1 Introduction
A biosimilar is a biologic medicine that is highly similar to a reference biologic (reference medicine) with no clinically meaningful differences in structure, biologic activity, efficacy, safety, or immunogenicity profiles [
1,
2]. Establishing biosimilarity with a reference biologic entails extensive structural and functional characterization, in vivo non-clinical assessments (if required by the regulatory agency), and clinical pharmacology studies [
3]. Following the approval of the first biosimilar in 2006 (somatropin [Omnitrope
®, Sandoz GmbH, Kundl, Austria]), as of the end of December 2021, the European Medicines Agency has recommended the approval of 84 biosimilars [
4]. By the end of December 2021, the United States (US) Food and Drug Administration (FDA) had approved 33 biosimilars since the approval of the first biosimilar in 2015 (filgrastim [Zarxio
®, Sandoz, Princeton, NJ, USA]) [
5‐
7]. The first biosimilars were small therapeutic proteins, such as hormones (somatropin and insulin glargine) and growth factors (filgrastim and epoetin). In recent years, complex biosimilars (monoclonal antibodies and fusion proteins) have been licensed globally for rheumatology, dermatology, gastroenterology, and hematology (cancer and nephrology) [
5].
In 2019, 27% of all novel cancer therapies approved in the European Union (EU), US, and Japan were biologics [
8], and numerous high-value biological drugs are coming off-patent within the next 5 years [
7,
9], highlighting a growing potential for future biosimilar development. Currently, clinical experience with biosimilars exceeds 2 billion patient-days, indicating an increase in global biosimilar adoption [
7,
10]. A biosimilar is commonly less expensive than the reference biologic, and therefore may increase patient access to effective treatments [
10‐
12]. By substituting biosimilars for reference biologics, the cost of high-priced medications used to treat diseases, such as cancer and rheumatoid arthritis (RA), might be reduced by $38.4 billion, or 5.9% of predicted total US biologics expenditure from 2021 to 2025 [
13]. Increasing real-world clinical data boost confidence in the use of biosimilars [
5,
10,
14], although there may be concerns about biosimilar use. For instance, clinicians and patients may mistakenly perceive that biosimilars have more adverse effects and less effectiveness than reference biologics due to lower costs and a different clinical development paradigm [
8]. Moreover, according to a US survey, 70% of cancer patients are unaware of biosimilars [
8]. The scientific literature available on the topic and educational materials provided by organizations and health authorities, including the American Society of Clinical Oncology and the European Society of Medical Oncology, are addressing these perceptions and misinformation and hopefully will have a meaningful impact [
8,
15‐
19].
Transitions from a reference biologic to a biosimilar, or from one biosimilar to another, are often the consequence of insurance mandates and/or pharmacy benefit managers implementing formulary adjustments or limitations to reduce costs [
20]. Patients might also transition between products if they relocate to a new region with different drug coverage (or if they are traveling). In a review published in 2017 of post-approval safety data of biosimilars and in a subsequent review published in 2021 of the safety, immunogenicity, and interchangeability of biosimilar monoclonal antibodies and fusion proteins, several individual members of European health authorities concluded that EU-licensed biosimilars should be regarded as interchangeable [
21,
22]. The authors also emphasized that transitioning between a reference biologic and its biosimilar will neither induce nor enhance immunogenicity [
21]. Based on evidence from 90 studies, including seven molecular entities, 14 indications, and 14,225 participants, a systematic review demonstrated that patients switching from reference biologics to biosimilars had no change in safety, efficacy, or immunogenicity [
14]. In another systematic analysis conducted 2.5 years later that analyzed data from 178 trials that collectively enrolled > 21,000 participants (randomized controlled studies and real-world evidence), Barbier and colleagues concluded that existing data do not indicate any major efficacy, safety, or immunogenicity concerns regarding switching from reference biologics to biosimilars [
5].
The possibility of multiple switches between biosimilars of the same reference biologic is already a reality, and these types of switches are expected to become more common in the future. Mysler and colleagues have reviewed all possible switching permutations in a multi-source environment when multiple biosimilars are available for a given reference biologic [
23]. They propose using the term ‘cross-switching’ to describe switching between biosimilars to the same reference biologic. However, this is a new term that is not intuitive, and it does not have a regulatory basis. It is preferable instead to use the term ‘biosimilar-to-biosimilar switching’ as it is unambiguous and precisely describes the nature of the switch.
