Switching from Adalimumab Reference Product to and Among Adalimumab Biosimilars Outside the USA: Insights for US Clinicians

Abstract

Ten adalimumab biosimilars have been introduced in the United States (USA) since 2023, while adalimumab biosimilars have been available for several years in other countries. These experiences of biosimilar uptake outside the USA can inform US-based healthcare professionals on switching in real-life practice settings. Considerations include how healthcare professionals might meaningfully address patient concerns about outcomes to improve patient satisfaction. A search of the MEDLINE database was used to identify publications on switching to and among adalimumab biosimilars in an ex-US setting, with no restriction on publication language and using a time frame of 1 January 2017 through 12 December 2023, coinciding with the European Union approval of the first adalimumab biosimilar, adalimumab-atto, in March 2017. This narrative review aims to provide insights into the efficacy and safety of transitioning to and among adalimumab biosimilars in adult patients from clinical studies but also, more importantly, using real-world evidence (RWE) from outside the USA. Overall, RWE suggested that efficacy and outcomes were consistent in patients who underwent switching from the reference product (RP) across various immune-mediated inflammatory diseases when compared to patients who did not switch from the RP. The ex-US RWE of RP and biosimilar adalimumab switches generally reflected the experiences observed in clinical trials; however, RWE findings elucidated several challenges to biosimilar uptake, including patient education, provider training, and supportive policies.

Key Points

The introduction of adalimumab biosimilars in the USA in June 2023 may help close gaps in patient care by potentially reducing healthcare costs, increasing access to treatment, and addressing patient populations that are undertreated with existing biologic therapies.

This review of real-world evidence from outside the USA, where adalimumab biosimilars were introduced as early as 2018, substantiates the efficacy data of reference product-to-biosimilar switching as observed in clinical trials across several immune-mediated inflammatory diseases.

Moreover, patient education, provider training, and supportive policies should be implemented to ensure successful integration of biosimilars into a US routine care setting.

Introduction

In the United States (USA), the Food and Drug Administration (FDA) defines a biosimilar as a biological product that is highly similar to a US-licensed reference biological product, notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biological product and the reference product (RP) in terms of the safety, purity, and potency of the product (Table 1). Although the US patent on the adalimumab molecule expired in 2016, additional patents delayed the US market entry of adalimumab biosimilars until 2023. The US has seen the introduction of ten adalimumab biosimilars beginning in 2023 through June 2024 [1]. Even so, US market uptake of adalimumab biosimilars has been slow [2]. By contrast, the patent expiration of the adalimumab RP Humira^® in the European Union (EU) in 2018 coincided with a surge in biosimilar approvals by the European Medicines Agency [3]. Following the introduction of adalimumab biosimilars, varying policy measures were implemented to encourage biosimilar uptake, including government-adopted guidelines and rebate controls, agreements with health systems, and tendering and negotiation with biosimilar sponsors [4]. By 2019, an estimated 35% of patients in the EU had been switched from adalimumab RP to a biosimilar [5], with reduced biosimilar pricing driven by competition resulting in increased access to biologic treatments and lower overall healthcare spending on adalimumab [6, 7]. Experiences of biosimilar uptake outside the USA can inform US-based healthcare professionals (HCPs) with considerations on switching in real-life practice settings, including effects on patient outcomes and methods to address patient concerns. This narrative review aimed to provide insights into the efficacy and safety of transitioning to and among adalimumab biosimilars in adult patients from clinical studies but also, more importantly, uses real-world evidence (RWE) from outside the USA.

Table 1.

European Medicines Agency (EMA) and US Food and Drug Administration (FDA) definitions on biosimilars

Term	EMA definition	FDA definition
Bioequivalence	The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of action when administered at the same molar dose under similar conditions in an appropriately designed study	The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study
Biologic	A medicine whose active substance is made by or derived from a living organism	Biological product means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings
Biosimilar	A biosimilar is a biological medicine highly similar to another biological medicine already approved in the EU (called 'reference medicine') in terms of structure, biological activity and efficacy, safety, and immunogenicity profile (the intrinsic ability of proteins and other biological medicines to cause an immune response)	A biosimilar is a biological product that is highly similar to a US-licensed reference biological product notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product
Interchangeability	Interchangeability refers to the possibility of exchanging one medicine for another medicine that is expected to have the same clinical effect	An interchangeable biological product is a biosimilar that meets additional requirements and may be substituted for the reference product at the pharmacy, depending on state pharmacy laws

Methods

The MEDLINE database was searched using PubMed to identify publications on adalimumab biosimilars and their switching, with no restriction on publication language. The time frame for the literature search was 1 January 2017 through 12 December 2023, coinciding with the EU approval of the first adalimumab biosimilars, adalimumab-atto (Amjevita™) (March 2017) and adalimumab-bwwd (Hadlima™) (August 2017). Search terms included “biosim*” AND (“Humira” OR “adalimumab”) in the title/abstract and (“interchange*” OR “switch*” OR “transition*” OR “substitut*”) in all fields. The asterisk denotes a truncation that broadens the search term (i.e., substitut* would return results that captured the terms substitute, substituted, substitution, or substituting). The results were then reviewed and underwent manual curation to identify relevant RWE and clinical trials evaluating switching from adalimumab RP to any corresponding adalimumab biosimilar in an ex-US setting. Studies that were excluded during the literature screening included preclinical studies, letters, commentaries, and any studies examining adalimumab biosimilars or RP-to-biosimilar switching in a US setting.

Results

The literature search returned 194 results that were manually curated to identify relevant RWE (n = 46) and randomized controlled trial (RCT) publications (n = 23) on biosimilar switching in an ex-US setting. Based on the exclusion criteria as previously described, irrelevant studies (n = 125) that did not assess outcomes of switching with adalimumab-specific products or evaluated adalimumab uptake pertaining to patients or clinical practice in a US-only setting, were not considered for the purposes of this review.

