Biosimilars in inflammatory bowel disease: Beyond evidence, toward trust and implementation

Abstract

The growing burden of inflammatory bowel disease (IBD) has increased pressure on healthcare systems to deliver effective biologic therapy at sustainable cost. Biosimilars offer an important opportunity to expand access to advanced treatment, yet their uptake in IBD remains inconsistent despite substantial evidence supporting comparable efficacy, safety, and immunogenicity. In this opinion review, we examine the current evidence for biosimilar use in IBD, including biologic-naive initiation, single switching, multiple switching, and emerging reverse-switch data. We also analyze the key controversies that continue to impede adoption, particularly immunogenicity, indication extrapolation, non-medical switching, and switch-back decisions. Beyond evidence-level debates, we examine the multi-level barriers that shape biosimilar implementation in practice, including the nocebo effect, physician hesitation, and system-level implementation constraints. We further propose a pragmatic 5-step framework to support structured biosimilar initiation or switching in routine IBD care. Finally, we consider the distinctive challenges of biosimilar implementation in resource-limited settings and introduce the concept of a “nocebo-prone environment” as a proposed explanatory lens for understanding barriers to equitable biosimilar integration.

Key Words: Biosimilars; Inflammatory bowel disease; Nocebo effect; Biologic switching; Health equity

Core Tip: Biosimilars in inflammatory bowel disease have moved beyond a narrow question of pharmacological equivalence. Although current evidence supports their efficacy, safety, and use across multiple clinical scenarios, adoption remains limited by nocebo-related discontinuation, physician hesitation, and system-level implementation barriers. This opinion review synthesizes current evidence, examines persistent controversies, and proposes a pragmatic 5-step framework for biosimilar initiation or switching in routine care. It also highlights the special challenges of resource-limited settings and introduces the concept of a “nocebo-prone environment” as a practical lens for understanding barriers to equitable biosimilar integration.

INTRODUCTION

The rising global burden of inflammatory bowel disease and the cost imperative

Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is no longer a disorder concentrated in Western countries alone[1]. As its incidence rises across Asia, the Middle East, and Latin America, IBD is becoming a global chronic disease challenge that increasingly strains healthcare systems already facing constraints in specialist capacity, long-term monitoring, and access to advanced therapy[1,2]. In this evolving landscape, the central therapeutic question is not only how to control moderate-to-severe disease, but how to make effective biologic treatment available at scale. Recent epidemiologic analyses suggest that many newly industrialized regions are now following the same trajectory previously observed in North America and Europe, with rapidly increasing disease burden and a growing need for sustained, high-cost care[3].

The economic implications of this shift are profound. Although biologic therapies have transformed the management of moderate-to-severe IBD, their cost remains a major barrier to timely initiation and long-term continuity of care[4,5]. In the United States, spending on biologics for IBD increased nearly nine-fold from 2014 to 2023[4], while in many Asian settings, the annual cost of anti-tumor necrosis factor therapy remains far beyond the reach of most patients[5]. In resource-limited settings, the problem is not simply whether biologics are clinically effective, but whether patients can access them at all. Biosimilars offer an important response to this access crisis. They are biological products that are highly similar to an already approved reference product, with no clinically meaningful differences in safety, efficacy, or immunogenicity[6,7]. By creating additional budgetary flexibility, biosimilars may help create opportunities for broader treatment access or support the reallocation of resources toward other unmet therapeutic needs[8]. In Europe, biosimilar adoption has yielded savings representing 4.6% and 3.9% of national pharmaceutical budgets in the Netherlands and Sweden, respectively[8].

Biosimilars: Regulatory framework and the confidence gap

Unlike small-molecule generic drugs, which are chemically identical to their reference products, biosimilars are complex biologic products manufactured in living systems, which makes exact replication neither expected nor scientifically necessary for regulatory approval[8,9]. Regulatory agencies have therefore developed rigorous, stepwise approval pathways that rely on totality-of-evidence assessments rather than requiring full-scale clinical development programs. The World Health Organization updated its biosimilar evaluation guidelines in 2022, establishing a robust global framework that is broadly consistent with the approaches of both the European Medicines Agency and the United States Food and Drug Administration[6,7]. The European Medicines Agency provides product-specific guidance documents, while the United States Food and Drug Administration adopts a case-by-case approach; both require a step-wise approach of head-to-head analytical, non-clinical, and clinical comparisons to demonstrate biosimilarity[7]. A key regulatory concept underpinning biosimilar approval is the principle of indication extrapolation, whereby approval in one indication may be extended to other indications of the reference product without requiring separate clinical trials in each disease, provided sufficient scientific justification[7,9].