While switching from a reference biologic to a biosimilar may be studied in a randomized clinical trial environment, biosimilar-to-biosimilar switching is most likely to be evaluated in real-world settings, including observational studies and registries [
23‐
25]. Based on the structural similarities of existing biosimilars, transitioning from one biosimilar to another of the same reference biologic would not be expected to lead to changes in clinical or immunologic responses. Nonetheless, evidence is required to support this expectation. A single literature review on the topic has been published, but it was not conducted in a systematic manner consistent with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology; in addition, this prior review identified only seven studies to assess [
23]. Here, an extensive systematic review was performed of published biosimilar-to-biosimilar switch studies, identifying 23 studies that met criteria for inclusion and analysis; two use-pattern studies and one case report are also discussed because it is believed that they also provide useful information.
2 Methods
2.1 Data Sources and Search Strategy
The search strategy was developed based on the research question (biosimilar-to-biosimilar switching), employing controlled vocabulary specific to each database and free text. As a starting point, hand searching was performed for biosimilar-to-biosimilar switching studies, and after reading the identified articles, the following free-text terms based on the research question were also incorporated in the search string: switching between two different biosimilars, biosimilar-to-biosimilar switch(es), cross‑switch, double biosimilar switch, double-switching, multiple switches, single- or double-switch, successive switches to different biosimilars, switching from one biosimilar to another, second switch, switching between adalimumab/etanercept/filgrastim/infliximab/insulin/pegfilgrastim/rituximab/somatropin/terapatide biosimilars.
A systematic search was undertaken using the following electronic databases (to the end of December 2021): Biosis, Embase, MEDLINE, and EBM Reviews/Cochrane Database of Systematic Reviews via Ovid. The Medical Subject Heading (MeSH) ‘biosimilar pharmaceuticals’ OR ‘biologic factors’ was used. A biologic medication was included if a biosimilar version of the reference medicine was approved in the US or the EU. In addition, MeSH keywords were included for all smaller and bigger protein biologics (erythropoietin, human growth hormone, filgrastim, etanercept, adalimumab, infliximab, and rituximab).
2.2 Study Selection
Publications were evaluated for effectiveness or safety data linked to switching from one biosimilar to another. The inclusion criteria were kept wide to collect as much accessible data on biosimilar-to-biosimilar switching as possible. Non-English publications, non-human research, editorials, comments, and brief surveys were excluded. Literature specialists conducted the literature search and screened the results retrieved via the electronic databases. Screening was based on reading the titles and abstracts of publications and included all results that mentioned biosimilar-to-biosimilar switching. Screening results were reviewed by a subject matter expert (HC) who recommended exclusion or inclusion of a publication based on the research question. Based on his knowledge of the literature, he also had the ability to recommend inclusion of additional studies. These recommendations were then checked by another subject matter expert (SH). In the event that the two experts disagreed, a third subject matter expert (WB) reviewed the conflict and made the final decision regarding whether or not to include/exclude a publication. Peer-reviewed and published case reports were excluded from consideration as a ‘study,’ but were included in the discussion because they provided useful information. Studies that were published in multiple abstracts were only considered once, so a given data set was not duplicated. Likewise, if a study was published as an abstract and subsequently published as a full peer-reviewed publication, only the peer-reviewed publication was included.
Data were collected from the full-text publications relevant to biosimilar-to-biosimilar switch, including trial design, patient demographics, safety, effectiveness, immunogenicity, and adverse events (AEs). Data were then imported into MS Excel, which was then validated by other researchers (SH and WB). Citation of a full-text publication that included all study data was favored over previously published abstracts. A cross-study quality evaluation was not performed due to the diversity of individual studies.
The objective of these analyses was to evaluate clinical outcomes from studies relevant to biosimilar-to-biosimilar switching. All endpoints were reported in a descriptive manner; no meta-analysis was performed because of varying study designs, endpoints, and statistical methodologies used in the selected studies.