Clinical Study Evidence

Of the 23 clinical studies identified, one RCT exclusively compared immunogenicity between the RP and biosimilar [8], one RCT reported on quality of life (QoL) and patient-reported outcome (PRO) measures [9], while the remaining RCTs evaluated single RP-to-biosimilar switching compared with maintenance on RP to establish clinical efficacy, safety, and/or immunogenicity. RCTs that assessed repeated switches between adalimumab RP and one adalimumab biosimilar found that multiple switches did not diminish the efficacy, safety, or immunogenicity of the biosimilar [8–14].

Several of these RCTs were characterized in a systematic review of adalimumab RP-to-adalimumab biosimilar switching across both US or EU settings across 21 studies from 2004 to 2021; overall findings were consistent for eight adalimumab biosimilars across eight studies of patients with rheumatoid arthritis (RA), six studies in patients with psoriasis (PsO), six studies in patients with inflammatory bowel disease (IBD), and one miscellaneous rheumatic disease [15]. Furthermore, multiple switches between adalimumab RP and a biosimilar saw sustained improvements in PRO and QoL scores across patients with RA, psoriatic arthritis (PsA), and PsO, with no negative impact on PROs related to treatment switching during the study duration [9]. Notably, demonstrating that multiple switches between a biosimilar and its RP has no impact on safety, efficacy, or immunogenicity outcomes is required by the FDA for regulatory designation as an interchangeable biosimilar in the USA, such that a substitution can be made by a pharmacist without first consulting the prescribing HCP [16]. There is no legal or regulatory equivalent to this in the EU; however, where the term “interchangeable” is understood as the ability of an HCP to replace the originator with a biosimilar without changing the clinical effect on a patient [17].

Real-World Evidence (RWE)

While RCTs have established the standard for efficacy and safety comparisons between biologic RPs and biosimilars, HCPs may encounter important differences in the conditions they see in real-life practice settings. Patients may have a wide variance in age, disease severity, comorbid conditions, concomitant medications, response to therapy, adherence, and other patient-specific factors when switching to biosimilars that are not reflected in the inclusion and exclusion criteria of RCTs. RWE can provide an important source of additional information on biosimilar adoption, revealing the uptake of biosimilars and real-life clinical outcomes across a broad patient population and across medical specialties. In this way, RWE can complement RCT data to inform clinical decision-making by reflecting clinical outcomes in patient populations that are not constrained by the stringent inclusion and exclusion criteria of RCTs.

Switching from Biologic Reference Product (RP) to Biosimilar

Our search identified 46 relevant articles that presented RWE, of which 27 cohort and/or registry studies evaluated outcomes of switching to or among biosimilars (Table 2). In a French population-based study that compared biosimilar market penetration, only 17% (n = 9285) of patients using adalimumab RP switched to the corresponding biosimilar, compared with biosimilar switching rates of 19% (n = 5907) and 46% (n = 9417) for etanercept and infliximab (due to its hospital delivery modality), respectively. While adalimumab RP initiation was highest in patients with IBD, rheumatic conditions, and PsO, respectively, when stratified by specialty, adalimumab biosimilar transition rates were highest in rheumatology, followed by dermatology and gastroenterology, respectively [18].

Table 2.

Baseline characteristics in real-world evidence (RWE) studies of adalimumab reference product (RP) and biosimilar switching

Publication authors	Indication	Treatment	Sample size				Disease duration (years)	Previous therapies		Duration of follow-up
			Initiating/maintenance RP	Initiating biosimilar	RP-to-biosimilar	Biosimilar-biosimilar		Biologic	Non-biologic
Becciolini et al. [32]	RA, axSpA, PsA	Adalimumab-atto	724	129	193		9.1 (RA)/4.4 (PsA)/4.0 (axSpA) [median]		CS, csDMARDs	9805.6 patient-months
Brouwer et al. [19]	RA	Adalimumab-atto			52		15 ± 11 (median, IQR)			12 months
Bruni et al. [20]	RA, axSpA, PsA, JIA	Adalimumab-bwwd			172		13.2 ± 7.6 (mean, SD)		NSAIDs, CS, csDMARDs	12 months
Burlando et al. [42]	HS		171	61	66		10 (5, 19) [median, IQR]		CS, immunomodulators	10–13 months (median)
Cingolani et al. [36]	IBD	Adalimumab-atto/bwwd	38		55				CS, AZA	6 months
Deprez et al. [29]	IBD	Adalimumab-bwwd			110		11.3 (median)			12 months
Derikx et al. [46]	IBD	Adalimumab-bwwd		225	256		Biosimilar-initiating, 6.3 (1.5–17.1); switching, 10 (5.8–16.2) [median, IQR]	Anti-TNF, ustekinumab, vedolizumab	Tofacitinib, thiopurines, MTX, CCI	8.3–13.7 months (median)
Di Giuseppe et al. [30]	RA, PsA, SpA, or other rheumatic conditions	Adalimumab-atto/adaz			137/157 (adalimumab-atto/adalimumab-adaz)		10.5–12.6 (mean)			24 months
Jin et al. [27]	IBD	Adalimumab-atto		239	136				CS, immunomodulators, 5-aminosalicylate	7 months (median)
Kirsten et al. [41]	HS	Adalimumab-atto	94		94					14 weeks
Loft et al. [23]	PsO	Adalimumab-adaz	378		348		Maintenance RP, 28.5 (12.6); RP-to-biosimilar, 30.6 (12.6) [mean, SD]		MTX	12 month
Lontai et al. [54]	IBD				174	102	RP-to-biosimilar, 12.5 (8–17); biosimilar-to-biosimilar 8 (3–13) [median, IQR]	Biologics (unnamed)	CS, AZA	40 weeks (median)
Lukas et al. [28]	CD	Adalimumab-bwwd	101		74		Maintenance RP, 14.3 (10.7); RP-to-biosimilar, 13.2 (8.5) [mean, SD]		CS, immunosuppressive therapy	104 weeks
Lukas et al. [24]	IBD	Adalimumab-bwwd	93		93		Maintenance RP, 7 (4–8); RP-to-biosimilar, 7 (3–9)) [median, IQR]		CS, MTX, AZA, 5-aminosalicylate	10 weeks
Macaluso et al. [34]	IBD	Adalimumab-atto	219		340		7 (3, 14) [median, IQR]	Anti-TNF	CS, AZA, MTX	403.4 patient-years
Montero-Vilchez et al. [40]	HS				17					Every 12 weeks
Nabi et al. [37]	RA, axSpA, PsA	Adalimumab-adaz/bwwd			1318		14 (9–20) [median, IQR]	Biologics (unnamed)	MTX	12 months
Redeker et al. [33]	RA, axSpA, PsA				121		RA, 4.5 (3.0–8.0); axSpA 5.0 (2.0–8.8); PsA, 7.0 (3.0–11.0) [median, IQR]		NSAIDs, CS, csDMARDs	2 years
Ribaldone et al. [57]	CD	Adalimumab-atto/bwwd	–			61		Adalimumab-atto	CS, thiopurines	6 months
Ribaldone et al. [26]	CD	Adalimumab-atto	25		62		RP-naïve, 16.5; RP-to-biosimilar 17.3 (mean)			6 months
Roccuzzo et al. [43]	HS				37		10.65 (difference between mean age at onset and diagnosis)			12 months
Scrivo et al. [55]	RA, axSpA, PsA	Adalimumab-atto/bwwd			110	40				4 months
Tapete et al. [25]	IBD	Adalimumab-bwwd	48		98		9.10 (0.3–37) [mean, min–max]	Anti-TNF	CS, immunosuppressive therapy	12 months
Tursi et al. [59]	IBD	Adalimumab-aacf/adaz/atto/bwwd			153		8 (5–14) [median, IQR]			12 months (median)
Tursi et al. [58]	IBD	Adalimumab-aacf/adaz/atto/bwwd				533	6 (3–13) [median, IQR]	Biosimilar (unnamed)	CS, thiopurines, mesalazine, probiotics	> 6 months
Van Adrichem et al. [35]	RA, SpA, PsA, JIA, sarcoidosis	Adalimumab-atto			603		8.7 (median)		NSAIDs, CS, csDMARDs	12 months
Vernero et al. [35]	IBD	Adalimumab-adaz		29	33	10	9 (5–17) [median, IQR]	Infliximab, ustekinumab, vedolizumab	Immunosuppressive therapy	12 months

