Clinical evaluation for SaMD is distinct from hardware testing, as it focuses on three pillars: Clinical Association, Analytical Validation, and Clinical Validation. Clinical Association proves there is a valid link between the software's output and the targeted clinical condition. Analytical Validation ensures the software correctly processes the input data (e.g., the code is bug-free and mathematically accurate). Clinical Validation proves that the software yields a clinically meaningful result in the intended population.

To facilitate this, SaMD developers are increasingly utilizing Real-World Evidence (RWE). Because SaMD is often connected to the internet, it can collect anonymized data on how the software performs in actual clinical practice across thousands of users. To understand how RWE is used to support label expansions and post-market surveillance, refer to the Software as a Medical Device Market resource.

RWE allows for a more dynamic understanding of software performance than traditional clinical trials alone. For instance, a SaMD used for managing diabetes (Digital Therapeutic) can demonstrate long-term HbA1c reduction across a diverse global population, providing a level of evidence that would be cost-prohibitive to achieve in a controlled trial setting. This data-driven approach is fundamental to the "Value-Based Healthcare" model.