Abstract
Background
The efficacy, safety and immunogenicity risk of switching between an originator biologic and a biosimilar or from one biosimilar to another are of potential concern.
Objectives
The aim was to conduct a systematic literature review of the outcomes of switching between biologics and their biosimilars and identify any evidence gaps.
Methods
A systematic literature search was conducted in PubMed, EMBASE and Cochrane Library from inception to June 2017. Relevant societal meetings were also checked. Peer-reviewed studies reporting efficacy and/or safety data on switching between originator and biosimilar products or from one biosimilar to another were selected. Studies with fewer than 20 switched patients were excluded. Data were extracted on interventions, study population, reason for treatment switching, efficacy outcomes, safety and anti-drug antibodies.
Results
The systematic literature search identified 63 primary publications covering 57 switching studies. The reason for switching was reported as non-medical in 50 studies (23 clinical, 27 observational). Seven studies (all observational) did not report whether the reasons for switching were medical or non-medical. In 38 of the 57 studies, fewer than 100 patients were switched. Follow-up after switching went beyond 1 year in eight of the 57 studies. Of the 57 studies, 33 included statistical analysis of disease activity or patient outcomes; the majority of these studies found no statistically significant differences between groups for main efficacy parameters (based on P < 0.05 or predefined acceptance ranges), although some studies observed changes for some parameters. Most studies reported similar safety profiles between groups.
Conclusions
There are important evidence gaps around the safety of switching between biologics and their biosimilars. Sufficiently powered and appropriately statistically analysed clinical trials and pharmacovigilance studies, with long-term follow-ups and multiple switches, are needed to support decision-making around biosimilar switching.
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We believe that sufficiently powered and appropriately statistically analysed trials and pharmacovigilance studies, with long-term follow-ups and multiple switching sequences, are still needed to support decision-making around biosimilar interchangeability. |
In the interim, switching should remain a clinical decision made by the treating physician and the patient based on available evidence and individual patient circumstances. |
1 Introduction
Biological medicines (‘biologics’) are derived from living organisms, often by using recombinant DNA technology. Biologics differ from traditional, small molecule medicines, which are generally structurally simple, chemically synthesised and easily characterised analytically. Post-translational modifications of biologics are particularly vulnerable to manufacturing process conditions, and maintaining batch-to-batch consistency is essential [1]. Small process changes (‘evolution’) or unintentional deviations (‘drift’) can lead to changes in the biological end product and, ultimately, to product divergence, a concept that has particular relevance in the setting of biosimilars [2].
Quality assessment of biologics in terms of efficacy and safety requires physicochemical and functional assays, pharmacokinetic and pharmacodynamic evaluations, toxicity testing in animals and clinical pharmacology [3,4,5]. Unwanted immune responses are a concern, both in terms of adverse events (e.g. anaphylaxis, infusion reactions) and neutralisation of either the therapeutic biologic or the endogenous counterparts by neutralising antibodies, and have terminated development of some biologics [6].
Biosimilars have established similarity to the biologic reference product in terms of safety and efficacy. There are stringent regulatory requirements for demonstration of biosimilarity—including demonstration of comparable physicochemical characteristics, biological activity, efficacy and safety/immunogenicity—and these are laid down in the respective US Food and Drug Administration (FDA) and European Union (EU) guidance documents, and the approval process of biosimilars in these highly regulated markets is rigorous [4, 5, 7,8,9,10]. However, unlike generics of small molecule medicines (which can be fully characterised structurally, thus allowing for the same drug substance to be produced), biosimilars of biologic reference products can differ in terms of the overall structure of their drug substance and are similar to, but not identical to, the originator product. This is because biologics are large and structurally complex, meaning that, unlike the characterisation of generics, current analytical methodology may not be able to detect or characterise all relevant structural and functional differences between biologics, a distinction that is also noted in the FDA guidance on demonstrating biosimilarity and the Australian Therapeutic Goods Administration (TGA) biologic nomenclature consultation [3, 11]. Data on the efficacy and safety of initiating therapy with a biosimilar versus with an originator biologic, generated as part of regulatory approval and post-approval phases, have been widely reviewed [12,13,14] and are not the focus of the current article.