axSpA axial spondyloarthritis, AZA azathioprine, CCI calcineurin inhibitors, CS corticosteroid, CD Crohn’s disease, csDMARDs conventional synthetic disease-modifying anti-rheumatic drugs, HS hidradenitis suppurativa, IBD inflammatory bowel disease, IQR interquartile range, JIA juvenile idiopathic arthritis, MTX methotrexate, NSAIDs non-steroidal anti-inflammatory drugs, PsA psoriatic arthritis, PsO psoriasis, RA rheumatoid arthritis, RP reference product, SD standard deviation, SpA spondyloarthritis, TNF tumor necrosis factor

Overall, RWE on biosimilar switching suggested that outcomes including efficacy, safety, patient satisfaction, patient QoL, and incidence of adverse events (AEs) are consistent in patients who switched from RP to biosimilar across various immune-mediated inflammatory diseases [19–27]. In these studies, patients who transitioned to a biosimilar were compared to a control cohort group of patients treated with adalimumab RP or were evaluated for changes in disease activity based on enrollment of patients with stable clinical remission or baseline disease activity measurements prior to switching. RWE ranged from single- and multi-center studies to large-scale database or registry studies that retrospectively identified patients who underwent switching. Several RWE studies that found no differences in disease severity in patients who switched to an adalimumab biosimilar did report a greater incidence of AEs after switching. Reported AEs were primarily dermatologic (i.e., injection-site reactions and pain) and were attributed to factors including the nocebo effect, low-concentration formulations requiring a greater injection volume, different syringes or injection devices, and the presence of sodium citrate, a compound known to be responsible for more painful injections [23, 28, 29]. However, most adalimumab biosimilars are currently available in the USA as high-concentration, citrate-free formulations, including adalimumab-atto (Amjevita™), adalimumab-bwwd (Hadlima™), adalimumab-adbm (Cyltezo^®), adalimumab-adaz (Hyrimoz^®), and adalimumab-ryvk (Simlandi^®). Three of these biosimilars, adalimumab-adbm, adalimumab-adaz, and adalimumab-ryvk, also have an interchangeability designation from the FDA (Table 3) [1].

Table 3.

Current approved adalimumab biosimilars in the USA [1]

Adalimumab biosimilar	Route of administration	High/low concentration	Citrate-free formulation	Interchangeable status with RP	Patient support programa
Abrilada (adalimumab-afzb)	Single-dose SC prefilled pen, glass PFS, and vial (for institutional use only)	Low	Yes	Yes	Pfizer enCompass (patient assistance program only) [74]
Idacio (adalimumab-aacf)	Single-dose PFS	Low	Yes	No	KabiCare® [75]
Amjevita (adalimumab -atto)	Single-dose SC prefilled SureClick® autoinjector and glass PFS	Both	Yes	Yes	Amgen® SupportPlus [76]
Hulio (adalimumab-fkjp)	Single-dose SC prefilled pen and plastic PFS	Low	Yes	Interchangeability data available [77, 78]	Hulio360™ [79]
Cyltezo (adalimumab-adbm)	Single-dose SC prefilled pen and glass PFS	Both	Yes	Yes	BI Solutions Plus® [80]
Hadlima (adalimumab-bwwd)	Single-dose SC prefilled autoinjector and glass PFS	Both	No for low concentration; yes for high concentration	Yes	Hadlima™ For You [81]
Hyrimoz (adalimumab-adaz)	Single-dose glass PFS, glass PFS with BD Ultrasafe PassiveTM Needle guard, and prefilled pen	Both	No for low concentration; yes for high concentration	Yes	Sandoz One Source [82]
Simlandi (adalimumab-ryvk)	Single-dose prefilled autoinjector	High	Yes	Yes	SIMLANDI Savings Program [83]
Yuflyma (adalimumab-aaty)	Single-dose SC prefilled autoinjector, PFS, and PFS with safety guard	High	Yes	Interchangeability data available [84, 85]	Celltrion CONNECT® [86]
Yusimry (adalimumab-aqvh)	Single-dose SC glass PFS	Low	Yes	No	YUSIMRY Solutions™ (co-pay card only) [87]

