As of 23 July 2024, FDA has approved 56 biosimilar products [2], a significant milestone in the landscape of biologicals, targeting 17 different reference products. Out of these, 13 have been approved as interchangeable, indicating their high level of similarity and clinical effectiveness compared to their reference products, see Table 1. With over 38 biosimilars already in the market, these products are not only expanding treatment options but also significantly driving down healthcare costs.

The economic and therapeutic impact of biosimilars
Since their introduction in 2015, biosimilars have generated substantial savings, amounting to US$23.6 billion in the US healthcare system. These savings are a direct result of biosimilar competition, which has led to lower prices for both biosimilars and their reference products. Additionally, biosimilars have been used in more than 694 million days of patient therapy, providing an additional 344 million incremental days of therapy. This expansion in therapy days demonstrates the pivotal role biosimilars play in enhancing patient access to essential medications.

The role of interchangeable biosimilars
An interchangeable biosimilar product is a designation available in the US. A biosimilar approved with an interchangeable status can be substituted for the reference product at pharmacies without the intervention of the prescribing healthcare provider, subject to state pharmacy laws.

This feature facilitates easier access for patients, potentially improving adherence to treatment regimens and outcomes. However, not all biosimilars are requested for interchangeable status; companies can choose to seek approval either as a biosimilar or as an interchangeable biosimilar.

Evaluating the need for switching studies/Reduce clinical data
Past data have shown that safety and immunological concerns about switching between a biosimilar and its reference product – whether once or multiple times – have not been demonstrated in controlled clinical studies for FDA-approved biosimilars [3].

FDA is seeking to improve the efficiency of biosimilar and interchangeable biosimilar development involves by balancing current expectations for 351(k) Biologics License Applications (BLAs) with efforts to reduce the scope of clinical studies [4]. 

The goal is to develop alternatives to or minimize the size of human subject studies by increasing reliance on analytical data to demonstrate biosimilarity. This approach enhances the role of clinical efficacy studies in supporting biosimilarity and emphasizes ‘switching studies’ to validate interchangeability. By refining these processes, the development of biosimilars can become more streamlined and cost-effective while maintaining rigorous safety and efficacy standards.

However, some are concerned that removing the interchangeable designation could jeopardize physician confidence and patient health regarding biosimilars [5]. They argue that the US interchangeable standard has helped drive physician and patient confidence and uptake of biosimilars, and advocate for preserving this standard [6].

FDA’s 2025 Fiscal Year legislative proposal
One of the goals in the FDA’s FY 2025 proposal is to eliminate the statutory distinction between the approval standards for biosimilar and interchangeable biosimilar products and to deem that approved biosimilars as interchangeable. The reasons are as follows:

• To avoid confusion or misunderstanding among patients and healthcare providers about the safety and efficacy of biosimilars and whether they are less safe and effective than interchangeable biosimilars
• To align the US biosimilar programme more closely with current scientific understanding and global regulatory approach, including those of the European Union
• To potentially increase uptake of biosimilars, as well as competition, access, and affordability

In June 2024, FDA issued a draft guidance for industry ‘Considerations for Demonstrating Interchangeability with a Reference Product: Update’. This draft seeks comments on a revised approach in which such studies will generally not be required [7].

*M. Stacey Ricci, MEng, ScD, Director, Scientific Review Staff, Office of Therapeutic Biologics and Biosimilars | OND |CDER, US FDA

Related articles
FDA issues draft guidance on biosimilars and interchangeable biosimilars labelling

An update on the joint EMA-HMA statement on interchangeability of biosimilar

References
1. 20th Biosimilars Medicines Conference, April 2024 Medicines for Europe. Enhancing Efficiency of Biosimilar Development. M Stacey Ricci.
2. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in the   US [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2024 Jul 30]. Available from: www.gabionline.net/biosimilars/general/biosimilars-approved-in-the-us
3. GaBI Online - Generics and Biosimilars Initiative. Switches between biosimilars and their reference products [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2024 Jul 30]. Available from: www.gabi-journal.net/switches-between-biosimilars-and-their-reference-products.html
4. GaBI Online - Generics and Biosimilars Initiative. FDA proposal to remove biosimilar interchangeability status in FY25 [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2024 Jul 30]. Available from: www.gabionline.net/policies-legislation/fda-proposal-to-remove-biosimilar-interchangeability-status-in-fy25
5. Reilly MS, McKibbin RD. Misinformation about interchangeable biosimilars undermines US health policy, physician confidence, and patient health. Generics and Biosimilars Initiative Journal (GaBI Journal). 2024;13(2): Epub ahead of print.
6. Reilly MS. Preserve the US interchangeable standard that has helped drive physician and patient confidence in biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2024;13(1): Epub ahead of print.
7. GaBI Online - Generics and Biosimilars Initiative. FDA interchangeable biosimilars guidance update on revised approach to switching studies [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2024 Jul 30]. Available from: www.gabionline.net/guidelines/fda-interchangeable-biosimilars-guidance-update-on-revised-approach-to-switching-studies 

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