‘Interchangeability’ is the medical practice of changing one medicine for another that is expected to achieve the same clinical effect in a given clinical setting and in any patient, on the initiative, or with the agreement, of the prescriber [15, 16]. ‘Switching’ refers to the treating physician exchanging one medicine with another medicine with the same therapeutic intent in a given patient [17]. Substitution is the practice of dispensing one medicine instead of another equivalent and interchangeable medicine at the pharmacy level without consulting the prescriber [15]. Implied in this is that a biosimilar has been shown to produce the same result as the originator in any patient and that there are no signals suggesting loss of efficacy or increased toxicity if multiple switches are made in the cases in which the medicine must be administered on many occasions.
Definitions of biosimilarity and interchangeability used in the USA, the EU and Australia are summarised in Supplementary Table 1 (see the electronic supplementary material) [4, 5, 7,8,9,10]. For a reference product and a biosimilar to be considered interchangeable, the FDA requires sponsors to demonstrate that the risk in terms of side effects or diminished efficacy of switching is not greater than the risk of using the reference product without such alternating or switching [18]. Recently published FDA draft guidance on the specific data required to achieve a designation of interchangeability states that for products that are administered more than once, marketing applications are expected to include data from switching studies in appropriate conditions of use [19]. In the EU, substitution policies are within the remit of each member state [4]. However, officials from Finnish, Dutch, German and Norwegian national regulatory agencies concluded in a recent ‘current opinion’ article, published in BioDrugs, that “biosimilars licensed in the EU are interchangeable” [17]. In Australia, the TGA has responsibility for marketing authorisation (focusing on safety, efficacy and quality), with the Pharmaceutical Benefit Advisory Committee (PBAC) advising the government about whether a drug should be subsidised (focusing on cost-benefit) [20]. The PBAC has proposed that biosimilar substitution at the pharmacy level is acceptable when there is “absence of data to suggest significant differences in clinical effectiveness or safety compared with the originator product” that argue against such action [8]. The interchangeability of an originator biologic and a biosimilar or between biosimilars is considered by the PBAC on a case-by-case basis [8].
Switching between an originator biologic and a biosimilar medicine or between biosimilars can be categorised as either medical or non-medical. Medical switching is initiated by the prescriber because of medical concerns such as adverse events, or convenience of dosing or administration. For example, the incidence of injection site reactions in phase 3 clinical trials was lower with biosimilar than originator tumour necrosis factor (TNF) inhibitors, a difference that was explained by a lack of l-arginine in the formulation and of latex in the needle shield of the biosimilar products [21]. Non-medical switching occurs because of non-medical concerns, including treatment cost or availability. Recommendations from professional societies around switching are summarised in Supplementary Table 2 [22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]. Importantly, across the USA, Canada, Europe and Australia, professional societies state that the decision to switch has to be taken by the treating physician. In the USA, for example, the American Academy of Dermatology (AAD) and the American College of Rheumatology (ACR) support switching only if it is deemed suitable by the prescribing provider [22, 26], and the Australian Rheumatology Association (ARA) position is that the decision to prescribe any medication should rest with the prescriber, in consultation with an informed patient, and substitution should not occur without the knowledge and consent of the patient [35]. The Australian Diabetes Society and Australian Diabetes Educators Association (in a collective statement with Diabetes Australia), the Gastroenterological Society of Australia and the Australian Inflammatory Bowel Disease Association strongly oppose recommendations of biosimilars as interchangeable on the grounds of patient safety [23, 33]. This is in stark contrast with the Pharmaceutical Society of Australia and the Pharmacy Guild of Australia, who support substitution by the pharmacist if the patient agrees and if the prescribing physician has not specifically indicated that no substitution should occur [38, 39].
Ongoing areas of scientific debate and potential concern around biosimilars are (1) extrapolation of approval of biosimilars across multiple clinical indications, (2) presence of impurities or chemical alterations not detected with standard comparability testing [40,41,42], and (3) whether the efficacy, safety and immunogenicity risk of therapy are affected when patients are switched between originator and biosimilar products or from one biosimilar to another, in particular when multiple switching occurs. This article will focus on the third point, namely the key principles around biosimilarity and interchangeability, and analyse the available evidence around switching between originator biologics and biosimilars or between biosimilars based on a systematic review of the published literature, identifying any significant evidence gaps.
