In May 2019, the FDA released guidance to clarify the level of evidence required from manufacturers to support interchangeability between a biosimilar and the reference product. Section 351(k)(4) of the Public Health Services (PHS) Act defines an interchangeable biologic as a biological product meeting the criteria for biosimilarity to the reference product (being expected to have the same clinical result in any given patient as the reference product), as well as demonstrating that safety and efficacy risks associated with switching between the interchangeable biologic and the reference biologic are no greater than the risks expected with continued use of the reference biologic. Section 351(i)(3) of the PHS Act allows a product deemed interchangeable to be substituted for the reference product without intervention of the prescriber, similar to generic small molecule medications.

Following licensure as a biosimilar, sponsors seeking interchangeability status will need to submit additional evidence for consideration; the guidance indicates that the level of evidence required will vary based on the qualities and use of the product. Generally, the submission will include well-designed, prospective, controlled switching studies, which evaluate 2 or more exposures, alternating between the biosimilar product and the reference product. Pharmacokinetic and pharmacodynamic parameters are recommended to be used as the primary endpoints evaluated, as they may be more sensitive to exposure changes following product switching compared with clinical outcomes. Data related to safety, immunogenicity, and outcomes should be descriptively included as secondary outcomes. The guidance document also details recommendations on trial design, sample size, number and duration of switches, and timing of pharmacokinetic sampling.

The FDA may require additional data, especially for products with complex structures and/or mechanisms, as well as products with immunogenicity concerns. Postmarketing data describing the real-world experience with the biosimilar product is one example of the type of data that could be submitted to support demonstration of interchangeability. The FDA recommends that sponsors meet with the FDA as early as possible in development to discuss switching study design, use of postmarketing data, and overall presentation content.

Once a product has met the requirements for interchangeability for the studied condition, the sponsor may request extrapolation of interchangeability status to one or more of the reference product’s other licensed indications. As a result, we could see biosimilar products that are interchangeable in conditions where they have not been studied.

With the slow uptake in biosimilars to date, a pathway to interchangeable status could provide a boost for this market. The additional data and rigor required to obtain interchangeable status may increase prescriber and patient confidence in these products and result in more existing users transitioning to biosimilars. Additionally, with the prescriber not required to sign off on a switch from reference product to interchangeable product, other stakeholders such as payers and health systems will likely have a greater ability to influence the choice of product. One may conclude that the competition in the biologics market will increase, but it remains to be seen if interchangeable biosimilars will follow the same trajectory as traditional generics in both price and utilization.


United States Food and Drug Administration. Considerations in demonstrating interchangeability with a reference product guidance for industry. Accessed May 31, 2019.