FDA's recent actions indicate a shift in the approval framework for biosimilars, moving toward an emphasis on analytical and pharmacokinetic data while reducing reliance on comparative clinical efficacy studies. In its October 2025 draft guidance, FDA stated that comparative efficacy studies (CES) "may not be necessary" for many therapeutic protein products when analytical characterization, pharmacokinetic similarity, and immunogenicity assessments adequately address residual uncertainty. FDA also noted that modern analytical methods may be more sensitive than clinical trials at detecting differences relevant to biosimilarity. This marks a significant transition, with CES, once the default, potentially now becoming the exception for most therapeutic proteins.

This shift is illustrated by FDA's 2025 decision to waive a clinical efficacy study for a biosimilar referencing Stelara (ustekinumab). Generally, monoclonal antibody biosimilars have included at least one Phase 3 clinical study, but FDA exercised its statutory authority to waive that requirement based on analytical comparability and targeted clinical pharmacology data. While the statute permits FDA to waive evidentiary elements when appropriate, eliminating the need for clinical efficacy comparison, and relying almost solely on physiochemical characterization, may raise scientific issues, particularly for complex biologics.

FDA standards for establishing biosimilar interchangeability with the reference product also continue to evolve. In June 2024, FDA determined that clinical switching studies, once routine for demonstrating interchangeability, are generally no longer needed. FDA has indicated that the same analytical and pharmacokinetic evidence used to support biosimilarity may also be sufficient for interchangeability, further narrowing the practical difference between the two designations.

Recent policy discussions have focused on removing the two-tier structure. Both the prior and current administrations, along with bipartisan members of Congress, have endorsed eliminating the statutory distinction between biosimilars and interchangeables. The FDA Commissioner stated at an October 2025 press conference that FDA is taking a strong stance to advance interchangeability and that "all biosimilars should be interchangeable," and legislative proposals such as the Biosimilar Red Tape Elimination Act reflect this view. Absent new legislation, FDA will continue making case-by-case determinations, but the number and timing of interchangeability designations are expected to increase while the supporting data needed for such a designation is expected to decrease.

The erosion of the distinction between interchangeable and non-interchangeable biosimilars has implications for biosimilar utilization, as many states permit pharmacy-level substitution only when FDA has granted an interchangeability designation.