2 Methods
2.1 Systematic Literature Searches
A systematic literature review was conducted in PubMed, EMBASE and Cochrane Library to 10 June 2017 to identify studies reporting efficacy and/or safety data on switching between originator biologics and biosimilars or between biosimilars, using the following search string: ((biosimilars OR biosimilar OR biosimilarity OR “subsequent entry biologic” OR “subsequent entry biologics” OR “similar biotherapeutic product” OR “similar biotherapeutic products” OR “similar biological medicinal product” OR “similar biological medicinal products” OR “follow-on biologic” OR “follow-on biologics”) AND (equivalent OR equivalence OR comparability OR substitute OR substitution OR substitutability OR switch OR switched OR switching OR interchange OR interchanged OR interchangeable OR interchangeability)). Records in PubMed were retrieved using the title and abstract (‘tiab’) search filter. Records in EMBASE were retrieved using the ‘ex/mj’ syntax to capture synonyms and apply major focus for all terms.
The following meetings from the main societies representing key therapeutic areas for biosimilars were checked for relevant abstracts published in 2015 or 2016: American Association of Clinical Endocrinologists (AACE); AAD; ACR; American Diabetes Association; American Gastroenterology Association; American Society of Clinical Oncology (ASCO); American Society of Nephrology; European Crohn’s and Colitis Organisation; European Renal Association/European Dialysis and Transplant Association European Society for Medical Oncology; and European League against Rheumatism. In addition, ASCO was also checked for relevant abstracts published in 2017.
The reference lists of identified primary articles and literature reviews were hand searched for any additional, potentially relevant articles. To supplement the systematic searches, an exploratory literature search was undertaken to support the overview section around the principles of biologics, biosimilarity and interchangeability.
2.2 Study Eligibility and Data Extraction
Studies were excluded if they presented data on switching only between different classes of originator biologics and biosimilars or between different classes of biosimilars. Pharmacokinetic/pharmacodynamic cross-over studies in healthy volunteers were included if more than one dose of study drug was administered and if data were reported separately for the post-washout/post-switch study period. Studies comprising fewer than 20 switch patients were excluded. No exclusion criteria were applied regarding study type (clinical or observational), retrospective or prospective analysis or publication date.
Data were extracted on treatment, indication, study design, comparators, patient numbers and demographics (age, sex), reason for treatment switching, efficacy, safety and anti-drug antibodies (ADAs).
All data were tabulated separately by study type (clinical or observational) and reason for switching (medical or non-medical). No meta-analyses were performed given the heterogeneity of study designs, interventions, populations and methods of analysis.
2.3 Role of Funding Source
The funding source had no role in the conduct of the present study.
3 Results
The systematic literature search identified 63 primary publications, covering 57 switching studies that reported efficacy and/or safety data [43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105]. A flow chart of the systematic searches is shown in Figure 1. Forty-one of the identified studies were reported as full articles; the remaining 16 studies were covered only in abstract form. In terms of design, 23 were clinical studies [22 randomised controlled trials (RCTs), including 11 open-label extensions of RCTs; and one non-RCT cross-over study] and 34 were observational (24 prospective, 10 retrospective).
Flow chart of systematic literature searches. RCT randomised controlled trial
Patient demographics and other study characteristics are summarised in Supplementary Table 3 [43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105]. The number of included patients per study ranged from 20 to 802, except for a retrospective chart review with N = 3018 [72] and an insurance database study with N = 6177 [76]. The average age, where reported, ranged from younger than 10 years to 71 years, and the proportion of men, where reported, ranged from 0% to 87%.
The reason for switching was reported as non-medical in 50 studies, of which 23 were clinical studies (Table 1) and 27 were observational studies (Table 2). The remaining seven studies did not report whether the reasons for switching were medical or non-medical; all were observational (Table 3). None of the studies reported having only medical reasons for switching.
