FDA ends interchangeability statement requirement for biosimilar labels

The U.S. Food and Drug Administration (FDA) recently issued new revised draft guidance on “Labeling for Biosimilar and Interchangeable Biosimilar Products,” which most notably dispenses with any recommendation that interchangeable biosimilars include an “interchangeability statement.” Instead, it recommends that biosimilar labeling – interchangeable or otherwise – include a “biosimilarity statement.” As we discuss below, this change may be part of an effort by FDA to place greater reliance on the agency’s Purple Book and to emulate for biologics the agency’s approach to communicating therapeutic equivalence determinations for drugs through the Orange Book. Also, earlier this month, a team within FDA published a journal article reporting the results of a meta-analysis describing risks of switching between biosimilars and their reference products and what that may mean for switching studies as the default approach to support interchangeability. These two developments may not be related, but both are worth watching.

FDA is seeking comments on the draft guidance through November 17, 2023.

The Biologics Price Competition and Innovation Act (BPCIA) defines “interchangeability” as requiring a product to not only be biosimilar to its reference product, but to also be “expected to produce the same clinical result as the reference product in any given patient” and, “if the biological product is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological product and the reference product [must not be] greater than the risk of using the reference product without such alternation or switch.” Interchangeable biosimilars may be eligible for pharmacy-level substitution, subject to state law. The first interchangeable biosimilar version of a reference product benefits from a period of “interchangeable exclusivity” before another biosimilar can receive an interchangeability designation. To date, FDA has approved 43 biosimilar products, including five interchangeable biosimilars.

In September, FDA issued new revised draft guidance on “Labeling for Biosimilar and Interchangeable Biosimilar Products,” updating final guidance from July 2018 and its March 2016 predecessor draft guidance. Most notably, under the revised draft guidance, FDA does not recommend that labeling for interchangeable biosimilar products include an “interchangeability statement”; instead, FDA recommends that labeling for interchangeable biosimilars and non-interchangeable biosimilars both include the same “biosimilarity statement.” Accordingly, FDA also withdrew from an updated draft Q&A guidance on biosimilar development the corresponding question and answer recommending the inclusion of an interchangeability statement in the labeling of interchangeable biosimilars.

The labeling for each interchangeable biosimilar product licensed before issuance of the revised draft guidance includes a prominent statement indicating that the product is interchangeable with the reference product, with a footnote detailing the specific requirements and significance of an interchangeability determination. Under the newly revised draft guidance, interchangeable biosimilar products should include the same statement as all biosimilar products, indicating the product is biosimilar to the reference product, with a footnote detailing the requirements and significance of a finding of biosimilarity. This new policy appears to have been applied to Abrilada™ (adalimumab-afzb), approved October 4, 2023, as an interchangeable biosimilar to Humira (adalimumab).

In the Notice of Availability for the revised draft guidance, FDA suggested that the interchangeability statement was creating confusion for biosimilars stakeholders and a false impression of a separate safety and efficacy standard for interchangeable biosimilars. FDA stated that information about interchangeability is more appropriately located in the Purple Book rather than product labeling because the question of whether a biosimilar is approved as interchangeable is relevant at the point of pharmacy dispensing.

FDA is inviting public comments on the draft guidance with regard to biosimilarity statements, specifically:

  • how useful the inclusion of a biosimilarity statement in biosimilar product labeling has been for HCPs and the public,

  • whether such statements can be improved to provide more clarity on what biosimilarity means, and,

  • whether biosimilar and interchangeable biosimilar product labeling should include such a statement at all.

Aside from the proposal to include only the biosimilarity statement in labeling for interchangeable biosimilars, the revised draft guidance adds explication to the 2018 version of the guidance regarding how:

  • the text of a biosimilar label should reflect current safety and efficacy information and should track the reference product label, but doesn’t need to be identical.

  • “indications and usage” information should be consistent with information on the reference product but specific to the indications for which the biosimilar was approved.

  • clinical data obtained with the reference product can be anonymized with regard to studies in indications for which the biosimilar is not seeking approval.

  • pediatric labeling should state whether clinical trials with pediatric patients were conducted and if they supported the product’s use. The revised draft guidance adds examples of statements on pediatric uses that can be used on biosimilars’ labels.

The revised draft guidance also comes near in time to a journal article by an FDA team, reporting the results of a meta-analysis on the clinical risks associated with switching between biosimilars and their reference products. The paper concluded that its findings “support reducing the regulatory burden of switching studies as the default approach for addressing the switching standard for the interchangeable designation.” The article raised important questions on the role switching studies may have in applications for interchangeable biosimilars, and it remains to be seen if and how the findings will correlate to guidance from FDA on interchangeable biosimilars.

The revised draft guidance and the publication on switching studies bear close watching in the evolving area of interchangeability determinations. Whether or not related, they may suggest an underlying current within the agency around the distinction between biosimilarity and interchangeability. Given the few interchangeability determinations to date, however, little can be said with any certainly about the agency’s broader thinking on these issues.

FDA is seeking comments on the draft guidance through November 17, 2023. If you may want to submit a comment, or have questions on the interchangeability designation or biosimilar labeling more generally, please feel free to contact any of the authors of this alert or the Hogan Lovells attorney with whom you regularly work.


Authored by Philip Katz, Dave Fox, Jason Conaty, and Deborah Cho


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