PFS prefilled syringe, RP reference product, SC subcutaneous

^aIncludes coverage of co-pay card and patient assistance program, unless otherwise indicated

Treatment Retention

Treatment retention following biologic RP-to-biosimilar switching appears to be consistent with that in patients who continued to receive the RP. In a cohort study of rheumatology patients who underwent non-medical switching, 1-year retention rates were 86% (95% confidence interval [CI] 82–89) in patients who switched to adalimumab-atto (n = 137), 92% (95% CI 89–94) in patients who continued RP (n = 137), and 90% (95% CI 79–95) in patients who switched to adalimumab-adaz (n = 157), compared with 95% (95% CI 88–98) in patients who continued RP (n = 157) [30]. van Adrichem et al. likewise reported a successful transition to and retention after 1 year of adalimumab biosimilar in 93% of patients (N = 603) with stable inflammatory rheumatic joint diseases including RA, PsA, and spondyloarthritis (SpA) [31]. Becciolini et al. observed a similar outcome in a switching study that reported an 18-month retention of 88% in patients with RA, PsA, and axial spondyloarthritis (axSpA) (n = 193) who switched to adalimumab-atto [32]. In contrast, Redeker et al. found a 2-year retention rate of 73% in patients with chronic inflammatory rheumatic diseases (N = 121), though the investigators noted that the lower retention rate compared to other switching studies may be explained by the lower proportion of patients who were in remission at baseline [33].

Inflammatory arthritis patients (RA, PsA, axSpA) who were naïve to adalimumab RP (n = 724) or adalimumab biosimilar (n = 129) had 18-month retention rates of 81.5% and 84.0%, respectively [32]. Evidence from other immune-mediated inflammatory diseases demonstrated similar outcomes regarding retention. A cohort study of patients with PsO found a 1-year retention rate of 92.0% (95% CI 89.0–94.9) in the switching cohort and 92.1% (95% CI 89.4–94.8) in the adalimumab RP cohort [23], and in a cohort study of patients with IBD who switched to adalimumab-bwwd (n = 110), 82 patients (72% [95% CI 65.2–81.6]) retained treatment with the biosimilar at the 1-year follow-up [29]. A cohort study by Macaluso et al. likewise reported higher treatment persistence estimated using Kaplan-Meier analyses for patients with IBD who switched from RP to biosimilar (90.6% [n = 340]) compared with adalimumab-naïve patients (75.6% [n = 189]) at 48 weeks [34].

In addition, cohort studies comparing patients with IBD who initiated adalimumab biosimilar and those who underwent RP-to-biosimilar switching found higher rates of disease remission after 1 year in the switching cohort. In patients who switched from RP to adalimumab-bwwd and adalimumab-adaz, respectively, remission was maintained in 74.5% (n = 98) and 78.8% (n = 33) in the switching cohort, compared with 60.4% (n = 48) and 58.6% (n = 29) in the naïve cohort initiating adalimumab-bwwd and adalimumab-adaz [25, 35].

Discontinuation and Switchback

Discontinuation of adalimumab biosimilar therapy following switching from a biologic RP has been attributed to either lack of efficacy, AEs, and/or disease-specific medical complications [36, 37]. Certain patient populations were more likely to experience poor outcomes following switching that resulted in treatment discontinuation, including patients in remission for over 2 years, pregnant women, and patients who had difficulty reaching remission [38]. Bruni et al. also identified baseline use of corticosteroids or non-steroidal anti-inflammatory medications as predictive factors for treatment discontinuation post-switch, with the use of concomitant therapies possibly associated with suboptimal disease control at baseline [39].

In contrast to studies in other indications, several switching studies in patients with hidradenitis suppurativa (HS) have observed worsened efficacy and safety outcomes following the switch from RP to biosimilar. A cohort study by Montero-Vilchez et al. in patients with HS found a higher rate of poor outcomes following switching as compared with other reports on switching in patients with RA, Crohn’s disease (CD), and PsO, with 58.8% (n = 17) of patients reporting AEs or loss of response (median 13.6 weeks of biosimilar treatment) resulting in treatment discontinuation or switching back to RP [40]. Similarly, Kirsten et al. reported that 33.3% (n = 94) of patients with HS developed AEs or loss of response within 12–14 weeks following switching to adalimumab-atto [41]. A comparison of the treatment effect in patients with HS (n = 94) who switched or who exclusively received the RP or biosimilar found the incidence of treatment ineffectiveness before and after switching, graded using the Hurley staging system, was 4.9 per 100 person-months (95% CI 3.6–6.3) while taking the RP compared with 10.7 per 100 person-months (95% CI 8.3–13.5) after the same patients switched to treatment with the biosimilar. In this study, 82.2% (95% CI 75.4–89.6) of patients who received only the RP reported effective treatment after 10 months, compared with 60.5% (95% CI 48.6–75.5) of patients who received only the biosimilar [42]. The investigators attributed the difference in switching rates to disease-specific factors related to HS. Patient sensitivity to pain and loss of response were the most frequent AEs, with a third of patients who had a loss of response failing to recover after switching back to the RP [40].