3.1 Non-medical Switching: Clinical Efficacy and Safety Data
Of the 23 clinical, non-medical switching studies (Table 1) [53, 55, 56, 60, 61, 69, 70, 73,74,75, 81, 82, 84,85,86, 91,92,93,94,95,96,97,98,99, 101,102,103,104], 22 reported data on main efficacy parameters in switched versus non-switched or pre-switch versus post-switch groups. The originator biologics/biosimilars assessed were infliximab (six studies [53, 55, 56, 61, 69, 70, 73]), erythropoietin-stimulating agents (ESAs) (four studies [74, 75, 81, 82]), filgrastim [93,94,95] (three studies), insulin [84,85,86], adalimumab [96,97,98], rituximab [60, 99] and etanercept [101,102,103] (two studies each), and genotropin [83, 92] and follicle stimulating hormone [104] (one study each).
Of these, 15 included statistical analyses of disease activity or patient outcomes in switched versus non-switched groups, pre-switch versus post-switch groups or observed versus predicted outcomes [53, 60, 61, 73, 74, 81, 82, 84,85,86, 91,92,93,94,95, 99], with five studies specifying a formal equivalence or non-inferiority margin [53, 74, 81, 82, 95]. There were no statistically significant differences between groups (based on P < 0.05 or predefined acceptance ranges), with the exception of a significant weight gain that was observed in patients with type 1 diabetes mellitus switched to biosimilar compared with patients remaining on originator insulin (+ 1.0 kg vs + 0.2 kg, respectively; P < 0.05) in the open-label extension of the ELEMENT 1 RCT, although the range of weight changes was wide in both groups [84]. The NOR-SWITCH infliximab trial was conducted across six indications and used a non-inferiority margin of 15% (adapted from rheumatoid arthritis studies), with results suggesting no loss of efficacy and no unexpected treatment-emergent adverse events (TEAEs) [53]. Eight studies reported similar outcomes between groups, but failed to provide a formal statistical analysis of between-group comparisons [55, 56, 69, 70, 75, 98, 102,103,104].
Most studies reported similar safety profiles between groups. An exception was the PLANETAS extension study of infliximab in patients with ankylosing spondylitis, in which TEAEs were considerably more frequent in the switched group [71% (60 patients out of 84) vs 49% (44 patients out of 90) in the group remaining on originator biologic] and included TEAEs that were considered related to the study drug [39% (33 patients out of 84) vs 22% (20 patients out of 90)] [61].
3.2 Non-medical Switching: Real-world Efficacy and Safety Data
All of the 27 observational, non-medical switching studies reported data on main efficacy parameters after switching compared with baseline/before switching (Table 2) [43,44,45,46,47,48,49,50,51,52, 54, 58, 62, 63, 65,66,67,68, 71, 72, 77, 79, 83, 87,88,89,90, 105]. The originator biologics/biosimilars assessed were infliximab (20 studies [43,44,45,46,47,48,49,50,51,52, 54, 58, 62, 63, 65,66,67,68, 71, 72]), ESAs (two studies [77, 79]), insulin (two studies [83, 87]) and growth hormone (three studies [88,89,90]).
Of 16 studies that reported statistical analyses, 13 found no statistically significant differences for main efficacy parameters [43, 46,47,48,49, 58, 62, 67, 68, 71, 77, 79, 87], although six of these observed changes for some parameters (in favour of the pre-switch and post-switch treatments in five studies and one study, respectively). There was a need for additional medication to control increased disease activity after switching from originator to biosimilar infliximab in four of 83 patients with inflammatory bowel disease (IBD) [68] and in 13 of 28 patients undergoing chemotherapy and switching epoetins [77]; a significant increase in median C-reactive protein values (from 1.95 to 4.0 mg/L; P < 0.05) and median pain scores (from 28.8 to 38.1 mm on a scale of 0–100; P < 0.05) in patients with IBD switching from originator to biosimilar infliximab [43]; a significant increase in disease activity (mean Bath Ankylosing Spondylitis Activity Index, from 3.8 to 4.3; P < 0.05) in patients with spondyloarthritis after switching to biosimilar infliximab [71]; a small, significant increase in total daily insulin dose (from 0.62 to 0.65 U/kg/day; P < 0.05) in patients with type 1 or type 2 diabetes mellitus switched to a biosimilar insulin [87]; but a significant decrease (i.e. improvement) in duration of morning stiffness [median duration, from 7.2 to 5.8 (no units provided); P = 0.02] in patients with arthritis switching from originator to biosimilar infliximab [47]. In the three remaining studies that included statistical analyses, IBD disease activity significantly improved in paediatric patients switched from originator to biosimilar infliximab (P < 0.05; actual values not reported) [66], but significantly worsened in adults who underwent a similar switch (median IBD-Control-8 score, from 11 to 14; P < 0.05) [63], and primary failure was significantly lower in patients with IBD switched from originator to biosimilar infliximab than in patients switched from other biologics or who were treatment naïve (0 vs 11 and 10%, respectively; P < 0.05) [50].
