The Use of Biosimilars

The use of biosimilars will differ from generics because of their complexity. Each biosimilar represents a distinct therapeutic choice.

Biosimilars may have different uses - for new patients, for existing patients, and potentially for pharmacy-level substitution if determined to be interchangeable or therapeutically equivalent. Each biosimilar may come to market with different data packages, including clinical data in specific diseases. Based on the nature and extent of totality of evidence, some biosimilars may be approved for all diseases that the reference product is approved for while other biosimilars may be approved only for the disease for which it was tested in clinical trials or a subset of the reference product indications of use. Accordingly, biosimilars for the same reference product could differ from each other in terms of totality of evidence and the product label specifying approved designation of use in treating a specific set of diseases.


Each biosimilar will differ in terms of product label, including relevant pharmacology and clinical data, which will be influential in guiding correct use of biosimilars. It is imperative for healthcare providers to understand key aspects of each biosimilar, including functional data and/or clinical data to make a choice whether to 1. initiate a new patient, 2. transition a stable patient, or 3. support automatic substitution to a biosimilar.


New patient initiation on a biosimilar

It is expected that approved biosimilars in highly-regulated markets have demonstrated a high level of similarity in analytics, and an absence of clinically meaningful differences in efficacy and safety to their reference products. This being true, new patients requiring use of a reference product can be initiated on a prescribed biosimilar. The basis for this is the assumption that the “totality of evidence” has demonstrated a high level of similarity, meaning that the biosimilar has matched the critical quality attributes and the function of a reference product, and that a patient should experience no clinically meaningful differences in the efficacy and safety of the biosimilar as compared with the reference product.

Transition of stable patients to a biosimilar

Some biosimilars will come to market with clinical data supporting physician-controlled, single transition of patients from a reference product to a biosimilar — sometimes referred to as therapeutic substitution. If a biosimilar has demonstrated that patients can be transitioned from a reference product to a biosimilar in a physician-controlled process with no additional risk introduced and similar efficacy maintained, physicians should feel comfortable making a one-time transition of a patient to a specific biosimilar.

Interchangeable biosimilars, also called automatic substitution

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.


It is widely agreed by a broad consensus of the scientific, regulatory and industry communities that biologic medicines have the potential to present unique risks when switched back and forth and should not be done without involving the prescribing physician.

Because of this broad consensus, Amgen has long held the view that pharmacists should not switch one biologic medicine for another without informing the prescribing physician, and—in the U.S.—only after the two biologic medicines, including biosimilar and the reference product, in question have received regulatory designation by the FDA as “interchangeable” with each other.

Variation in Global Substitution Guidelines