The Biologics Price Competition and Innovation (BPCI) Act gives FDA the authority to designate a biosimilar as interchangeable with its reference product. This means that the biosimilar may be substituted for the originator product by the pharmacist without reference to the prescribing physician. The criteria for establishing interchangeability of biosimilars, despite FDA issuing three draft guidance documents, are still not clear.

The BPCI Act makes a clear distinction between biosimilarity and interchangeability. In other words, biosimilarity does not imply interchangeability which is much more stringent.

Switching and alternating
Unlike small molecule drug interchangeability (in terms of prescribability and switchability), FDA has a slightly different perception of drug interchangeability for biosimilars. From FDA’s perspectives, interchangeability includes the concept of switching and alternating between an originator biological product (R) and its biosimilar (B).

Study design
For assessment of bioequivalence for chemical drug products, a standard two-sequence, two-period (2 x 2) crossover design is often considered, except for drug products with relatively long half-lives. Currently, approved biosimilars all demonstrated bioequivalence in a crossover design. For monoclonal antibodies and other biological products with relatively long half-lives, it is suggested that a parallel group design should be considered. However, parallel group design does not provide independent estimates of variance components such as inter-subject and intra-subject variabilities and variability due to subject-by-product interaction. Thus, it is a major challenge for assessing biosimilarity and interchangeability (in terms of the concepts of switching and alternating) of biosimilar products under parallel group designs.

In practice, for interchangeability of biosimilars and reference products, it is difficult, if not impossible, to demonstrate the ‘same clinical result in any given patient’. However, it is possible to demonstrate the ‘same clinical result in any given patient with certain assurance’. Under a given study design, the biosimilarity index and/or totality biosimilarity index may be considered to develop an alternating index and/or switching index for addressing interchangeability in terms of alternating and/or switching, although further research is necessary.

Conflict of interest
The authors declared that there were no conflicts of interest.

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Professor Shein-Chung Chow is a member of the International Editorial Advisory Board of GaBI Journal, an expert in bioavailability/biosimilarity and bioequivalence; and is the Guest Editor of the Special Issue (educational editorial series) on ‘Biosimilarity and Interchangeability‘ currently under production by GaBI Journal, contact us for more information on this Special Issue.

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