Switching from adalimumab biosimilar back to the RP has been attributed to a loss of therapeutic response or failure to manage AEs from the biosimilar, as well as clinical decisions against switching. In a cohort of 348 patients with PsO who switched from adalimumab RP to biosimilar, 8% (n = 28) of patients discontinued treatment after 12 months, of which 32% (n = 9) patients switched back to the RP [23]. In some instances, re-challenge with the RP following loss of efficacy with the biosimilar resulted in recovery of therapeutic response. Montero-Vilchez et al. reported on eight patients who were switched back to adalimumab RP (n = 17), of which AEs were resolved in all patients and 66.7% (n = 3) patients recovered clinical response [40]. A similar effect was observed in a cohort study of 603 patients with inflammatory rheumatic joint diseases, where 60% (n = 24) of patients who were switched back to adalimumab RP from the biosimilar experienced clinical improvement [31]. Subjective causes such as patient perceptions of an increase in AEs, a decrease in general therapeutic efficacy, unpleasant experience with the injection device, and self-reported disease worsening, have also been attributed to switchbacks [31]. Roccuzzo et al. noted that characteristics unique to drug products, such as packaging, formulation, and excipients, may influence outcomes following switching that have resulted in a switchback [43]. Notably, while many switching studies report on the rates of discontinuation due to loss of response, very few studies report on the rate at which response is recaptured following re-challenge with the RP.

Causes for Therapy Failure

Nocebo Effect

Many RWE studies discuss the “nocebo effect” as a reason for variable efficacy and safety outcomes following switching. The nocebo effect, defined as the perceived lack of drug efficacy and subjective increase in disease activity and pain-related AEs beyond patient-specific factors or drug-related effects, is an important clinical consideration in the adoption of biosimilars. Negative patient expectations toward switching and perceived worsening in disease severity or AEs can significantly worsen patients’ subjective assessment of well-being following switching [29]; this in turn can negatively impact patients’ adherence to treatment and contribute to worsening outcomes. The nocebo effect ranges from 10 to 30% for studies of non-adalimumab biosimilars, though evidence to the contrary has been reported in studies of adalimumab biosimilars [44, 45]. A systematic review of adalimumab switching studies found no significant differences in treatment cessation following switching due to more frequent or severe AEs [15]. In an RWE study comparing treatment retention of biosimilar products following non-medical switching, the investigators found no evidence of a nocebo effect between the RP and three adalimumab biosimilars [30]. In this study, the investigators noted that patient education on switching had a role in mitigating the nocebo effect.

Serum Drug Levels and Immunogenicity

The development of anti-drug antibodies (ADAs) and neutralizing ADAs (nAbs) to adalimumab has been associated with a loss of therapeutic response, though RWE is limited to select studies in patients with IBD. In a switching study of patients with IBD (n = 93), no clinically meaningful differences in adalimumab drug levels were observed at 10 weeks (biosimilar 13.0 μg/mL [95% CI 9.2–17.6] vs. RP 13.7 μg/mL [95% CI 9.2–17.6]) [24]; ADAs were reported at a 2% rate. Similarly, a 6-month study of patients with IBD found no significant differences in ADA incidence in 17 patients with mean levels of ADAs before the switch and at 3 and 6 months being 15.38 ng/mL (± 59.24), 15.51 ng/mL (± 58.33), and 15.29 ng/mL (± 58.37), respectively [25]. Despite this, limited evidence suggests that the development of ADAs may be a reason for poor switching outcomes. A 12-month study of patients with IBD who underwent RP-to-adalimumab-bwwd switching found that of 25.4% (n = 28) of patients who discontinued biosimilar treatment following switching, high ADAs (17.9%, n = 5) were second only to AEs (57.1%, n = 16) as the chief reason for discontinuation [29]. Another study of patients with IBD who switched twice from adalimumab RP to adalimumab-bwwd (n = 256) and then to adalimumab-atto (n = 35) supports the possibility of a double biosimilar switch where immunogenicity is a concern [46]. In this study, while patients had detectable ADAs prior to, or developed new ADAs during, treatment with adalimumab-bwwd after the first switch from RP, no patients developed detectable ADAs or discontinued treatment after switching to the second biosimilar. None of these studies reported on neutralizing antibodies.

In IBD, therapeutic drug monitoring (TDM) of adalimumab, assessing drug serum concentrations and ADA assays, is often performed proactively or reactively to adjust adalimumab dose and frequency according to target drug level and/or clinical response [47]. Importantly, antibodies to the RP may neutralize a biosimilar and affect the biosimilar drug level in the same way they affect the RP, and the same assays (and target values) used to measure drug levels and ADA of the RP can be used for biosimilars. Patients who achieve clinical remission without the presence of neutralizing ADAs can be maintained on their current maintenance dosing of the RP or switched to a biosimilar at similar dosing and frequency. Those with inadequate clinical response and detectable ADAs would be eligible for treatment intensification (increasing dose and/or frequency of anti-tumor necrosis factor [TNF]), adding an immunomodulator to suppress ADAs, or switching to another agent. Patients on adalimumab RP with loss of response due to ADAs are not good candidates for switching to an adalimumab biosimilar since these ADAs will also neutralize the biosimilar product. Finally, patients in clinical remission but with measurable ADAs could be monitored to assess whether the formation of ADAs is transient or persistent, the latter of which may entail consistently increasing antibody titers over time leading to an eventual loss of response [48]. This finding is consistent with supportive evidence on the use of TDM in patients with IBD as a decision guidance tool for HCPs following a loss of therapeutic response, with TDM contributing to improved patient outcomes and cost savings when switching to a biosimilar [47].

Patient Perceptions of Switching

RWE studies that surveyed patients have characterized patient perceptions of biosimilars and switching in addition to post-switching PROs. In general, patient surveys were dominated by concerns about the patient experience of switching rather than clinical efficacy or interchangeability. An interview study in patients with CD (n = 35) identified five common themes in patients’ perceptions of successful biosimilar switching: prior understanding and awareness of biosimilars, motivation to make the switch, initial apprehensions prior to switching regarding a loss of efficacy and AEs from the biologic brand that they were accustomed to, acceptance of biosimilars based on patient trust in their healthcare team, and the patient experience of transitioning to a biosimilar [49].