Eight studies reported that switching generally had no noticeable effect, but did not provide a formal statistical analysis of between-group comparisons or based this conclusion on modelling [44, 45, 52, 65, 83, 88,89,90]. Two studies reported on switching from infliximab originator to biosimilar. In one, relapse was reported in seven of 23 patients with rheumatic diseases within about 2 months after switching [51], and in the other, three of 36 patients with IBD discontinued within 1 year of switching because of loss of efficacy [54].
In terms of safety data after switching, eight studies reported no concerns or similar safety profiles before and after switching [43, 44, 47, 50, 62, 63, 79, 87, 89], six studies reported no general safety data [45, 51, 72, 77, 83, 90], and 12 studies reported adverse events such as injection site pain, acute hypersensitivity reactions, rash and infusion reactions after switching (although most did not provide comparative data from before switching) [46, 48, 49, 52, 54, 58, 65,66,67,68, 71, 88].
3.3 Switching, Reasons Not Reported: Efficacy and Safety Data
All seven observational studies that did not include reasons for switching assessed efficacy parameters after switching compared with baseline/before switching (Table 3) [57, 59, 64, 76, 78, 80, 100]. Three involved infliximab [57, 59, 64], three ESAs [76, 78, 80] and one rituximab [100].
Two studies included statistical analyses, both of which found no significant differences for main efficacy parameters [57, 78]. In one of these studies, on ESAs in patients on haemodialysis, switching to a biosimilar resulted in higher mean drug dose requirements (from 8765 to 10,886 IU/week; P < 0.05) to maintain haemoglobin levels [78]. Of the five studies not reporting a formal statistical analysis of between-group comparisons, four reported that switching had no noticeable effect [64, 76, 80, 100] and one reported disease worsening in five of 46 evaluable patients with IBD (11%) during 30 weeks of follow-up after switching from infliximab originator to biosimilar [59].
In terms of safety data after switching, one study reported similar patterns to before switching [57], one (in patients with IBD) reported three cases of infusion reaction and one of pneumonia in the switch group, which comprised 60 patients (vs none in the treatment-naive group, which comprised 113 patients) [59], one reported adverse events (cutaneous leishmaniasis) only when these were a reason for treatment discontinuation [64], and four studies did not report safety data [76, 78, 80, 100].
3.4 Switching: Immunogenicity Data
The relative frequency of ADAs in biologic originator and biosimilars was reported in 27 studies, of which 18 were clinical studies [53, 55, 56, 60, 61, 69, 70, 73, 81, 82, 84,85,86, 91, 92, 95,96,97,98,99, 101,102,103,104] and nine were observational [46,47,48, 52, 57, 63, 67, 68, 71, 105]. In 26 studies (17 clinical: follow-up 12–52 weeks [53, 55, 56, 60, 61, 69, 70, 73, 81, 82, 84, 85, 91, 92, 95,96,97,98,99, 101,102,103]; nine observational: follow-up 6–13 months [46,47,48, 52, 57, 63, 67, 68, 71, 105]), there were either no cases of ADAs, or the incidence of ADAs was similar in both groups.
A significantly higher proportion of patients with ADAs in the switched group than the non-switched group (19% vs 8% overall; P = 0.01) was reported in a clinical study of insulin in type 2 diabetes mellitus (ELEMENT 2) during 24 weeks of follow-up [84,85,86].
Comparative data regarding neutralising ADAs were reported in six studies (all clinical); none of which observed any clinically relevant [60, 96, 97, 104] or significant [61, 73, 96] differences between groups. No studies reported any treatment failure related to the development of ADAs.