4 Discussion
Because of the availability of encouraging evidence on the safety and effectiveness of transitioning patients from reference biologics to biosimilars [
5,
14,
26,
51], clinicians are becoming more confident about this scenario. There is a paucity of data, however, on switching between biosimilars of the same reference biologic. The primary sources of information for understanding biosimilar-to-biosimilar switches are observational studies and registry data. Randomized controlled trials (RCTs) are not practical; devices would have to be comparable to avoid a nocebo effect, and such research would be costly [
52,
53]. Fortunately, data from a wide variety of settings on biosimilar-to-biosimilar switching are beginning to emerge and are the focus of this systematic review. The current examination of literature on this topic revealed 23 observational studies that included 3657 patients; two use-pattern studies and one case report have also been reported on the topic. The present systematic analysis indicates there were no clinically meaningful differences in safety or effectiveness up to 12 months between two biosimilars of the same reference biologic for infliximab, adalimumab, etanercept, or rituximab in studies conducted to date. These findings may help clinicians feel more confident about switching patients between two biosimilars of the same reference biologic.
Existing regulatory frameworks for development and approval of biosimilars all focus on comparisons of the proposed biosimilar and their corresponding reference biologic. To the best of our knowledge, there are no regulations or guidance anywhere in the world that discuss the option of biosimilar-to-biosimilar switching. Indeed, it would not be practical to mandate such studies, and if such studies were conducted the sheer number of studies would strain regulatory resources. Further considering the value of randomized clinical trials in the development of biosimilars, evidence has accumulated that phase 3-style efficacy and safety studies rarely contribute pivotal data to the totality of data supporting initial approval [
54‐
56]. Likewise, analysis of the data from the studies identified in this systematic review clearly reveals that meaningful data on biosimilar-to-biosimilar switching can be obtained without the need for RCTs.
4.1 Immunogenicity
At present, immunogenicity is an important consideration when switching from a reference biologic to a biosimilar or between two biosimilars of the same reference biologic [
41]. It is well established that the presence of ADAs to biologic therapies may result in a reduction in trough-serum drug levels, a decrease in therapeutic response, and at times an increase in AEs. Because infliximab is one of the most immunogenic biologic treatments, preventing immunogenicity and managing its side effects is a major concern for physicians. However, consecutive use of two biosimilars of infliximab did not result in an increased risk of immunogenicity in comparison with that observed in trials that focused on the use of a single biosimilar alone [
41].
Studies of the antigenic response to CT-P13 and infliximab originator in IBD patients showed similar epitope recognition [
57]. Another study of epitope recognition revealed that the adalimumab biosimilar SB5 showed cross-immunogenicity to the adalimumab reference biologic but not to infliximab in IBD and RA patients [
58].
In addition, cross-immunogenicity among infliximab biosimilars was observed in two studies, both of which examined immunogenicity and cross-reactivity across biosimilars [
59,
60]. In the first study, serum samples taken from IBD patients receiving infliximab reference biologic or biosimilar CT-P13 were examined for ADAs to the reference biologic, CT-P13, or SB2 [
23,
60]. The anti–reference-infliximab and anti–CT-P13 sera were tested for cross-reactivity using an enzyme-linked immunosorbent assay customized for reference infliximab [
23,
60]. Anti–reference-infliximab and anti–CT-P13 sera cross-reacted with reference infliximab, as well as the biosimilars CT-P13 or SB2, demonstrating immunogenic similarities [
23,
60]. In the event of an immune response to reference infliximab or an infliximab biosimilar, the study underlined the ineffectiveness of biosimilar cross-switching [
23]. In vitro evidence of complete cross-reactivity also supports the safety of cross-switching [
23]. The second study in patients with IBD showed that antibodies to biosimilar infliximab reacted identically to the reference infliximab and the two approved biosimilar molecules; these findings support safe switching between CT-P13 and SB2 biosimilars, and that switching between biosimilars and reference biologics will not result in differences in the production of antibodies to infliximab [
59].
4.2 Case Report
Pagnini and colleagues described an IBD patient who developed PsO after an infliximab biosimilar-to-infliximab biosimilar switch, which then resolved after reverting to the first biosimilar [
61]. A close examination of this case raises questions about the attribution of PsO exacerbation to the second infliximab biosimilar, because the induction or exacerbation of PsO during anti-TNFα therapy in IBD patients is well known and is already described as a common AE in product labeling. A systematic literature review of such cases based on 222 cases revealed that the mean latency time between initiation of anti-TNFα therapy and onset of the psoriatic lesions was 13.8 months [
62], which is close to that observed by Pagnini et al. in their case report [
61].
