FDA’s new biosimilar guidance explained: Key changes in reference product requirements

The FDA has issued new draft guidance that clarifies for sponsors when clinical data from non-US-licensed comparator products can be used to support biosimilar marketing applications.¹ This new draft guidance reflects a significant shift in FDA expectations for the data required to bridge between non‑US‑sourced and US‑sourced reference products, and the scientific justification required for bridging studies. 

Here is what you need to know: 

You may now use non-FDA-approved comparators  

Under certain conditions, sponsors may use clinical data from a non-US-licensed comparator product to support biosimilarity. Sponsors must provide adequate scientific justification showing the comparative data is relevant to demonstrating biosimilarity to the US-licensed reference product. Final decisions on data adequacy will be made during 351(k) application review. 

Key requirements  

• All products (proposed biosimilar, US reference, and non-US comparator) are highly purified therapeutic proteins that can be thoroughly characterized with current analytical technologies. 
• The non-US comparator has the same or only minor differences in inactive ingredients compared to the US reference product. 
• Any analytical differences between products will not prevent a biosimilarity conclusion. 

Critical considerations for using non-FDA-approved comparators 

Key determinants of the acceptability non‑US–licensed reference products are the quality system, manufacturing oversight, and the analytical similarity package. It will be critical to perform adequate due diligence on the source of the reference product, ensure a robust clinical comparability program is conducted, and fully justify any differences between the US–licensed and non‑US–licensed reference products as being of no clinical relevance. 

Manufacturing & regulatory standards: 

Non‑US–licensed comparator product may be acceptable only if the product is: 

• Licensed by a regulatory authority with standards comparable to the FDA, and 
• Manufactured under a regulatory system with quality oversight comparable to the FDA 

Analytical assessment 

To establish a CMC bridge between non‑US–licensed and US–licensed comparator product, sponsors will need to: 

• Ensure lots used in clinical studies are also used in comparative analytical assessment 
• Conduct head-to-head comparisons against the non-US comparator lots and US reference product lots 

Referencing publicly available information alone is not sufficient— comparative analytical data must be provided. 

IND requirements 

IND requirements for importing and studying non‑US comparators are: 

• A single IND may include both the proposed biosimilar and the non‑US comparator product 
• Non‑US comparators are treated as investigational drugs in the US and require CMC information or a waiver request 
• Sponsors must supply evidence of foreign regulatory oversight comparable to FDA (e.g., ICH‑aligned authorities) 

Conclusion 

Overall, the new FDA guidance provides more explicit analytical bridging, clearer justification standards, and tighter controls on comparator use in clinical trials intended to support FDA approval.   

The FDA’s change in policy creates additional opportunities for sponsors to streamline their biosimilar development programs for FDA approval. To date, three-way PK studies have been the standard requirement in order to bridge the non-FDA-approved comparator to the US-licensed reference product and the investigational biosimilar. However, such three-way PK studies have been associated with significant supply challenges for sponsors as they have tried to source and import the non-US comparator. With this new FDA policy, biosimilar clinical studies may become less burdensome, and patients can benefit from earlier access to less expensive biologics medicines. 

Nevertheless, while FDA permits the use of comparative clinical data from a non-US-licensed product approach under specific circumstances, robust analytical data and scientific justification are essential. 

Early engagement with FDA is strongly encouraged before conducting studies with non-US comparators.  

With over 20 years of pioneering biosimilar development—our multidisciplinary team of ex-agency and industry experts delivers the integrated CMC, clinical, and regulatory insights that bring complex biosimilar programs to market faster.  

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References 

1. FDA Draft Guidance for Industry, New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 4), March 2026  

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