4 Discussion
4.1 Clinical Considerations
This systematic literature review reveals important evidence gaps around the safety of switching between originator biologics and biosimilars or between biosimilars. There is a paucity of data from large studies of sufficient statistical power for efficacy, safety and immunogenicity risk considerations. There is little information on immunogenicity outside of clinical studies, with only nine of 34 included observational studies (26%) reporting such data. There is a general lack of robustness of evidence and no long-term data, with only eight of the included studies having a post-switch follow-up period beyond 1 year. This is important because patients may be exposed to treatment long-term and, although safety issues such as ADAs occur most commonly early on during treatment with biologics [106], they have been reported to arise only after the first year of treatment in some patients [107, 108]: a meta-analysis of 68 studies on incidence of ADAs to TNF inhibitors found that these first developed as early as 2 weeks, but also as late as 3 years, after treatment initiation [108]. There is large heterogeneity in the design of available studies including the number of switches and permutations of switch scenarios, use of formal equivalence or non-inferiority margins, and assessment of safety and immunogenicity risk, making it difficult to draw conclusions from the data.
Demonstration of interchangeability is a complex process that requires clinical studies in addition to those conducted to establish biosimilarity [109]. In the absence of specifically designed cross-over or multiple switch studies, demonstration of biosimilarity is not adequate to establish interchangeability [109]. The study duration needs to be clinically informed and will not be the same in every setting. Long-term studies are needed if treatment is chronic. A particular challenge when designing interchangeability studies is how to define the non-inferiority or equivalence margin, a topic that is covered by the recent FDA draft guidance [19]. In most studies in the current review, analyses around interchangeability were fairly limited, for example, taking a lack of a statistically significant difference as a lack of need for concern even when confidence intervals were wide [60]. Only five studies specified a formal equivalence or non-inferiority margin [53, 74, 81, 82, 95]. Formal, standardised definitions around margins are needed.
To demonstrate interchangeability, a study needs to show that even multiple switches between products deemed biosimilar do not affect patient safety or treatment effectiveness. The FDA draft guidance on interchangeability states that the switching arm should incorporate at least two separate exposure periods to each of the two products (i.e. at least three switches, with each switch crossing over to the alternate product) [19]. The EGALITY (etanercept) and NOR-SWITCH (infliximab) trials focused specifically on the impact of switching between these TNF-α originator biologics and their corresponding biosimilars, but NOR-SWITCH was not designed to assess the effects of multiple switches [53, 103]. In the EGALITY study, patients with chronic plaque psoriasis either continued with their original therapy or underwent three treatment switches at 6-weekly intervals [103]. TEAEs were shown to be similar between groups, ADAs were low titre and transient, and no neutralising antibodies were detected. Although the study follow-up period was short and numbers small (200 switched patients), the study is an important addition to the evidence.
In NOR-SWITCH, 240 patients were switched across six diseases, with numbers per disease indication ranging from 16 patients for psoriatic arthritis to 77 patients for Crohn’s disease. Disease worsening, the primary endpoint in NOR-SWITCH, was defined differently across the six diseases, with the data then pooled across indications for analysis. The study showed similar results for switched and non-switched groups for disease worsening and safety although, as the authors of the study commented, it was not powered to demonstrate non-inferiority within each diagnostic group, and thus the pooled analysis used does not allow conclusions about individual diseases [53, 110].
Both EGALITY and NOR-SWITCH were relatively small, short-duration studies, and larger studies with longer-term follow-up are still needed, in particular for patients with rheumatic diseases and IBD who are exposed to treatments over many years. In general, once interchangeability is deemed to be established, the relevant information will need to be passed on to healthcare providers to allow them to make individualised treatment decisions for their patients.
Differences exist regarding the regulatory approval pathways for biosimilars in different parts of the world. The regulatory framework around biosimilars is robust in the highly regulated markets of Europe, the USA, Canada, Australia and Japan, with South Korea also having positioned itself as a high-quality global biosimilars leader, while in emerging markets in south-east Asia, Latin America and Africa the regulatory pathways for biosimilars are still evolving [111]. These differences need to be taken into account when interpreting results from switching studies. Almost all of the studies identified for inclusion in the current review originated from highly regulated markets, with the exception of seven studies that included emerging markets [75, 83, 87, 93, 94, 99, 100], of which six reported similar outcomes for switched and non-switched groups and one, from South Africa, reported a requirement for increased insulin dose post-switch [87].
