Koneksa’s unique expertise in designing, developing, and deploying digital health technology (DHT)-enabled biomarkers in clinical trials, and our experience analyzing the corresponding data, can provide value to your product’s journey. As regulatory requirements and definitions continue evolving, Koneksa is actively following the updates and participating in the work of the scientific community pushing for greater acceptance of DHTs as tools in drug development.
Endpoints Based on DHTs Are Blurring the Line Between Biomarkers & eCOA
DHTs are rapidly changing the landscape of clinical development. Their biggest benefit is the ability to objectively collect data about patient function, such as the ability to walk or exercise (1), instead of relying on a patient’s or physician’s perceptions of this functionality, which can be variable. For example, it has been documented that patients overestimate how much they exercise (2). The variability of a measure drives the number of subjects in clinical studies and the corresponding budgets. DHTs collect data objectively and can reduce measurement error by providing dense data collected by patients remotely (3) instead of relying on a few data points collected when a patient sees his or her doctor.
The promise offered by DHTs also creates a conundrum. Should the DHT-enabled functional tests be considered biomarkers, or should they be considered electronic clinical outcome assessments (eCOAs)? To understand why this distinction matters, it’s important to know that DHTs, along with the data they generate, are considered drug development tools (DDTs). In the current U.S. regulatory landscape, the definition of the DDT category determines the experiments that would be needed to achieve a regulatory endorsement for a tool’s use in drug development. DHTs are newcomers in the clinical trial space, and the regulatory requirements surrounding them are still evolving. Recently, Koneksa provided comments on the FDA guidance (4) released in 2021 for DHT remote data acquisition in clinical investigations, which is a big step toward putting DHTs on equal footing with more traditional biomarker technologies, such as laboratory assays and imaging (5).
Let’s take a closer look at the difference between eCOAs and biomarkers. eCOAs are subjective in nature because the data is collected by patients, physicians, observers, or, in the form of functional tests, administrated by trained personnel (6). On the other hand, biomarkers are indicators of a biological process, a disease pathology, or a response to a therapeutic intervention, done by instrument-based methods—and, therefore, are objective in nature. As such, the requirements for validating eCOAs, versus those for validating biomarkers, reflect the distinct natures of the two types of measurements.
“Conflating the terms can hamper communication and evidence expectations between medical product developers and regulators,” as the FDA recently said (7). This creates a unique challenge for sponsors who wish to deploy DHTs in their clinical studies because many DHT-based functional assessments share characteristics of both biomarkers and eCOAs. Both methods collect data about patient function, which qualifies them as a performance outcome assessment (PerfO), but the in the case of DHTs, data is collected objectively and can be interpreted as an indicator of a disease pathology, e.g., impaired gait in Parkinson’s patients.
The recent commentary by the FDA in Nature Portfolio Journal Digital Medicine (7) helped to demystify the distinction between digital biomarkers and eCOAs. This article provides examples from peer-reviewed literature of digital biomarkers and a hypothetical example (assessing hand function using a smartphone) to highlight the differences. While this clarification is very helpful, more real-life examples are needed to illustrate and understand how DHT-enabled measures can accelerate and enhance drug development.
This publication further emphasizes the point made earlier by the FDA that data acquisition using DHTs requires a partnership between the pharmaceutical and the technology industries (8). DHTs are at the core of digital medicine, an interdisciplinary intersection of device engineering, software development, data analytics, clinical research, and regulatory science (9). As recognized by the FDA, the development of digital DDTs is a complex process requiring input from many experts and institutions, which is best done in partnerships and collaborations that allow everyone to learn together.
At Koneksa, we bring DHT expertise to the table when collaborating with pharma and biotech sponsors, and help them answer key questions:
- What is the concept of interest?
- Can it be measured by a DHT?
- How can it be measured?
- What will be required of patients to collect the data?
- How will the data be analyzed?
The answers to these questions constitute a dossier package, which is then presented to regulators to discuss the use of DHTs in clinical investigations. There are multiple pathways for engaging the FDA: pre-IND, investigational device exemption (IDE), or DDT qualification program. The choice of a pathway depends on the nature of measurement, the role in the drug development cycle, and whether it is linked to a specific medicinal product or has a broader application in a disease indication. However, the key principles outlined in these questions always apply. We are looking forward to new studies that incorporate DHT-based data collection to bring much-needed clinical research and novel medicines to patients, which we believe will make digital medicine more accessible, both literally and perceptually, to patients in need.
1. Viceconti M, Hernandez Penna S, Dartee W, Mazzà C, Caulfield B, Becker C, et al. Toward a Regulatory Qualification of Real-World Mobility Performance Biomarkers in Parkinson’s Patients Using Digital Mobility Outcomes. Sensors (Basel). 2020;20(20).
2. Vassbakk-Brovold K, Kersten C, Fegran L, Mjåland O, Mjåland S, Seiler S, et al. Cancer patients participating in a lifestyle intervention during chemotherapy greatly over-report their physical activity level: a validation study. BMC Sports Sci Med Rehabil. 2016;8:10.
3. Huang C, Izmailova ES, Jackson N, Ellis R, Bhatia G, Ruddy M, et al. Remote FEV1 Monitoring in Asthma Patients: A Pilot Study. Clin Transl Sci. 2021;14(2):529-35.
4. Digital Health Technologies for Remote Data Acquisition in Clinical Investigations. Draft Guidance for Industry, Investigators, and Other Stakeholders [Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/digital-health-technologies-remote-data-acquisition-clinical-investigations.
5. Izmailova ES, Wood WA. Biometric Monitoring Technologies in Cancer: The Past, Present, and Future. JCO Clin Cancer Inform. 2021;5:728-33.
6. BEST (Biomarkers, EndpointS, and other Tools) Resource [Available from: https://www.ncbi.nlm.nih.gov/books/NBK338448/.
7. Vasudevan S, Saha A, Tarver ME, Patel B. Digital biomarkers: Convergence of digital health technologies and biomarkers. NPJ Digit Med. 2022;5(1):36.
8. C Path Institute and FDA: Developing Digitally Derived Endpoints that Measure what Matters to Patients: The Case for Collaboration [Available from: https://globalforum.diaglobal.org/issue/december-2021/developing-digitally-derived-endpoints-that-measure-what-matters-to-patients-the-case-for-collaboration/.
9. Defining Digital Medicine [Available from: https://www.dimesociety.org/about-us/defining-digital-medicine/.