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  5. Safety Outcomes When “Switching” Between Biosimilars and Reference Products
  1. Spotlight on CDER Science

Safety Outcomes When “Switching” Between Biosimilars and Reference Products

Biological products (biologics) play an important role in clinical care, providing safe and effective treatments for many disorders. They are a diverse category of products that include vaccines, proteins (such as insulins, monoclonal antibodies, and growth factors), as well as blood and blood products.

Biosimilars are biologics that are highly similar to, and without clinically meaningful differences from, a corresponding biologic reference product (an FDA-approved biologic against which a biosimilar is compared). The Biologics Price Competition and Innovation Act of 2009 created an abbreviated regulatory approval pathway for biosimilars. More biosimilars enhance market competition for biologics, which can lead to reduced drug costs and increased treatment availability.

The first biosimilar in the U.S. was approved in 2015. As of November 15, 2023, FDA has approved 44 biosimilars to 14 different reference products that treat conditions such as macular degeneration (a disease affecting vision), rheumatoid arthritis, multiple sclerosis, diabetes, inflammatory bowel disease, and several cancers. Biosimilars can be prescribed for patients who have previously been treated with the reference product (i.e., treatment-experienced), as well as for patients who have not previously received the reference product (i.e., treatment-naïve). Because patients may be switched from a reference product to a biosimilar once it becomes available, FDA would not approve a biosimilar if there were concerns about switching. However, patients and their health care professionals still have reservations about switching a patient to a biosimilar whose condition is stable on the reference product.

For this reason, FDA investigators conducted a systematic review and meta-analysis (the combination of results from two or more studies) using statistical methods to determine whether there were safety outcome differences between individuals who switched between a biosimilar and a reference product and individuals who did not switch. i In particular, the researchers were focused on any statistical differences in the number of deaths, non-fatal serious adverse events, and study discontinuations due to an adverse event. Immunogenicity (the ability to provoke an immune response) events, such as the development of antidrug antibodies and neutralizing antibodies, were also examined and compared following switching.

In their systematic review, the researchers identified previously conducted, randomized controlled studies and extension studies of randomized controlled studies (designed for investigators to observe longer-term effects) that contained a “switch treatment period” (STP). For each STP, individuals were switched to or from a biosimilar and its reference biologic one or more times. The STPs included in the review were required to have a “no-switch” arm (in which participants did not switch between products) to serve as the control. Researchers performed searches of publicly available databases for clinical studies contained in biologics license applications for (ultimately) approved biosimilars, as well as from additional public biomedical literature databases.  

Altogether, the researchers identified 44 STPs that met eligibility criteria from 31 unique studies. All studies included at least one STP during which participants were switched one or more times between a reference biologic and a biosimilar candidate that ultimately received FDA approval. Among the 44 identified STPs, 28 had a single switch and 16 had multiple switches within the STP time period. Altogether, the studies evaluated 21 biosimilars corresponding to eight different reference products. This translates to 5,252 participants who underwent at least one switch and 5,770 individuals who served as no-switch controls.

Safety Comparisons and Conclusions

In the meta-analyses, the researchers found zero difference in the risk of death, serious adverse events, and treatment discontinuations between participants who switched between biosimilars and reference products and participants who did not switch. Immunogenicity data showed similar incidences of antidrug antibodies and neutralizing antibodies in individuals who switched and individuals who did not switch. Immune-related adverse events such as anaphylaxis (severe allergic reactions), hypersensitivity reactions, and injections site reactions were similar in switched and non-switched people.

Based on these data, the researchers concluded that there were no differences in the risk of death, serious adverse events, or treatment discontinuations between the switch and no-switch arms. These results were not affected by the reference product class, the direction of the switch (reference product to biosimilar or vice versa), or the number of switches (single switch vs. multiple switches). These findings are consistent with previously published non-statistical descriptive reviews of switching biosimilars. They provide additional evidence for patients and their health care providers that switching between biosimilars and their reference products is not associated with major safety events.

Additional Resources:

  • iHerndon TM, Ausin C, Brahme NN, Schrieber SJ, Luo M, Andrada FC, Kim C, Sun W, Zhou L, Grosser S, Yim, S, Ricci, MS. Safety outcomes when switching between biosimilars and reference biologics: A systematic review and meta-analysis. 2023. PLoS ONE 18(10): https://doi.org/10.1371/journal.pone.0292231.
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