4.3 Use-Pattern Studies
Many healthcare systems, at both country and commercial organization levels (e.g., a healthcare maintenance organization), utilize tender processes for selection of biologic drugs, whereby the reference biologic and biosimilar companies submit competitive bids for a given contract that is in place for a set period of time. Healthcare systems have used tenders to select infliximabs, adalimumabs, etanercepts, filgrastims, and other biologics. When multiple biosimilars are available for a given reference biologic, it is possible that patients may be switched from one biosimilar to another based on the sequence of biologic drugs selected. Use-pattern studies can document these occurrences. We found two examples of use-pattern studies in the literature, but it is likely that this has occurred elsewhere as well. Use-pattern studies were not included in our results because they do not provide effectiveness or safety data, although these two publications provide the first published documentation that wide-scale biosimilar-to-biosimilar switching is already occurring in some real-world settings.
Kozlowski et al. described the uptake and use patterns of biosimilar infliximab in the US Medicare system from July 1, 2016 to December 31, 2018 [
63]. While most patients during this time interval received reference infliximab, the authors found that 201 patients who received infliximab-abda during this interval had previously received infliximab-dyyb. This study did not include safety or effectiveness data [
63]. Johnson et al. reported infliximab use patterns in the US VA healthcare system from January 1, 2016 to December 31, 2019 [
64]. The VA is among the largest fully integrated healthcare system in the US and selects drugs for inclusion in a national VA formulary [
64]. One biosimilar, infliximab-dyyb, was preferred by the VA national formulary from May 2017 to September 2018, after which the VA national formulary switched to preferring a second biosimilar infliximab (infliximab-abda) [
64]. During the time window of May 2017 to August 2018, 30–50% of patients received infliximab-dyyb [
64]. At the next time interval, from September 2018 to December 2019, 60% of patients already treated with either reference infliximab or infliximab-dyyb received infliximab-abda. While exact numbers are not provided in this publication, in a separate analysis of the same database, Cunningham et al. identified 607 patients who were switched from infliximab-dyyb to infliximab-abda [
43].
These studies illustrate that biosimilar-to-biosimilar switches are already happening on a large scale. However, further conclusions regarding safety or effectiveness cannot be drawn from these use-pattern data or case reports without further epidemiological and statistically validated investigation.
4.4 Education
Patient education continues to be critical in helping patients build a strong relationship with their physician [
25]. Improved medication adherence in patients with IBD has been shown to benefit from shared decision-making, demonstrating the importance of providing quality information to patients [
25]. Many, if not most, patients would consider the use of a biosimilar if they were educated in a systematic way, and if biosimilars had the same clinical profile as reference medicines [
25]. Indeed, patient education is also key to help minimize a potential nocebo effect. The nocebo effect is described as the incitation or exacerbation of symptoms generated by any unfavorable attitude resulting from non-pharmacologic therapeutic intervention, sham treatment, or active therapy [
53]. When a patient expects a negative impact connected with an intervention, medicine, or medication change, they may either suffer an increase in the severity of the effect or experience the effect for the first time, depending on the situation [
53]. Given the crucial role that biosimilars play in delivering cost-effective alternatives to reference biologics, expanding physician treatment choices, and providing patients with access to effective biologic therapy, it is critical that a nocebo effect is recognized and measures are taken to decrease it wherever feasible [
53].
In addition, nurses play an important role in the community as the healthcare professionals (HCPs) primarily delivering therapies to patients, monitoring them frequently while they are undergoing treatment, and spending the most time with patients [
65]. Nurses regularly rank as the most trusted group of HCPs. As a result, they are often asked questions regarding medicines by patients and therefore play a unique role in offering essential information to patients. Nurses also have the potential to influence biosimilar adoption, especially in terms of patient education, as a result of their frequent contact with patients. It is therefore essential for nurses to understand biosimilar medicines and their regulatory status in order to convey their effectiveness, safety, and possible advantages to patients correctly [
65].
