Submitted: 3 December 2024; Revised: 17 December 2024; Accepted: 18 December 2024; Published online first: 18 December 2024

Letter to the Editor to comment on the article by Reilly MS and McKibbin RD: Misinformation about interchangeable biosimilars undermines US health policy, physician confidence, and patient health.GaBI Journal, 2024;13(2):55-60.

The US Food and Drug Administration (FDA) has updated its guidance on interchangeability [1]. It now states that the risk in terms of safety or diminished efficacy is insignificant following single or multiple switches between a reference product and a biosimilar product. Therefore, it proposes that clinical interchangeability (switch) studies are not required for automatic substitution.  If implemented, the interchangeability designation will become obsolete. Updated guidance is a rational step in the evolution of the biosimilar concept in the USA. It also increases possibilities to harmonize regulatory requirements globally which is necessary to fully exploit the full potential of biosimilars.  Furthermore, the updated guidance will mitigate the confusion and misunderstandings concerning interchangeability among prescribers, patients, and policymakers globally.

The proposed new policy followed a large and thorough review and meta-analysis of safety and immunogenicity switching studies by experts of FDA [2]. The results were in line with several previous reviews of the safety, efficacy, and immunogenicity of switches between originators and their biosimilars.

The article of Reilly and McKibbin [3] representing the lobbying organization Alliance for Safe Biological Medicines presents harsh criticism of the study of FDA experts and opposes proposals to abandon clinical switch studies currently required for interchangeability designation. Their arguments are based on opinions, perceptions, beliefs, and fundamental misunderstandings of the ability of randomized clinical trials to detect differences of proteins shown to be highly similar in terms of structure, function, immunogenicity, efficacy and safety.

Reilly and McKibbin admit that FDA-approved biosimilars are indisputably safe and effective medications and the physician may choose to prescribe either to their patient, whether naïve or stable.  Furthermore, they state that all FDA-approved biosimilars may be substituted in place of the reference product by the physician. Thus, the core of the matter is the passing of prescribers in selection of the brand of therapeutically equivalent products and the removal of clinical switch studies from the FDA guidance. The authors refer to surveys showing that many prescribers are reluctant to switch from originator to its biosimilars. Surveys and opinion polls have also demonstrated that physicians have limited knowledge of the relevant literature and the underlying science as well as of the economic impact of biosimilars. Prescribers’ expectations of the role of randomized clinical trials in the demonstration of potential small differences between biosimilars and originator products are unrealistic.

The authors ignore previous large review articles of clinical switching studies [2]. These studies suggest that single or repeated switches between originators and biosimilars or between biosimilars of the same originator do not have significant adverse effects on efficacy, safety and immunogenicity. Thus, potential switch-related differences are rare or very small after a single or repeated switches.  Randomized clinical trials cannot detect these potential problems.

In 2019, when the first FDA guidance was published, there was limited experiences of repeated switches. As a result, FDA decided to require a clinical study with three consecutive switches to detect a potential immunological boosting effect that could lead to adverse effects. In this context, clinical efficacy endpoints were too insensitive to detect decreased efficacy in a meaningfully sized clinical study. Instead, changes in immunogenicity and pharmacokinetics were used as surrogates for efficacy. However, even with a reasonable sample size, the sensitivity for detecting these changes remained poor [4].

Despite the current understanding of the limitations of randomized clinical switch studies, Reilly and McKibbin argue that, without conducting switching studies, it is unknown whether efficacy diminishes or if side effects arise more frequently following a switch. They also ignore the review and meta-analysis of the FDA experts and previous reviews on the safety, efficacy and immunogenicity of switches. They go even further and complain about the lack of confirmatory studies in different diseases and patient populations. In the absence of clear signals of switch-related adverse effects, these claims are invalid from the scientific and regulatory point of view. Considering the current state of knowledge, continuation or even expansion of the current switch studies would be unethical and an unnecessary burden to patients and industry.

The authors statement that the automatic substitution of biosimilars at the pharmacies in the US would represent a dramatic contrast to European practices is misleading. There is a common scientific definition of interchangeability in the EU that is not in conflict with the prosed guidance of FDA [5]. In contrast, EU Member states have adopted a variety of practical measures that are based on the common scientific definition, such as automatic substitution, regional or national tendering, prescription quotas, and price control according to national legislation and the structure of health care.

Ironically, the title of the article of Reilly and McKibbin is ‘misinformation about interchangeable biosimilars undermines US health policy, physician confidence, and patient health’. I fully agree with this statement.

Funding sources

No funding was received to write this letter.

Disclaimer

The author alone is responsible for the views expressed in this article and they do not necessarily represent the views, decisions or policies of the institutions with which he is affiliated.

Competing interests: The author declares no conflicts of interest.

Provenance and peer review: Not commissioned; internally peer reviewed.

References
1. US Food and Drug Administration. Considerations in demonstrating interchangeability with a reference product: update June 2024 [homepage on the Internet]. [cited 2024 Dec 17]. Available from:https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-demonstrating-interchangeability-reference-product-update
2. Herndon TM, Ausin C, Brahme NN, Schrieber SJ, Luo M, Andrada FC, et al. Safety outcomes when switching between biosimilars and reference biologics: a systematic review and meta-analysis. PLoS ONE. 2023;18(10):e0292231.
3. Reilly MS, Ralph D 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):55-60. doi:5639/gabij.2024.1302.009
4. Alvarez DF, Wolbink G, Cronenberger C, Orazem J, Kay J. Interchangeability of biosimilars: what level of clinical evidence is needed to support the interchangeability designation in the United States? BioDrugs. 2020;34(6):723-32. doi:10.1007/s40259-020-00446-
5. European Medicines Agency. Statement on the scientific rationale supporting interchangeability of biosimilar medicines in the EU [homepage on the Internet]. [cited 2024 Dec 17]. Available from:
https://www.ema.europa.eu/en/documents/public-statement/statement-scientific-rationale-supporting-interchangeability-biosimilar-medicines-eu_en.pdf

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