Latest FDA Updates: Biosimilar Development Guidance

In March 2026, the U.S. Food and Drug Administration (FDA) published a revised draft guidance titled “New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 4)”. The document provides updated regulatory interpretations and practical recommendations related to the development and approval of biosimilars and interchangeable biological products under the abbreviated licensure pathway defined in section 351(k) of the Public Health Service Act.

The guidance forms part of the broader regulatory framework established by the Biologics Price Competition and Innovation Act (BPCI Act), which was enacted in 2010 to enable a streamlined approval pathway for biosimilars. This pathway allows sponsors to demonstrate that their biological product is highly similar to an already approved reference product, without clinically meaningful differences in safety, purity, or potency.

The latest revision introduces updates to several questions and answers that address common challenges faced by biosimilar developers. One of the key clarifications concerns the use of non-U.S.-licensed comparator products in clinical development programs. The FDA confirms that comparative clinical data generated using such products may be acceptable under certain conditions. Sponsors must, however, provide strong scientific justification demonstrating the relevance of the comparator to the U.S.-licensed reference product. This includes analytical evidence that the products are highly comparable and that any differences in formulation or manufacturing do not affect clinical performance.

The guidance also emphasizes the importance of comparative analytical assessment. Sponsors must perform direct comparisons between the proposed biosimilar and the U.S.-licensed reference product, and acceptance criteria for similarity must be derived exclusively from reference product data. Analytical datasets from non-U.S. comparators cannot be combined with reference product data to establish these criteria.

Another important update concerns reserve sample retention for products used in pharmacokinetic (PK) and pharmacodynamic (PD) studies. The FDA recommends that sponsors retain reserve samples of biosimilar candidates and comparator products for at least five years after approval of the biosimilar application - or, if the application is not approved, five years after completion of the relevant clinical studies. These samples allow regulators to verify the identity and integrity of the tested products and support potential follow-up investigations.

The document also reiterates expectations regarding the demonstration of “same strength” for injectable biosimilars. Sponsors should demonstrate that the proposed product has the same total drug substance content and the same concentration as the reference product. For lyophilized products, equivalence in total drug substance content must be shown, while the reconstituted concentration should also match that of the reference product.

Finally, the FDA clarifies regulatory procedures for clinical trials involving non-U.S.-licensed comparator products in the United States. Such products are considered investigational drugs and therefore require an Investigational New Drug (IND) submission. However, sponsors may submit a single IND covering the entire biosimilar development program, including studies involving non-U.S. comparator products.

Overall, the updated guidance is intended to enhance regulatory transparency and provide clearer scientific expectations for biosimilar developers. By addressing practical questions around comparator selection, analytical requirements, and clinical study design, the FDA aims to support efficient biosimilar development while maintaining rigorous standards for product quality, safety, and efficacy. Read the complete document "New and Revised Draft Q&As on Biosimiliar Development and the BPCI Act" on the FDA website.