As a general rule, automatic substitution is usually permitted with generic small molecules where FDA has determined the two products to be therapeutically equivalent. Often this regulatory determination is made on the basis that the active substance is identical to the reference product. Different regulatory guidelines apply to biosimilars on the basis that the drug substance is found to be highly similar, but not identical to the reference product. Similar in concept to a therapeutic equivalence rating, the U.S. biosimilars pathway offers the ability for a drug manufacturer to demonstrate “interchangeability” as a separate and higher standard than “biosimilarity.” Interchangeability is the ability to safely change back and forth between two specific biologic medicines — a biosimilar and the reference product. According to regulators, making the transition from biosimilar to interchangeable will primarily be a matter of successfully conducting switching studies in which patients alternate between the reference and biosimilar products with no loss in efficacy or safety versus continued use of the reference product1,2. Once interchangeability designation is acquired, a biosimilar may be automatically substituted for the prescribed reference product without the intervention of the prescriber if permitted by state laws.
The U.S. is the only country to formally include an “interchangeable” designation for biologic medicines. The requirements for being designated as “interchangeable” in the U.S. are separate and in addition to being designated “biosimilar.” Thus, interchangeable biological products are not expected to be available when biosimilars are first introduced in the U.S. While FDA designates interchangeability, states control drug substitution laws. Most states’ substitution laws have not yet been updated to expressly permit the substitution of biological products.