Lastly, when considering education, clinical pharmacists have a broad understanding of the clinical, logistical, and supply chain aspects of biosimilars; thus, they can also be valuable assets in educating stakeholders, such as prescribers, formulary committee members, other pharmacists, nurses, administrative personnel, and patients, around biosimilars in an effort to improve access and rational usage [
66].
4.5 Limitations
The current systematic review has several limitations. Conclusions about biosimilar-to-biosimilar switches for those biosimilars for which there are currently only one or two such studies should be made with caution. Another limitation is that all studies were observational in nature, with varying outcome assessments, a lack of appropriate controls, and an absence of long-term effects of biosimilar-to-biosimilar switching. Additionally, the inclusion of conference abstracts may be seen as a constraint. Abstracts often do not provide sufficient detail about methodology and findings to allow assessment for scientific rigor. Also, conference abstracts may contain preliminary/interim data, and they do not always undergo peer review. Nonetheless, given that biosimilar-to-biosimilar switching is a relatively new phenomenon with a significant amount of meaningful data available in abstract form only, abstracts were included in this review in an attempt to gather all available data while being open about the source. Since observational studies are by nature subjective, there is risk of individual researcher bias. Finally, use-pattern studies do not provide safety or efficacy data related to biosimilar-to-biosimilar switching, but only document that this practice is occurring in a real-world setting.
It should be noted that since biosimilar-to-biosimilar switching is already occurring in some settings, additional data on this topic will likely become available in the future. Nonetheless, given that it is a current topic of interest to HCPs, their patients, and healthcare systems, it is useful to collate and evaluate existing data even while acknowledging that additional data will likely become available in the future.
5 Conclusions
Economic considerations, formulary decisions, and relocation or travel can motivate switching between two biosimilars of the same reference biologic. Lower medication costs can translate into increased access to high-cost therapies for a greater percentage of patients. Thus, proof that biosimilars from the same reference biologic are equivalent in terms of effectiveness and safety is required to support switching between biosimilars of the same reference biologic.
Data from the literature provided in this systematic review suggest that switching between two biosimilars of the same reference biologic is a safe and effective clinical practice, although it is not covered by current health authority regulations or guidance. No reduction in effectiveness or increase in AEs was detected in biosimilar-to-biosimilar switching studies conducted to date, although there are limitations in the individual studies included in the current analysis. As is the case with all biologic drugs, ongoing pharmacovigilance is essential to detect uncommon AEs and unanticipated changes in effectiveness or safety profiles that may arise as a result of modifications in the manufacturing process. Comprehensive pharmacovigilance of all biosimilars should improve patient, HCP, and public trust in biosimilars, resulting in increased adoption of these medications with the economic and access advantages that they can bring.
Declarations
Conflict of interest
AB has served as a speaker for AbbVie, Leo, and UCB as well as a scientific adviser and/or clinical study investigator for AbbVie, Abcentra, Aligos, Almirall, Amgen, Arcutis, Arena, Aslan, Athenex, Boehringer Ingelheim, Bristol-Myers Squibb, Dermavant, EcoR1, Eli Lilly and Company, Evommune, Forte, Galderma, Incyte, Janssen, Landos, Leo, Novartis, Pfizer, Rapt, Regeneron, Sanofi Genzyme, Sun Pharma, UCB Pharma, Vibliome, and Xencor. SD has served as a speaker, consultant and an advisory board member for AbbVie, Allergan, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Hospira, Johnson & Johnson, Merck-Serono, Merck Sharp and Dohme, Takeda, Mundipharma, Pfizer, Sandoz, Tigenix, UCB Pharma, and Vifor. TKK has received fees for speaking from Amgen, Celltrion, Egis, Evapharma, Ewopharma, Hikma, Oktal, Sandoz, and Sanofi. He received consulting fees from AbbVie, Amgen, Biogen, Celltrion, Eli Lilly, Gilead, Janssen, Mylan, Novartis, Pfizer, Sandoz, and Sanofi. Research funding for Diakonhjemmet Hospital was provided from AbbVie, Amgen, BMS, MSD, Novartis, Pfizer, and UCB. HC is an employee of Sandoz Inc., a division of Novartis. He may own stock in Novartis. SH and WB are employees of Sandoz Biopharmaceuticals GmBH, a division of Novartis. They may own stock in Novartis. Sandoz manufactures and markets multiple biosimilars worldwide, including several discussed in this publication.