Examining the impact of biosimilar-to-biosimilar transition on effectiveness and safety

KEYWORDS:

• Biosimilars
• cross-switching
• efficacy
• safety

1. Introduction

The treatment of various medical conditions has been entirely revolutionized by biologic medications. However, their high cost was a significant barrier that limited patients’ access to these medication [1], which accelerated the development and approval of biosimilars, bringing them into close alignment with approved biologic therapies [2]. A biosimilar medication is defined by NHS England as ‘a biological medicine which has been shown not to have any clinically meaningful differences from the originator medicine in terms of quality, safety and efficacy’ [3].

Biosimilars reduce healthcare costs by introducing market competition that drives down drug prices and by necessitating fewer expensive clinical trials compared to original biologics, leading to lower development and manufacturing costs [4]. One key reason biosimilars are less costly than their biologic alternatives lies in their expedited regulatory approval processes. Biologic drugs, which are made up of complex biotechnology molecules derived from living organisms, require considerable research and development investment that often spans years and requires significant financial capital to bring to market. As manufacturers seek to recover the significant resources expended during production, their high market prices reflect this lengthy and costly process. Biosimilar drugs do not necessitate as much intensive research and development due to being highly similar to a Food and Drug Administration-approved biologic, therefore decreasing overall costs related to bringing them to market. Since they resemble an already proven and established biologic, their path to market typically involves less extensive trials or research activities, leading to reduced overall development costs of taking biosimilar products to market.

The development of biosimilars necessitates comparability investigations to ensure that there are no clinically meaningful variations between the reference product and the biosimilar in terms of potency, safety, purity, and effectiveness [5]. The U.S. Food and Drug Administration (FDA) states that biosimilars are recognized as safe, efficient, and more affordable treatment options for a range of medical conditions such as ankylosing spondylitis, inflammatory bowel disease, rheumatoid arthritis, plaque psoriasis, type 1 diabetes mellitus, and specific cancer types [6]. With the expansion of the biosimilars market, the demand for a switch from a biosimilar to another (cross-switching) for the purpose of enhancing health outcomes is expected to increase [7,8].

There are several reasons for biosimilar-to-biosimilar transitions. These include availability, cost, and preference. These transitions offer benefits such as maintaining treatment efficacy and potentially reducing costs, compared to reverting to a more expensive reference biologic. The clinical judgments and availability of different biosimilars are the key factors determining the frequency of such switches.

A randomized controlled trial (PLANETAS) conducted on individuals diagnosed with ankylosing spondylitis revealed that transition from the reference drug, infliximab to its biosimilar CT-P13, did not sacrifice efficacy or safety in patients with ankylosing spondylitis. Moreover, CT-P13 demonstrated effectiveness and good tolerability throughout the two-year treatment period [9]. Similar findings were also reported in another randomized controlled trial conducted on patients with rheumatoid arthritis for the same purpose [10].

Although numerous potential biosimilar-to-biosimilar transition scenarios exist, studies on therapeutic exchanges of biosimilars have predominantly focused on a limited number of cases examining immunogenicity, safety, and efficacy [9,10]. Moreover, biosimilars’ long-term data for safety and efficacy are less abundant compared to those available for reference products. Concerns also arise regarding immunogenicity when switching from one biosimilar to another of the same reference product.

In terms of regulatory affairs, United States (US) and European Union (EU) regulations regarding biosimilar development share many similarities but present distinct approaches and requirements that warrant consideration when developing biosimilars. The US FDA emphasizes comparability across parameters, including clinical, pharmacokinetic/pharmacodynamic, biological activity, and has recently initiated a program to create interchangeable biosimilars, requiring further evidence for interchangeability. Conversely, the European Medicines Agency (EMA) uses classification-based guidelines when reviewing biosimilars and has approved their interchangeability with reference medicines, making development and access easier for biosimilars. These variations in regulatory frameworks governing exclusivity periods, assessment fees, and interchangeability criteria significantly affect biosimilar adoption, market penetration, and potential cost savings in healthcare across each region [11].

The current evidence and regulatory approval processes for biosimilars have robustly established their safety and efficacy. This editorial aims to discuss the evidence pertaining to how switching between biosimilars affects efficacy and safety, with highlights for future implications.

2. The current evidence

In regions where biosimilars are accessible, tumor necrosis factor inhibitors (TNFIs) biosimilars are used in the usual protocol of care for patients with rheumatoid arthritis (RA) who are taking biologic disease-modifying antirheumatic medications [12–14]. When contemplating a switch or replacement of treatment for a patient, the decision-making process should rely on the most robust and reliable evidence available [12]. Therefore, it is crucial to ascertain whether switching from the reference product to a biosimilar or undergoing several switches could impact the treatment response or compromise the patient’s safety. It is important to note that the studies that have been conducted are often underpowered to draw definite conclusions.

