Submitted: 27 November 2021; Revised: 15 December 2021; Accepted: 15 December 2021; Published online first: 28 December 2021
Biosimilars have been used for 15 years in the European Union (EU). They are able to trigger price competition and reduce costs as well as to increase access to important biological medicines . In spite of the long experience and excellent safety record, many prescribers and other healthcare professionals still have concerns about the quality, safety, efficacy, and especially interchangeability of biosimilars . Systematic clinical switch studies to demonstrate interchangeability of biosimilars are required in some jurisdictions while theoretical considerations and current clinical data question the feasibility and relevance of such studies.
Differences in terminology and regulatory approach hurt biosimilars
In the EU, interchangeability is a scientific and clinical concept meaning that switching between a biosimilar and its reference product does not change the efficacy or safety . Interchangeable products can be switched under the control of the prescriber (physician-led switch) or at the pharmacy without consultation of the prescriber (automatic substitution). Both scenarios are practical applications of interchangeability. Several European national regulatory authorities have issued position papers that endorse physician-led switching . Automatic substitution is a political, administrative, and practical measure that may require changes to the legislation and needs to be adapted to local circumstances.
In the US, interchangeability is regarded as a higher level of biosimilarity that allows automatic substitution. The US Food and Drug Administration (FDA) may grant interchangeable status to already licensed biosimilars if they fulfill the requirements of its interchangeability guideline . The main hurdle is the conduct of a controlled clinical trial consisting of three switches. The switch studies constitute a significant burden to developers and patients. In addition, the results may not give a definite answer . Thus far, the interchangeable status has been granted to only two products by FDA; Semglee (insulin glargine-yfgn) in July 2021 and Cyltezo (adalimumab-adbm) in November 2021.
In spite the fact that switch studies are not required in the EU, the concept a clinical switch study is deeply rooted in the minds of prescribers and policymakers also in the EU, as seen in some position papers of national regulatory authorities and learned societies  and in the hesitance among prescribers . Manufacturers whose old blockbuster products are threatened by biosimilars support requirements for systematic multiple switch studies and even switch studies between biosimilars and repeated demonstration of interchangeability [7-9] – obviously because extensive switch studies discourage biosimilar development. The feasibility of conducting extensive switch studies has been questioned [6, 10]. Moreover, it is difficult to find detailed theoretical justifications and clinical data to support systematic switch studies. Thus, the crucial question is not what kind of comparative switch studies should be done but whether these studies are justified and feasible at all.
The hypothesis of switch-related immunogenicity
Immunogenicity is presented as the risk of switching between a biosimilar and its reference product. The FDA interchangeability guideline states,‘in the context of switching between the products, multiple exposures to each product may potentially prime the immune system to recognize subtle differences in structural features between products’ and‘the overall immune response could be increased under these conditions’ . Some proponents of switch studies explain this hypothesis by the discontinuation theory . Thus,‘subtle’ differences in the structure, notably the glycosylation profiles of active substances of biosimilars and their reference product seem to be a cornerstone for the immunogenicity hypothesis . This theory may be relevant to vaccines that are designed to be‘foreign’ to human immune system and immune response is amplified by adjuvants ― a completely different situation compared to therapeutic proteins that are made highly similar. Thus, this possibility is also highly unlikely after switching between a biosimilar and its reference product that have already been shown to be highly similar and which are expected to have some degree of immunological tolerance due to their resemblance to human proteins .
It is also suggested that exposure to different sets of antigenic epitopes upon switching might enhance anti-drug immunity by epitope spreading. This situation has been observed in epoetin alpha (epoetin-α) products where a poor product formulation or inappropriate storage may lead to cross-reacting neutralizing antibodies to endogenous erythropoietin. The root cause of the induction of neutralizing erythropoietin antibodies is aggregation of proteins in a poor formulation . Thus far, there is no clinical data to support above-mentioned immunogenicity theories in the context of switching between a reference product and its licensed biosimilar version.
Switch-related immunogenicity: a remote risk
Switch-related immunogenicity is often seen as an unpredictable reaction of the immune system. However, the factors triggering of anti-drug immunity are well known. Immune recognition is essential for identifying proteins as‘self’ or‘non-self’. Recognition of the protein as‘non-self’ may be associated with transient or persistent immune reactions. The switching between highly similar versions of the same active substance is not sufficient to break tolerance and to raise persisting and strong T cell-dependent immunogenicity such as affinity maturation, isotype switch or strong recall response due to the identical amino acid sequence and highly similar secondary structure. Differences in glycosylation profiles have never triggered immunogenicity of different versions of therapeutic proteins . Such differences are found after changes in manufacturing process and even between different batches of therapeutic proteins without immunological problems . Studies of originator and biosimilar infliximab and adalimumab support the similarity of important antigenic epitopes in biosimilars and their reference products [14-16].
B cells may be stimulated independently by impurities, such as bacterial endotoxins as well as by degraded and aggregated proteins . Such problems may be due to inappropriate storage or poor formulations, i.e. not due to‘subtle differences’ in the active substances of highly similar products in normal use. These cases, such as the formulation change of originator epoetin-α or one of its biosimilar versions have made developers and regulators very careful in assessing formulations and stability studies of biosimilars . Therefore, it is unlikely that licensed biological products will have immunogenicity triggered by impurities .
The clinical evidence
Review of 178 clinical switch studies of biosimilars and their reference products found no evidence of switch-related adverse effects, including harmful immunogenicity . More recent reviews of newer biosimilars confirm the lack of switch-related adverse effects [19, 20]. From a theoretical perspective, the lack of adverse effects is the expected outcome whereas the hypothesis of switch-related adverse effects is not supported by current evidence [6, 11, 21]. Furthermore, clinical switch studies will not be able to detect potential rare adverse effects. Thus, the risk management of switching should be based on pharmacovigilance and pharmaco-epidemiological studies.
Clinical switch studies: time for a re-evaluation
The concept of systematic switch studies is becoming obsolete, but FDA keeps requiring extensive studies due to US legislation. The innovative industry is promoting even more extensive switch studies due to their commercial interests, experts do not dare to challenge FDA and the existing dogma, and prescribers are confused. Ironically, a similar situation has been described in the old tale‘The Emperor’s New Clothes’ .
The moral of the tale of systematic switch studies is that EU regulators should have the courage to issuing a common position in interchangeability of biosimilars . The message should be that EU-licensed biosimilars are interchangeable with its reference product without systematic clinical switch studies.
No financial support was received for conducting this research.
The opinions expressed in this article are personal views of the author and should not be understood being made on behalf of or reflecting the position of the agencies or organizations with which the author is or has been affiliated.
Competing interests: None.
Provenance and peer review: Not commissioned; externally peer reviewed.
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Author: Adjunct Professor Pekka Kurki, MD, PhD, University of Helsinki, 19 Lukupolku, FI-00680 Helsinki, Finland
Disclosure of Conflict of Interest Statement is available upon request.
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