A survey of Brazilian and European patients with IBD (n = 102) found that while 27% of patients would accept a switch to a hypothetical “interchangeable” biosimilar if approved by their physician, 35% of patients would be opposed to switching if they were not aware of the exchange, highlighting the importance of keeping patients informed when switching to a biosimilar [50]. Following a treating physician explaining biosimilars to them, 30.6% of patients expressed confidence in switching, 37.1% would be worried but accepting of switching, 11.3% would seek a second opinion from another physician, and 11.3% would not accept the switch. Another survey of nine families (children diagnosed with juvenile idiopathic arthritis and their parents) found that anxiety surrounding the experience of switching was a concern when switching to a biosimilar [51]. Patients and caregivers were most concerned about the experience of switching to a different medication, namely the route of administration, the presence of citrate causing a stinging sensation, and the different color of the medication and packaging. Families also expressed apprehension regarding unknown AE outcomes, being unable to switch back in the event of an AE or drug inefficacy, and the effect of the transition on receiving their medication on time.

Patient-Reported Outcomes

In studies assessing PROs, injection devices were identified as important considerations to patients’ experiences of biosimilar switching. Following a 2019 mandated adalimumab switch in Iceland, patients reported that the biosimilar was more challenging to use, citing more painful injections, burning sensations during injection, and experiencing a prolonged injection compared with the RP [52]. However, it should be noted that while over 90% of the 198 patients surveyed stated that they had received individualized instruction on using the RP injection device, only 18% accepted instruction in the case of the biosimilar injection pen. While high-concentration and citrate-free formulations have been developed to improve the prolonged timing and burning sensation associated with administration, respectively, patient education on administration and expectations may improve outcomes. In line with this, outcomes reported by patients with rheumatic diseases also suggest that higher patient satisfaction is correlated with the availability of training for the biosimilar device, provider education, and availability of patient support programs. Patients who underwent transition to a biosimilar reported high overall satisfaction with being informed early on during the transition process by physicians, pharmacist support during the transition, and the availability of the biosimilar. Patients were least satisfied with the lack of injection supplies provided with biosimilars and patient support programs provided by the manufacturer, particularly nurse support and text/email reminders to inject that they were previously receiving as a benefit of the patient support program provided by the RP manufacturer [21].

In a UK survey of patient satisfaction following switching, a third of patients who expressed reservations regarding switching felt that their concerns were not adequately addressed [22]. In this study, patients who expressed worsening symptom control following switching also tended to report greater dissatisfaction with all aspects of the switching process, including a lack of information from providers, education, and implementation; the investigators partially attributed the most reported problem, worsened injection pain, to the nocebo effect. Conversely, satisfaction with written and verbal information about the switch provided by HCPs has been associated with fewer reported side effects. Deprez et al. found that among patients who did not switch to a biosimilar from adalimumab RP, the most common reasons included fear of disease flare, ease of remaining on the RP, lack of trust in biosimilars, and negative experiences with disease burden [29]. In patients who switched, the main reasons for patient dissatisfaction following switching included insufficient information provided by patient support organizations, inadequate training for the new device, device quality, perceptions of biosimilar safety and efficacy following switching, and the availability of alcohol wipes and sharps bins [53].

Inter-Biosimilar Switching

Switching Between Biosimilars

As adalimumab biosimilars become available across multiple disease indications, RWE can provide relevant and valuable evidence for HCPs to complement data derived from clinical trials when implementing switching among biosimilars in a practice setting. There is limited evidence on outcome comparisons between patients who switched between adalimumab biosimilars and those who switched from adalimumab RP to an adalimumab biosimilar. Lontai et al. found no significant differences in clinical remission rates at any time point over 24 weeks in patients with IBD who underwent switching from RP to the biosimilars adalimumab-adaz, adalimumab-atto, or adalimumab-aacf (Idacio^®) (n = 174) and biosimilar-to-biosimilar switching (n = 102) from adalimumab-atto (n = 85) or adalimumab-aacf (n = 17) to adalimumab-adaz [54]. Similarly, Scrivo et al. reported no differences in PROs in patients with RA, PsA, and axSpA in RP-to-adalimumab-bwwd switching (n = 110) over 4 months [55]. However, the same study identified worsening in the patient global assessment Visual Analog Scale in patients with PsA or RA, and a worsening in Health Assessment Questionnaire in patients with RA following adalimumab-atto-to-adalimumab-bwwd switching (n = 40) over a similar period. Investigators also reported a significant reduction in remission and significantly higher risk for moderate–high disease activity after switching (relative risk 2.6 [95% CI 1.2–5.7], p = 0.01) in the RP-to-biosimilar cohort compared with baseline disease activity just before switching. However, in the biosimilar-to-biosimilar switching cohort, no differences were observed in outcomes or the percentage of patients in remission compared with baseline, and PROs [54, 55].

Real-world studies on biosimilar-to-biosimilar switching reported similar efficacy and safety with respect to disease activity, remission rate, loss of response, AEs, and immunogenicity [54, 56, 57]. These findings were consistent over multiple switches where patients taking the RP were first switched to one biosimilar and then to a second one [55]. A comparison of four adalimumab biosimilars, adalimumab-atto, adalimumab-adaz, adalimumab-bwwd, and adalimumab-aacf, in an outpatient setting for the treatment of IBD found no significant differences in efficacy or safety between the four therapies [58, 59]. None of the studies that assessed immunogenicity observed a change in immune response for patients who switched between biosimilars.

RWE on Direct Biosimilar Comparisons

Limited evidence from head-to-head comparisons of biosimilars is available and the increasing number of biosimilars introduced to the market can make head-to-head comparison studies difficult to conduct [56, 60, 61]. While clinical studies conducted by sponsors for the approval of biosimilars comparing RPs to biosimilars focus on efficacy, safety, and immunogenicity, comparisons between biosimilars include factors in treatment retention such as discontinuation, requirement of additional therapies to prevent disease progression or worsening, or dose escalation.

