Objectives <p>This paper seeks to identify some of the complexities associated with determining meaningful change for endpoints derived from digital health technologies (DHTs) and propose possible methodologies for this process. Ultimately, this is a call to action to consider appropriate methods and practices required to enable digital endpoints (DEs) to achieve their full potential as Drug Development Tools.</p> Methods <p>Using the Food and Drug Administration (FDA) Patient-Focused Drug Development (PFDD) guidance documents as a framework, we explore the nuances and challenges that exist when determining meaningful change for DEs compared with traditional clinical outcome assessments (COAs).</p> Results <p>There are unique characteristics associated with DEs that provide distinct challenges when determining meaningful change. This complexity spans the totality of meaningful change considerations, from ensuring that the DE itself is meaningful from the patient perspective to selecting appropriate anchors that enable determination of the magnitude of change that is meaningful for patients.</p> Conclusions <p>With increased adoption of DHTs in clinical trials, their specific use is evolving, as evidenced by their being referred to as DHT-passive monitoring COAs in the FDA drug development tool (DDT) qualification program. However, the determination of meaningful change for these DEs can be more nuanced and challenging than for traditional COAs. Merely adapting existing approaches for traditional COAs does not readily support DEs derived from continuous datasets collected over long periods. New methods and approaches are required, and this can only be realised by working together, to ensure that the value and limitations of various methodologies as they relate to DEs can be refined.</p>