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Review: FDA Should Reconsider Interchangeability Requirements


Researchers contend the "totality of evidence" for biosimilar approval may be sufficient to demonstrate interchangeability.

A group of researchers from the biosimilar industry and academia have recommended in a review that the FDA widen the scope of acceptable studies for determining interchangeable status for biosimilars.

Interchangeability is a status that would enable pharmacists to make an automatic switch from reference product to biosimilar at the prescription counter without doctor consultation. No biosimilars have yet met the requirements for this designation, although interchangeability is considered important for the uptake of biosimilars and potential savings.

For biosimilars to meet the requirements for interchangeability, they must be shown to produce the same clinical result as the reference product and pose no greater risks of diminished efficacy than if patients remained on the reference product.

Challenges of PK Parameters

The authors, who include Pfizer employees, argue that use of pharmacokinetic (PK) parameters for evaluating potential differences in immunogenicity between reference and biosimilar products is challenging and that interchangeability should be “assessed on a case by case basis, considering the ‘totality of the evidence’ and biologic plausibility.

“Alternative approaches to statistical analysis (eg, use of asymmetric rather than symmetric margins to test equivalence) and study designs that meet the FDA’s expectations for demonstration of interchangeability should be considered,” they wrote.

The authors contend that interchangeability studies as required by the FDA are complicated and are not required by European regulatory authorities. “Without requiring additional clinical studies, individual national authorities in the European Union may endorse the switching from 1 reference or biosimilar product to another at the pharmacy level without consent of the prescriber,” they said.

“By definition, the biosimilar has already been deemed by the FDA not to be clinically different from the reference product. As such, there is little reason to expect altered PK, heightened immunogenicity response, increased safety risk, or improved or diminished efficacy in patients who switch back and forth from a reference product to the corresponding biosimilar.”

One reason the FDA has given for requiring immunogenicity studies is to demonstrate, beyond the existing body of evidence on biosimilar efficacy and safety, that multiple switches between reference and biosimilar drugs would not result in a different outcome; however, the authors contend that the “perceived drawback of multiple switching…is based on theoretical concerns and experience with switches between one biologic product and another that is different, and not its biosimilar.”

“There is a low likelihood that the incidence, titers, or specificity of antidrug antibodies will increase or change as a result of multiple switches between a reference product and its biosimilar,” the authors wrote.


Alvarez DF, Wolbink G, Cronenberger C, Orazem J, Kay J. Interchangeability of biosimilars: what level of clinical evidence is needed to support the interchangeability designation in the United States? BioDrugs. Published online September 29, 2020. doi:10.1007/s40259-020-00446-7

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