A head-to-head comparative study of adalimumab-adaz (n = 623) and adalimumab-bwwd (n = 695) following a mandatory switching policy in Denmark found slight differences in the 6-month remission rate and rates of discontinuation after 1 year in patients with RA, PsA, and axSpA [37]. Compared with adalimumab-bwwd, estimated risk of withdrawal for adalimumab-adaz was lower (hazard ratio [HR] 0.60; 95% CI 0.42–0.86) and the 6-month remission rate was higher (odds ratio [OR] 1.72; 95% CI 1.25–2.37). At the 1-year follow-up, 8.5% and 12.9% withdrew from adalimumab-adaz and adalimumab-bwwd treatment, respectively (primarily owing to lack of effect or AEs), of whom 48 patients (3.6%) switched back to the RP. Differences in outcomes between the two biosimilars were attributed to drug-specific confounders such as the injection device, injection-site reactions, and excipients (including the presence of citrate in the biosimilars associated with burning sensations at the injection site). The investigators also identified variance in the included patient populations such as socioeconomic status, disease severity, the presence of comorbidities, and geographic region as residual confounders of switching outcomes.

Another comparison of patients with IBD who switched from either adalimumab RP to adalimumab-atto (n = 55) or RP to adalimumab-bwwd (n = 25) found no differences in disease activity, drug survival, or need for drug regimen optimization of either biosimilar compared with the RP, indicating that switching did not affect effectiveness and safety [36]. However, a greater percentage of patients who switched to adalimumab-atto required the addition of temporary oral steroids (n = 8, 14.5%; p = 0.01) due to a disease flare. Patients who switched to adalimumab-atto also had higher rates of discontinuation (n = 8) compared with those who switched to adalimumab-bwwd (n = 1), with inefficacy (n = 6) being the chief reason for discontinuation.

Considerations for Biosimilar Uptake in the USA

An important distinction between the EU and the US biosimilar markets is the difference in terminology for defining biosimilar products in relation to the reference biologics, which may have considerable effects on the approval process for regulatory authorities (Table 1). With the launch of several adalimumab biosimilars in the USA in 2023, the adoption of biosimilars in clinical practice can close gaps in patient care by reducing healthcare costs, increasing access to treatment, and addressing patient populations that are undertreated with biologic therapy [62]. While no head-to-head trials between biosimilars exist currently, available evidence on RP-to-biosimilar switching has driven confidence in the proven efficacy and safety of biosimilars, and should be communicated with patients to ameliorate concerns or unfamiliarity with biosimilars [63]. However, evaluating the outcomes of reverse, multiple, and cross-switching among biologics and biosimilars due to third-party mandates and formulary changes will be a challenge for US-based HCPs.

An additional challenge for US HCPs is the FDA interchangeability designation for biosimilars that is unique to the USA, and the resulting variable requirement for pharmacists to notify physicians of switching to a biosimilar, where notification can occur before, during, or after the switch, depending on state laws [64]. This could be a major contributor to patient outcomes, particularly through the nocebo effect, as a pharmacist could make a switch without the patient being made aware of the change in advance or receiving appropriate education about the biosimilar. The specificity of state laws may also be of particular significance to patients who receive medications via mail-order pharmacies, as patients would be subject to pharmacy laws based in the state where the pharmacy is located, rather than the patient’s home state. If it were to become a finalized guidance, a June 2024 FDA guidance would obviate the need for specific switching studies to support the interchangeability designation and thereby potentially allow all interchangeable biosimilars to be considered at the time of initial approval without a requirement for additional clinical studies [65].

Several RWE studies noted the impact of the nocebo effect on patient outcomes. Strategies to prevent or mitigate the nocebo effect include framing patient communications in a positive context, proactively discussing the switch and addressing patient concerns, and providing healthcare workers with training on how to respond to patient concerns about biosimilars and subjective health complaints following switching [51, 66, 67]. Pharmacist counseling may also help to prevent the nocebo effect and improve the retention rate following biosimilar switching [44]. Some additional considerations for HCPs who are initiating a biosimilar switch with patients are summarized in Table 4.

Table 4.

Guidance for clinicians regarding switching from biologics to biosimilars [88]

Intervention	Implementation
• Assess patients’ information needs	• Assess patient knowledge of and attitudes toward biosimilars
• Develop a tailored communication strategy to reduce risk of nocebo effects	• Provide information tailored to the individual patients’ needs such as the patient’s beliefs, concerns, demographics, and health literacy, and utilizing information from scientific and medical associations, regulatory authorities, and patient associations
• Educate patients on what to expect	• Have pre-emptive discussions surrounding what the patient should expect after switching. Some questions patients may ask include: o Why does my pen look different? o Why is this coming in a syringe when before it was an autoinjector? o Why is the packaging a different color? Should I be worried about different inactive ingredients? • If the biosimilar is available as a different formulation or route of administration, provide information to the patient so that they are aware of the administration requirements and are comfortable with self-administration, if applicable
• Provide information with language that is patient-friendly and homogenous	• Materials provided to the patient should be consistent so as to avoid confusing the patients and promote higher acceptance and better treatment outcomes
• Utilize soft skills	• An open and positive attitude should be adopted by all healthcare providers (i.e., physicians, nurses, and pharmacists) who communicate with patients • This involves empathy, reassurance, and nonverbal elements in their communication toward patients when discussing medicines in general

Many factors must be considered when initiating biosimilar switching: switching data are not comparable across different biosimilars of the same biologic; differences in the incidence or type of AEs upon switching must be considered against the nocebo effect; and data from clinical trials that include rigorous inclusion and exclusion criteria that may not reflect the patients seen by HCPs in a practice setting [68]. Furthermore, these considerations may vary across therapeutic areas. As evidenced in the real-world studies presented in this review, clinical and safety outcomes, and even the availability of real-world data, vary across disease states from IBD to PsO to rheumatologic conditions.

