Submitted: 22 November 2023; Revised: 24 November 2023; Accepted: 27 November 2023; Published online first: 28 November 2023
Biologicals are the fastest-growing class of medications in the United States and account for a substantial and growing portion of healthcare costs. The Biologics Price Competition Act of 2009 created an abbreviated approval pathway for the US Food and Drug Administration (FDA) to help provide patients with greater access to safe and effective biological products. As of 1 November 2023, FDA has approved 44 biosimilar products, 7 of which are interchangeable biosimilars. These products can be used to treat many conditions such as chronic skin and bowel diseases, arthritis, kidney conditions, diabetes, multiple sclerosis, macular degeneration, and cancer.
Despite the rigorous requirements for comparative structural and functional analytical characterization data and one or more clinical studies that demonstrate a proposed biosimilar is highly similar to and has no clinically meaningful differences from the reference product, concerns of immune system mediated safety events associated with switching between biosimilars and their reference products persist.
Switching between biosimilars and reference products has been addressed in FDA guidance [1, 2]. As part of the demonstration of biosimilarity, a clinical immunogenicity assessment is expected to evaluate potential differences in immune responses and in some instances whether a single cross-over from the reference product to the proposed biosimilar would result in a major risk in terms of hypersensitivity, immunogenicity, or other reactions . For interchangeable biosimilars, FDA guidance states that applications generally will include data from a switching study or studies and FDA anticipates that the data will be useful in assessing the risk, in terms of safety and diminished efficacy, of alternating or switching between the products .
Since the publication of these FDA guidances, experience with biosimilars and interchangeable biosimilars has increased considerably. While switching of biosimilars has been addressed in descriptive reviews, statistical methods have not been employed in a definitive fashion. This systematic review and meta-analysis  includes all of the identified randomized studies with one or more switches of biosimilars that were approved by FDA. Randomized controlled studies and their extension studies containing a switch treatment period (STP) to or from a biosimilar and its corresponding reference biological were identified from publicly available information maintained by FDA. These findings were augmented with data from peer-reviewed publications containing information not captured in FDA reviews. Forty-four STPs were identified from 31 unique studies for 21 different biosimilars. Data were extracted and synthesized according to PRISMA guidelines.
Meta-analyses were conducted to estimate the overall risk difference across studies. A total of 5,252 patients who were switched to or from a biosimilar and its reference biological were identified and 5,770 patients who served as no switch controls. Safety data, including deaths, serious adverse events, and treatment discontinuation showed an overall risk difference (95% CI) of -0.00 (-0.00, 0.00), 0.00 (-0.01, 0.01), -0.00 (-0.01, 0.00), respectively, across STPs. Immunogenicity data showed a similar incidence of anti-drug antibodies and neutralizing antibodies in patients within a STP who were switched to or from a biosimilar to its reference biological and patients who were not switched. Immune related adverse events such as anaphylaxis, hypersensitivity reactions, and injections site reactions were similar in switched and non-switched patients.
Safety and immunological concerns with switching between a biosimilar and its reference product, once or multiple times, have not been demonstrated in controlled clinical studies for FDA-approved biosimilars. This work adds to the growing body of evidence that switching between biosimilars and their corresponding reference products has not been associated with a greater risk of immunogenicity or safety concerns and is expected to reassure patients and their care providers. Regulatory recommendations on the need for studies with switches as part of the demonstration of biosimilarity and interchangeability are under review.
Competing interests: The authors of the research paper  declared that there were no conflicts of interest.
Provenance and peer review: Commissioned; internally peer reviewed.
- Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (May 2019) found at: https://www.fda.gov/media/82647/download
- Guidance for Industry: Considerations in Demonstrating Interchangeability with a Reference Product (May 2019) found at: https://www.fda.gov/media/124907/download
- Herndon 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. PLoS One. 2023;18(10):e0292231.
Author: Dr Sarah Schrieber, PharmD, Office of Therapeutic Biologics and Biosimilars, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
Disclosure of Conflict of Interest Statement is available upon request.
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