Approved biosimilar medicines are required to have no clinically meaningful differences in terms of safety and efficacy from the relevant reference product. The approval is based on the totality of evidence from analytical, nonclinical, pharmacokinetic, and clinical studies.

Extrapolation is a scientific and regulatory principle that refers to the approval of a biosimilar for use in an indication held by the reference product but not directly studied in a comparative clinical trial with a biosimilar. Extrapolation of efficacy and safety data from one indication to another may be considered if biosimilarity to the reference product has been shown by a comprehensive comparability program including safety, efficacy, and immunogenicity, and there is sufficient scientific justification for extrapolation. Extrapolation is not automatic and is considered only after biosimilarity is established based on the totality of evidence.

Interchangeability is defined by statute in the United States to mean that the product may be substituted for the reference product without the intervention of the physician who prescribed the reference product. The legal standard for interchangeability is an additional standard beyond demonstration of biosimilarity.

To be deemed interchangeable, a biological product must be biosimilar to an FDA-approved reference product and meet additional standards for interchangeability set forth by the Biologics Price Competition and Innovation Act (BPCIA). By statute, in order for the FDA to deem a biological product interchangeable, the information submitted in the application (or a supplement to such an application) must be sufficient to show that: the biological product is biosimilar to the reference product; and can be expected to produce the same clinical result as the reference product in any given patient; and for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch. In the US, although federal law gives the FDA the authority to license biological products as interchangeable, it is individual state laws that govern the substitution of biologics and pharmaceuticals.

Interchangeability is defined by statute in the United States to mean that the product may be substituted for the reference product without the intervention of the physician who prescribed the reference product. Switching is a decision made by a physician to change a patient's treatment—to another course of therapy, from a reference product to a biosimilar, or potentially among biosimilar products. Neither the Biologics Price Competition and Innovation Act nor any other provision of law suggests or requires that a biosimilar meet the statutory definition of interchangeability as a prerequisite for a physician to switch (or transition) a patient from a reference biologic to a biosimilar (or other therapy).