The uptake of adalimumab biosimilars in the EU has seen significant healthcare cost savings generated by pricing competition as more biosimilars become available; however, there are some limitations for adalimumab biosimilars in a US setting. Differences in healthcare systems, government policies, and third-party payer mandates may affect the adoption of adalimumab biosimilars in the US market. Additionally, although pricing competition may drive down the cost of adalimumab biosimilars as more emerge on the US market, the lack of transparency in list pricing, rebates, discounts, and other incentives make it difficult to correlate the introduction of multiple adalimumab biosimilars with increased patient accessibility, lower out-of-pocket costs, and lower healthcare expenditure. For instance, the list price for adalimumab RP increased 141% from (US)$1153 to $2784 from 2013 to 2020 while rebates from manufacturers to pharmacy benefit managers (PBMs) increased from 2.4 to 34.9% of list price ($28 to $973) in the same time frame, thereby increasing the profit margins to PBMs when the originator biologic is dispensed [69]. This practice incentivizes PBMs to design their formularies so that HCPs and patients prioritize use of the originator biologic in place of biosimilars [70, 71]. Despite increasing rebates, the net price of adalimumab RP in 2020 was $1812 for US commercial and Medicare Part D insurance plans. In 2023, the lowest-cost formulation of adalimumab-atto had a list price of $1558, a 14% discount from the 2020 net price of adalimumab RP [72]. An analysis of US prescription net pricing data for TNF inhibitors identified a similar trend; despite growing manufacturer discounts, net prices of self-administered injectable TNF inhibitors increased at an average rate of 9.6% annually from 2007 to 2019. Overall, net prices tripled for adalimumab RP and more than doubled for etanercept, golimumab, and certolizumab RPs [69].

While potentially cost-effective in comparison to reference biologics when they first enter the market, whether newly approved adalimumab biosimilars will entail greater availability and accessibility to previously underserved patient populations cannot be realistically addressed in this review. However, experience from the introduction of infliximab biosimilars suggests that the availability of multiple biosimilars can lead to reductions in the price of the RP, and this effect has been further observed in trastuzumab, pegfilgrastim, and rituximab [71, 73]. Access to biologics may be clear for patients on commercial insurance plans because of pharmaceutical co-pay card programs. This help is largely unavailable to patients with government-funded plans such as Medicare (including Medicare Advantage) and Medicaid. Although some straight Medicare patients have supplemental insurance plans that may help offset or eliminate out-of-pocket costs, the other groups do not and thereby they may not be able to afford the co-pay—lower though this may be for biosimilars—limiting their access. Given this reality, while the aim of reducing the overall price of biologics and the cost to the system may be achieved, the overarching goal of increasing access to all patients in need remains elusive.

Future studies evaluating real-world outcomes of biosimilar utilization in the US market may benefit from a patient-oriented focus to evaluate how the introduction of biosimilars can be used to leverage gaps in care. HCPs in the US may benefit from RWE that discusses unmet needs, particularly where increased access and informational materials could improve outcomes for patients who are underserved, undertreated, or underinsured.

Conclusions

The overarching purpose for the introduction of biosimilar biologics is to increase competition in the marketplace to help lower prices and to increase access to patients in need. Inevitably, in real-world experience, switching to and among RPs and biosimilars will be happening. This article briefly describes clinical trial experience of adalimumab with very constrained conditions that provides evidence for no significant impact on efficacy, safety, and immunogenicity in populations of patients with immune-mediated inflammatory diseases who underwent a limited number of switches from RP to biosimilar and back.

More extensively described is the ex-US real-world experience of RP and biosimilar adalimumab switches which generally reflects the clinical trial experience. However, the success of real-world experience in essence lies in treatment retention of patients which reflects the goals of efficacy, safety, and inherent immunogenicity which can mitigate durability of therapy. From the evidence available, the retention rates after switches were in the 85–98% range for most studies of inflammatory arthritis and psoriasis, but in the 70% range for IBD. This could be related to higher degrees of immunogenicity in the IBD populations, although this was not reported. The relative high success of overall drug retention in the switching between and among bio-originator and biosimilars yields some level of confidence. But it clearly is not 100% successful given all of the factors that have been identified in this review, including the nocebo effect, secondary loss of efficacy, adversity, device confusion, and other patient preferences and perceptions of biologic switching. To counter these challenges, patient education, provider training, and supportive policies to ensure successful integration of biosimilars into routine clinical care should be employed.

This informs US clinicians of the need to anticipate variability of individual patient outcomes and adjust treatment strategies accordingly. The overall message, however, is given the reality of payer systems that pressure patients to switch biologics, one can conclude this forced strategy so far appears reasonably successful overall for adalimumab biologics. Future research should prioritize understanding of whether biosimilar adoption increases access for underserved populations, the role of therapeutic monitoring, and long-term implications of interchangeability in diverse healthcare settings. Given the future landscape of the utilization of bio-originators and biosimilars, use potentially could evolve in parallel with previous experience of small molecules. Rather than order medicines by brand name, clinicians will order by biologic name and the choice may be left to whichever RP or biosimilar is accessible to that patient.

Declarations

Funding

This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA. The authors received no payment related to the development of the manuscript.

Conflict of interest

JRPT is a consultant for Abbvie, Amgen, Boehringer Ingelheim, and Pfizer, is part of the speaker bureau for Abbvie, Amgen, and Pfizer, and has received research grants from Abbvie, Amgen, Biogen, Boehringer Ingelheim, and Pfizer. AC is a consultant and/or advisory board member for Abbvie, Boehringer Ingelheim, Eli Lilly, Janssen, Takeda, and Pfizer. AAH has no competing interests to declare that are relevant to the content of this article. The authors met criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. Jia Gao, PharmD, of Elevate Scientific Solutions LLC, provided medical writing, editorial support, and formatting support, which were contracted and funded by BIPI.

Data availability statement

Not applicable.

Ethics approval

Research ethics approval was not required as no participants took part in this study.

Patient consent to participate/publish

Not applicable.

Code availability

Not applicable.

Author contributions

JRPT, AC, and AAH contributed to the conceptualization of this review article, and subsequent literature search and interpretation of data. All authors reviewed the manuscript for important intellectual content and approved the final version of the manuscript. The authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.