FDA Updates Biosimilar Q&A Draft Guidance

By Suzanne M. Sensabaugh, BS, MS, MBA, EAS Consulting Group Independent Consultant

FDA has released a draft Guidance revising and replacing the New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 3) (September 2021).

FDA’s updated recommendations on how a clinical study comparing the proposed biosimilar with a non-U.S.-licensed comparator product could support a demonstration of biosimilarity to the U.S.-licensed reference product (here termed “the reference products”). Clinical studies include an assessment of pharmacokinetics (PK). Adequate data or information to scientifically justify why such comparative data are relevant to the assessment of biosimilarity needs to be submitted to the FDA for evaluation. Acceptable scientific justification includes:

• The proposed biosimilar product and reference products must be highly purified therapeutic proteins that can be structurally and functionally characterized;
• There should be the same or only minor differences in composition of inactive ingredients in the non- US-licensed reference product that would not be expected to affect clinical performance between the reference products; and
• If any analytical differences are identified in the product quality attributes between the non-US-licensed reference product used in the clinical study and the US-licensed reference product included in the comparative analytical assessment, these differences would not preclude a conclusion that data from a clinical study are relevant to a demonstration of biosimilarity to the US-licensed reference product.

This concept is described further in the FDA Draft Guideline on Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies (October 2025).

Issues that a sponsor may need to address to use a non-U.S.-licensed comparator product in a biosimilar development program include the location of manufacture, facility(ies) inspection(s), offshore licensing, and post-marketing information. In order for the non-US-licensed product to be considered in a biosimilarity program to support approval, the regulatory authority in the country in which the reference product was manufactured, licensed, etc. should have the same scientific and regulatory standards as FDA.

This draft Guidance also provides recommendations regarding the nature and extent of comparative analytical data between the reference products for the comparative analytical assessment. Lots used in a clinical study(ies) should be included in the analytical assessment. If differences are observed between the clinical lots, justification should be provided to scientifically support why these differences do not preclude a conclusion that the data from the clinical study comparing the reference products are relevant to the demonstration of biosimilarity.

The acceptance criteria used to support a demonstration that a proposed biosimilar product is highly similar to the U.S.-licensed reference product should be derived from data generated from a sponsor’s analysis of the U.S.-licensed reference product. The comparative analytical assessment should be based on a direct comparison of the reference products.

Sponsors are encouraged to discuss with FDA any plans to submit and scientifically justify clinical data derived from a non-U.S.-licensed product in support of approval of a biosimilar application as early as feasible during product development. A final decision about the adequacy of the data and information intended to scientifically justify its use will be made during the FDA review process.

FDA is requesting public comment on the usefulness of an analytical comparison between the proposed biosimilar product and the non-U.S.-licensed comparator product as part of the scientific justification to support the relevance of clinical data with a non- U.S.-licensed comparator product to a demonstration of biosimilarity to the U.S.-licensed reference product.