Study: No Difference Found in Safety of Reference Biologic, Biosimilar


In the first systematic review using statistical methods, investigators found switching from a reference biologic to a biosimilar was comparable in safety, but no conclusion on immunogenicity could be drawn.

In a systematic review published by PLoS One, investigators found no difference in the safety outcomes of patients who switched to a reference biologic or a biosimilar and those who remained on the original drug they were started on.1

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According to an article on Pharmacy Times, there has been confusion around the use of interchangeable biosimilar drugs compared to their reference product. The FDA has stated all biosimilars are already interchangeable for prescribers and the interchangeability label is for legal uses by pharmacies, the authors noted. This has created misperceptions that without the interchangeability designation, biosimilars cannot be switched with the reference product. The authors added that even without the designation, it does not affect the clinical benefits of the drugs for the patients.2

However, some patients and prescribers are still skeptical about the interchangeability of switching from a reference product to a biosimilar and vice versa. Investigators of the current study performed a systematic review using statistical methods to determine the occurrence of various safety events that followed a switch, using all identified controlled clinical studies with a biosimilar approved by the FDA.1

Investigators searched FDA databases with public access for data from January 1, 2000, through December 31, 2022. They used all clinical studies submitted as part of a biologics license application for an approved biosimilar. For information not included in the FDA reviews, investigators used Embase, MEDLINE, and PubMed for additional data.1

There were 21 publications that met the eligibility criteria, which included randomized, double-blinded, controlled studies or open-label extensions of a randomized, double-blinded, controlled study. All studies included at least 1 switch treatment period in which patients were switched 1 or more times between a reference product and the biosimilar candidate. There were 45 switch treatment period in 31 unique studies, according to the study authors.1

There were 8 different reference biologics included in the review, including adalimumab, epoetin-alfa, etanercept, filgrastim, infliximab, insulin-glargine, rituximab, and trastuzumab. The most common switching pattern included 1 switch from the reference biologic to the biosimilar compared to when the reference product was not switched. There were 16 switch treatment periods that had multiple switches, ranging from 3 to 5 switches. Furthermore, a total of 5252 individuals underwent at least 1 switch in the analysis.1

There were 3 safety outcomes evaluated: deaths, serious adverse events (SEAs), and discontinuations. Investigators found that there were 21 deaths out of 5252 individuals in the switch arm compared to 23 out of 5770 in the no switch arm. Additionally, there were 436 and 433 individuals with at least 1 SAE, respectively, and 142 and 160 discontinuations, respectively. The study authors reported that there were no statistically significant increases in the risk of a major safety concern when switching biologics.1

The study authors determined that it was not scientifically appropriate to compare the antidrug antibody levels or the neutralizing antibodies across the biosimilars due to patients maintaining biologic responses and exposure from the reference product prior to switching. They concluded that the safety results were consistent with the current evidence of interchangeability between the reference biologic and the biosimilar drug.1


  1. Herndon TM, Ausin C, Brahme NN, et al. Safety outcomes when switching between biosimilars and reference biologics: a systematic review and meta-analysis. PLoS One. 2023;18(10):e0292231. doi:10.1371/journal.pone.0292231
  2. Park J, Woollett G. Designation of interchangeability (IC) for biosimilars in the US: to be IC or not to IC? that is the question. Pharmacy Times. September 14, 2023. Accessed October 6, 2023.
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