While not the focus of the current review, changing from one originator biologic to another is relatively common in clinical practice, most likely because of inefficacy or intolerability issues with the initial treatment [112, 113]. It is important to note, however, that this scenario is very different from switching between an originator biologic and its biosimilar or between different biosimilars of the same biologic: for example, two originator biologics targeting a given molecule may bind different epitopes, whereas a biologic and its biosimilar or two biosimilars of the same biologic should bind the same epitope. This difference probably explains why ADAs to infliximab demonstrate identical reactivity towards its biosimilar, whereas ADAs to adalimumab do not cross-react with infliximab or its biosimilar [114].
4.2 Glycosylation Patterns
Originator biologics and their biosimilars are often glycoproteins, which may be inherently immunogenic, whereas small molecules and their generics are only sometimes immunogenic, usually due to haptenating endogenous proteins [115]. There are no well-designed investigations into the clinical implications of glycosylation differences that may occur in production of biosimilars [41, 116]. The terminal sugars of glycans attached to immunoglobulin heavy chain have been shown to be critical for safety and/or efficacy of therapeutic monoclonal antibodies. For example, removal of fucose residues from these glycans can result in up to a 100-fold increase in affinity of antibodies to natural killer cells, which mediate antibody-dependent cellular cytotoxicity [117, 118]. In addition, a high degree of galactosylation has been shown to promote activation of complement in vitro [119]. Different patterns of glycosylation have been shown to influence the pharmacodynamic and pharmacokinetic behaviour of biologics, sometimes resulting in a reduction of the serum half-life of therapeutic antibodies [120]. Such changes have been used purposely as part of the product development process, such as when two extra glycosylation sites were engineered into recombinant human erythropoietin (EPO), resulting in a new, stand-alone product—darbepoetin alfa, with a threefold longer half-life—that could be administered less frequently [121]. A recent study has also demonstrated that the biological activity of EPO glycoforms varies depending on the glycosylation site occupancy pattern [122].
At present, no clinical studies have shown adverse effects of immunogenicity associated with therapeutics with high levels of non-glycosylated heavy chains; however, Fc glycan structural elements may be involved in adverse immune reactions. A high prevalence of hypersensitivity reactions to cetuximab, a monoclonal antibody approved for use in colorectal cancer and squamous-cell carcinoma of the head and neck, has been reported [123]. NeuGc, a non-human sialic acid that is found on some therapeutic proteins, can reduce efficacy due to rapid clearance of the biotherapeutic, and has been reported to cause hypersensitivity. In summary, production processes can change the glycosylation profiles of product biosimilars [41], which may potentially affect safety and efficacy. To date, the clinical implications of these changes are not well understood.
4.3 Immunogenicity Risk
If glycoproteins are sufficiently different from endogenous analogues, then patients may not exhibit immunological tolerance to them, thus rendering such glycoproteins immunogenic. In addition, variations can occur as a result of insertion of xenogeneic amino acid sequences when biologics are made in xenogeneic cells, which can enhance their immunogenicity [124, 125]. Even when fully humanised and glycosylated, therapeutic monoclonal antibodies can be immunogenic because they form immune complexes with target proteins, undergo phagocytosis and potentially activate inflammation [126]. Even within the human population, genes encoding the constant domains of immunoglobulins are highly polymorphic (known as allotypes), and each therapeutic is made from only one variant, which, therefore, may be recognised as non-self in individuals who lack that polymorphism [40, 41, 127,128,129]. Therefore, tolerance to an originator biologic does not necessarily predict immunological tolerance to its biosimilar and vice versa.
