative puzzle, and that's what I find most enthralling about the whole process.
3. Clinical Trials. 80% of clinical trials are delayed due to patient recruitment issues, with travel being a major barrier to sign up. [8] Aside from patient recruitment challenges, clinical trials have increasing drop-out and lost-to-follow-up rates. The industry expectation is to plan for approximately a 30% drop-out rate; however, trial adherence rates can average 43%-78% in patients with chronic conditions. But what if patients could participate in trials from the comfort of home? And in the process, could we learn more about those patients thanks to the devices they use to participate in those very trials? That's the idea behind the emerging field of virtual clinical trials that leverages digital health technologies —such as mobile devices, mobile apps, remote monitoring devices, and online social engagement platforms— to expand access to clinical trials while addressing the challenges described above. This is not my area of expertise or daily operation, but when I do see these updates in my feed I make sure to follow leading voices and minds like Craig Lipset (Co-Chair of DTRA), Jen Horonjeff (CEO at Savvy Coop), and colleagues like Marc Leighton (Myriad Genetics), Brian Neman (Sanguine), and Henry Peck (LSI).
4. Why does it matter to patients? A second article published by DiMe in 2021 lays out the case for developing and selecting digital clinical measures that matter to patients. At the end of the day, patients seek professional care for their diseases, not for the numbers that show up on their mobile app or wearable, even if that data predicts or correlates with their illness. Here the DiMe team presents a four-step framework for meaningful measurement that includes: (i) Meaningful Aspect of Health (MAH); (ii) Concept of Interest (COI); (iii) Outcome to be measured; and (iv) Endpoints (exclusive to research). [7]
"Patient engagement, early and often, is paramount to thoughtfully selecting what is most important to measure."
5. FDA Clearance. One recent example to highlight is MIT Media Lab spinoff Empatica, which announced the clearance of its Empatica Health Monitoring Platform by the FDA in late November. MIT Professor Rosalind Picard and her team have developed a platform to accelerate the development of novel therapeutics and the adoption of digital endpoints in patient care and clinical trials. The FDA clearance includes data collection for the continuous monitoring of SpO2, electrodermal activity, skin temperature, and activity associated with movement during sleep. The team also announced the completion of their Series B, led by Sanofi Ventures and RA Capital Management. (PRN)
6. It's about time. According to a recent article in Healthcare Transformers, the opportunity for temporal biomarkers is staring us in the face.
The authors point out that a disproportionate number of biomarkers focus on spatial rather than temporal (time) dimensions, and for good reason. It was not until recently that we have been able to measure events at the milli-scale, particularly in medicine. Our eyes and facial movements reveal hidden clues and yet-to-be-uncovered insights about our health, and what better way to capture and analyze those data than the cameras in our pockets? The authors work for a company called BioTrillion that is developing a 10-second "Healthy Selfie" to put early disease detection in 3 billion pockets across the globe. [8] Think about all the fields of study related to our eyes where novel biomarkers may soon be developed. This notion that we can combine decades (or centuries) of research with exponential advances in computing now available in the products we buy regularly. That the same experts who previously relied on infrequent pen and paper assessments can now capture, create, and analyze data that shed new light on a patient's pathology and physiology. Areas like pupillometry (pupil size and reactivity), neurology and cognitive assessments stand to benefit greatly from digitization and advancements in the temporal realm.
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Voices
Linta Mustafa (Voyage 27) teaches us how Vitract is building the most advanced and comprehensive at-home gut test that decodes the gut microbiome. I'm excited to follow the massive impact Vitract has on chronic illnesses with strong ties to gut health thanks to advances in at-home testing and diagnostics. I'm sure we'll see Linta and her team share more about their clinical endpoints as they continue to grow their platform, data set, and user base leveraging Vitract for personalized nutrition and gut health measurement.
Christy Cheung, PharmD (Voyage 18) shares her take on the opportunity ahead of pharma to embrace digital, including digital biomarkers and expanding access to offerings for patients beyond medications. Christy shows us why stakeholder education is key when it comes to digital transformation and the introduction of digital health technologies inside and across large organizations like Sanofi.
As I mentioned in Signals From: [VR], Amir Bozorgzadeh?(Voyage 14) showed us why virtual reality brain training will transform healthcare. Cognitive assessment is foundational to their approach. Amar and his team at Virtuleap aim to elevate the cognitive assessment and training industry with the help of emerging technologies such as VR and AR. I love how the Virtuleap team describes the power of VR from a data perspective:
"Compared to screen-based devices, VR offers a multi-sensory and ecologically valid experience that engages the whole-body and captures volumetric datasets about the human condition, combining the psychological with the physical and physiological."
Marc Leighton (Voyage 11) takes us behind the scenes as an experienced product leader in the healthcare world, and specifically in the clinical trials space. Prior to his current role at Myriad Genetics (NASDAQ: MYGN), Marc served as Head of Product at Florence Healthcare. Thinking about the challenges faces by clinical sites and potential participants is paramount to launching a successful product to support those sites. At the end of the day, the user experience is everything, especially in an increasingly virtual world.
Henry Peck?(Voyage 06) taught us about how he and his prior team at Altoida were working to create a new gold standard in brain health. The company is building the precision neurology platform to power early Alzheimer’s disease diagnosis and personalized brain analysis, and digital biomarkers are a central part of that tool set.
Key Terms
Biomarkers (BMs) are defined characteristics that are measured as indicators of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic interventions (e.g. blood pressure).
Digital biomarkers (dBMs) are a characteristic or set of characteristics, collected from digital health technologies, that are measured as indicators of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions.
Digital health technologies (DHTs) are systems that uses computing platforms, connectivity, software, and sensors for healthcare and related uses. These technologies span a wide range of uses, from applications to support general wellness to medical device applications such as apps that provide a reminder to stay out of the sun to limit UV exposure. [9]
Clinical outcomes assessments (COAs) are subjective measures of how a patient feels, functions, or survives that can be made through a report by a clinician, a patient, or a non-clinician observer. Note: Biomarkers and clinical outcome assessments measure different concepts and both could be useful in understanding the impact of a condition on patients. More on that comparison and differentiation in a 2022 Nature article. [9]
Types of Biomarkers vary based on application, and there is overlap with other categories of biomarkers for given applications.
Note: For a deeper dive into definitions, studies, evidence, and all the things that make biomarkers fun and fascinating, please explore the references below.
References
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