Interchangeable Biosimilars vs Biosimilars vs Reference Biologics

Biological medicines play a critical role in modern therapy. Regulatory authorities such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) classify biological products into reference biologics, biosimilars, and, in the United States, interchangeable biosimilars.

1. Reference Biologics

A reference biologic is an original biological product approved based on a complete package of quality, nonclinical, and clinical data.
These products serve as the comparator for biosimilar development.

Examples

Adalimumab – Humira
Trastuzumab – Herceptin
Infliximab – Remicade

2. Biosimilars

A biosimilar is a biological product that is demonstrated to be
highly similar to a reference biologic, with no clinically meaningful
differences in safety, purity, or potency.

Biosimilars rely on a totality of evidence approach, focusing on
analytical similarity supported by targeted clinical studies.

FDA and EMA Position

Same mechanism of action
Same route of administration
Same dosage form and strength
No automatic pharmacy-level substitution

Examples

Adalimumab-atto – Amjevita
Trastuzumab-dkst – Ogivri
Infliximab – Remsima

Reference Biologic

Biosimilar Highly Similar

3. Interchangeable Biosimilars (US FDA Only)

An interchangeable biosimilar is a biosimilar that meets additional FDA requirements demonstrating that the product:

Is expected to produce the same clinical result as the reference product
Presents no additional risk when patients switch between products

Interchangeable designation allows pharmacy-level substitution
in the US, subject to state laws.

FDA-Approved Interchangeable Examples

Insulin glargine-yfgn – Semglee
Adalimumab-adbm – Cyltezo

Reference Biologic
Interchangeable
Switching Studies

EMA Perspective on Interchangeability

EMA does not grant an “interchangeable” designation.
Once approved, all EMA biosimilars are considered therapeutically equivalent to their reference products.

Decisions on substitution are made at the member state level, not by EMA.

Comparative Regulatory Summary

Criteria	Reference Biologic	Biosimilar	Interchangeable (US)
Full Clinical Program	Yes	No	No (Additional Switching Data)
Highly Similar	Not Applicable	Yes	Yes
Automatic Substitution	No	No	Yes (US only)
EMA Designation	Yes	Yes	Not Applicable

@credit: Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(2):97-8.

Key Regulatory Takeaway

All interchangeable products are biosimilars, but not all biosimilars are interchangeable.

EMA does not differentiate biosimilars on interchangeability, while the FDA applies a distinct legal designation.