While there are concerns about switching that may potentially result in heightened immune reactions, diminished efficacy, and increased safety risks, there is currently limited scientific basis to either confirm or deny these concerns [12,15]. A systematic review assessed the effect of switching between biologics and biosimilars of adalimumab, etanercept, and infliximab on efficacy and safety for rheumatoid arthritis and revealed that all trials incorporated in the analysis adopted a transitional study design, involving one switch from a reference biological product to a biosimilar. However, this pattern was not observed in the opposite direction, except for two trials [16]. The study additionally indicated that the collected evidence suggested that switching had no effect on immunogenicity, safety, or efficacy. However, the accuracy of the findings surrounding immunogenicity and safety was constrained, and the follow-up period might be insufficient for a thorough evaluation of long-term safety, especially concerning the risks associated with malignancy [16]. Notwithstanding these results, the study came to the conclusion that it is safe and effective to switch treatments within the class of TNFIs, whether from an original biological product to a biosimilar or inversely. This supports the rationale for the plan of alternating reference biological substances and biosimilar medications for infliximab, etanercept, and adalimumab in RA patients. However, it is significant to note that the data they have does not tackle the situation involving several switches or the issue of transitioning from a biosimilar to another within the exact same original biologic medication [16]. On the other hand, A review study assessed the clinical efficacy and safety of biosimilar-to-biosimilar switch in chronic inflammatory diseases including Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, and psoriasis. It included etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab drugs [17].

The review emphasized that the prevailing body of evidence negates the need for switching studies, given the absence of substantial issues in practice and the presence of stringent regulatory standards. Another review reported that the act of shifting between different biosimilars is both safe and clinically effective, and found no evidence of diminished effectiveness or heightened occurrence of adverse events in studies conducted thus far on biosimilar-to-biosimilar transition [18]. The nocebo response was not mentioned in these reviews.

Feagan and colleagues reviewed the current evidence from trials and real-world studies in the light of three different multiple-switch scenarios currently taking place in clinical practice. They found that the growing practice of switching between originator biologics and biosimilars, including multiple switches and biosimilar-to-biosimilar transitions, lacks robust evidence to fully address concerns regarding efficacy, immunogenicity, and safety [19].

Gasteiger and colleagues conducted a study assessing the confidence level of 142 pharmacists in discussing biosimilars with patients, as well as the type of information they would offer in response to typical questions. The majority of the pharmacists surveyed indicated that they had insufficient knowledge and confidence when it came to explaining the manufacturing processes and testing involved with biosimilars [20]. Another study surveyed patients after pharmacy-mediated replacement of the originator etanercept prefilled syringe with its biosimilar prefilled pen and found that most of the patients who responded to the survey were satisfied [21]. These studies highlight a significant knowledge gap among pharmacists regarding biosimilars, contrasted with generally high patient satisfaction when these alternatives are used, underscoring the need for improved pharmacist education to better support patient care and acceptance of biosimilars.

3. Expert opinion

While current evidence and regulatory standards firmly establish the safety and efficacy of biosimilars, exploring multiple or biosimilar-to-biosimilar transition scenarios is vital for future clinical practices. This exploration aims to understand biosimilars’ performance in a broader range of clinical situations, not to question their established safety or efficacy.

One key finding is the safety and efficacy of switching between reference biologics and biosimilars; however, no comprehensive studies specifically addressing multiple switches between various biosimilars exist, an issue especially pertinent given the growing diversity of available biosimilars as well as likelihood of multiple switches occurring clinically.

Based on the evidence that is currently available, switching from reference biologics to biosimilars and vice versa is safe and does not affect efficacy. Despite the predominant use of single-switch designs in most analyzed studies, the imprecise nature of immunogenicity and safety results, and the lack of long-term safety data for biosimilar-to-biosimilar transition, numerous studies consistently report comparable safety and efficacy outcomes in the transition from originators to biosimilars. This positive trend in findings has bolstered the acceptance of biosimilars among clinicians, leading to swift adoption in various countries and yielding significant cost savings.

Given that current evidence supports the safety and effectiveness of switching between various biosimilars, with no reported increased risk of immunogenicity or other concerns, clinicians could consider such transitions with close patient monitoring for any signs of side effects. Moreover, the competitive dynamics among biosimilars, leading to reduced prices, may result in patients being switched not only from the reference compound to a biosimilar but also between multiple biosimilars [15].

However, the existing systems for developing and approving biosimilars exhibit several gaps that need addressing to enhance confidence in these agents and meet clinical demands. These gaps include the complexity of comparing biosimilars due to the variety of single-switch study designs, the evolving and diverse clinical scenarios encountered in real-world practice that expose shortcomings in current research, the lack of long-term data supporting biosimilars in comparison to original compounds, and the time required to detect the development of antidrug antibodies (immunogenicity).Therefore, in future research evaluating the effects of treatment switching, these gaps should be targeted and addressed in ways that take into account crucial factors of accuracy and reliability.

An area of particular interest is the integration of real-world evidence from extensive healthcare databases. This approach can provide a broader perspective on biosimilar switching practices across different healthcare settings and patient populations, offering insights that are not always feasible in controlled trial environments.

4. Conclusion

Current studies assessing biosimilar-to-biosimilar transition, which mainly examine single switch scenarios, indicates that such practices are generally safe and do not compromise efficacy. However, more extensive research needs to be conducted in order to address certain gaps such as long-term safety data requirements, diverse study designs and possible immunogenicity concerns in multiple switch situations. Moving forward, real world evidence could offer better insight into biosimilar cross-switching in various clinical settings as biosimilar technology evolves; ultimately guiding clinical decisions for optimal patient outcomes in an age of biosimilars.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors have contributed equally to the study design development, data extraction, manuscript drafting and reviewing

Additional information

Funding

The paper was not funded.