There are many design features that fundamentally differ from traditional drug development clinical trials used for initial approval of a novel biological drug or for the addition of an indication. This chapter explains how the approach to clinical development of biosimilars has evolved beyond the studies applied in traditional regulatory science for originator products. The goal of the regulatory approval is to ensure that all prescribers and patients have confidence that the product produced with the newly amended, likely expanded, manufacturing process is "highly similar" to the original biologic and produces the same clinical response as the original product. In Europe, however, the regulatory process involved in the review and approval of manufacturing changes is often published in European Public Assessment Reports (EPARs). There is intense passion and interest in addressing the access issue, and clinicians become very interested in being involved with this process, thereby enabling more patients to benefit.