Significant effects of ADAs can be divided into those that neutralise the therapeutic action of the drug and/or its endogenous analogue and those that mediate hypersensitivity reactions to the drug. For example, EPO-induced ADA that neutralises endogenous EPO has been implicated in rare cases of pure red cell aplasia [130]. Unsurprisingly, there is also some evidence that ADAs arising against the reference product can also react to its biosimilars [114]. For example, in a retrospective analysis of 250 patients with arthritis who received either a reference biologic (infliximab) or a biosimilar, none of whom had undergone switching, ADAs against infliximab (detected in 126 patients) cross-reacted in in vitro antibody assays with either of two biosimilar products [114]. In the current review, no studies reported any treatment failure related to the development of ADAs. Comparative data on neutralising drug antibodies were reported in only three studies.
4.4 Regulatory Considerations
Ongoing post-marketing pharmacovigilance and accurate documentation of the specific product used by each patient are important. The current lack of standardisation of naming conventions for biosimilars poses several potential concerns. A unique name for the reference product and its biosimilar supports traceability in relation to pharmacovigilance and adverse event reporting [11, 131, 132]. Prescribers need to be able to distinguish between the reference product and its biosimilar to avoid prescribing errors. Naming conventions vary across regions, with the EU licensing biosimilars under the same international non-proprietary name (INN) as the originator and the FDA using a non-specific four-letter suffix (suggested by the sponsor) added to the non-proprietary name. The Australian TGA currently uses the locally approved name without any unique identifier for a biologic and its biosimilar, but is considering various options [11]; hence, at present, traceability may be difficult when multiple switches occur. A study on the traceability of biopharmaceuticals in spontaneous reporting systems over the period 2004–2010 found that, of six biosimilars approved in Europe at the time (sold under 12 different trade names), five contained the same INN as the innovator [133]. The product name was clearly identifiable for 90–96% of biopharmaceuticals for which biosimilars were available in the EU, although batch traceability was poorly maintained [133]. Given the evidence gaps and the difficulty of conducting randomised trials, particularly in the post-marketing setting, there is a need to establish or use pre-existing registries and administrative data, and to develop novel approaches to understanding the effectiveness data being generated by what are, in effect, natural, real-world experiments.
5 Conclusions
In summary, results from this systematic literature review show important evidence gaps around the safety of switching between originator biologics and biosimilars or between biosimilars. While emergent evidence from the EGALITY and NOR-SWITCH studies suggests that switching between TNF-α biologics and their corresponding biosimilars can be safe and efficacy is not compromised, we believe that sufficiently powered and appropriately statistically analysed clinical trials and pharmacovigilance studies, with long-term follow-ups and multiple switching sequences, are needed to support decision-making around biosimilar interchangeability. In the interim, switching should remain a clinical decision made by the treating physician and the patient based on available evidence and individual patient circumstances. Global harmonisation of the regulatory approach to these agents would facilitate an improved understanding of the safety and efficacy of biosimilars.
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Funding
Administrative and medical writing support was provided by Ms Donna Bartlett (Allori Pty Ltd, Australia) and Dr. Anja Becher (Sydney, Australia), and was funded through Medicines Australia with specific support from the Australian affiliates of AbbVie, Amgen, Eli Lilly, Janssen, Novo Nordisk, Roche and Sanofi. The sponsors were given the opportunity to review the final version of the article for accuracy pertaining to sponsored products and compliance with individual processes; however, they did not influence the content. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this manuscript.
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Ross McKinnon: Education and advisory service fees in relation to biosimilars for AbbVie and Sanofi Australia. Matthew Cook: Advisory board for Roche and Baxter. Winston Liauw: Advisory board for NPS MedicineWise. Mona Marabani: Consultancy, speaker fees or conference support from AbbVie, BMS, UCB, MSD, Pfizer, Janssen, Novartis and Sanofi. Ian Marschner: Research grant and consulting fees from Janssen-Cilag and consulting fees from Pfizer, AbbVie and Generic Health. Nicolle Packer reports having no conflicts of interest. John Prins holds clinical and scientific advisory board positions and/or has received speaking fees from Pfizer, Merck and Novo Nordisk.
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McKinnon, R.A., Cook, M., Liauw, W. et al. Biosimilarity and Interchangeability: Principles and Evidence: A Systematic Review. BioDrugs 32, 27–52 (2018). https://doi.org/10.1007/s40259-017-0256-z
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DOI: https://doi.org/10.1007/s40259-017-0256-z