However, a persistent disconnect exists between the rigor of regulatory approval and the confidence of prescribing clinicians. Despite the strength of the regulatory framework, survey data reveal that while 54%-94% of physicians report confidence in prescribing biosimilars, 65%-67% simultaneously express concerns regarding safety, efficacy, and immunogenicity[10]. A recent multinational survey of 233 IBD physicians across 63 countries confirmed that this perception gap persists even in the face of accumulating supportive evidence[11]. This paradox, whereby clinicians acknowledge the regulatory science yet hesitate at the point of prescribing, suggests that the barriers to biosimilar adoption extend far beyond evidence and into the domains of psychology, communication, and clinical culture.

Scope and thesis of this review

In this opinion review, we critically appraise the current evidence supporting biosimilar use in IBD, examine the persistent controversies that impede their adoption, and analyze the multi-level barriers (at the patient, physician, and healthcare system levels) that sustain the gap between evidence and practice. We also propose a structured, 5-step clinical framework intended to support the equitable integration of biosimilars into routine IBD care, with particular attention to the unique challenges faced by resource-limited and developing healthcare settings. Our central thesis is that the challenge has shifted from the basic demonstration of biosimilar validity to the responsible interpretation, communication, and implementation of that evidence in routine care[11,12]. In this context, the goal of this review is not to promote indiscriminate biosimilar substitution, but to examine how biosimilars can be integrated transparently, responsibly, and context-sensitively into IBD practice. Such an approach, we suggest, may be important if biosimilars are to support broader access to biologic therapy for patients who still face major affordability and availability barriers.

CURRENT EVIDENCE IN IBD: WHAT THE DATA SHOW AND WHAT THEY DO NOT

Efficacy and safety: From pivotal trials to real-world practice

The evidence base supporting the clinical use of biosimilars in IBD has matured considerably over the past decade, spanning randomized controlled trials, large prospective registries, and nationwide real-world cohorts (Table 1). Collectively, these studies now address not only efficacy and safety, but also switching outcomes, treatment persistence, and the practical performance of biosimilars in routine care.

Table 1 Key evidence supporting biosimilars in inflammatory bowel disease.

Ref.	Design	Population	Agent	Key finding	Clinical relevance	Contextual interpretation1
Jørgensen et al[13], 2017	RCT, double-blind, non-inferiority	482, IMDs including IBD	CT-P13 (IFX)	Non-inferior: Disease worsening 26% (originator) vs 30% (switch)	First RCT-level evidence that a single switch does not compromise outcomes	A pivotal trial, though IBD subgroup was underpowered. Provides reassurance for switching in stable patients but does not address biologic-naive initiation or multiple switches
Ye et al[14], 2019	RCT, double-blind, phase 3	220, biologic-naive CD	CT-P13 (IFX)	Comparable clinical response and remission at weeks 6 and 30	First IBD-specific RCT confirming biosimilar efficacy in naive CD	Provided IBD-specific randomized evidence that helped reduce concerns about extrapolation from non-IBD indications
Fiorino et al[16], 2017; Armuzzi et al[17], 2019	Prospective multicenter cohort	810 (initial cohort 547), IBD, Italy	CT-P13 (IFX)	Response: 73.7% naive, 78.9% switch at 24 weeks; 71% biologic-naive at 12 months	Largest prospective European biosimilar IBD cohort	Demonstrated real-world effectiveness across naive, pre-exposed, and switched patients. Response rates were broadly consistent with historical originator data, providing supportive real-world context for biosimilar use
Barberio et al[18], 2021	Propensity score-weighted	IBD cohort	ABP501, SB5 (ADA)	Comparable remission maintenance vs originator ADA	Extended biosimilar evidence beyond IFX to ADA	Methodologically valuable for using propensity-score weighting to reduce selection bias. It also extends the evidence base to adalimumab biosimilars, an increasingly relevant class in routine practice
Moura et al[19], 2026	Retrospective registry	Canadian IBD, multiple biosimilars	Multiple (IFX, ADA)	No significant difference in remission, hospitalizations, or ED visits	Real-world Canadian data supporting biosimilar initiation	Notably addresses initiation (not only switching). Observational design limits causal inference, but the breadth of outcomes measured strengthens clinical applicability
Komaki et al[15], 2017	Systematic review and meta-analysis	IBD, CT-P13 studies	CT-P13 (IFX)	Equivalent efficacy and safety across pooled studies	Systematic synthesis of early biosimilar IBD data	Did not identify a clear signal of inferiority across heterogeneous studies. Useful for clinicians seeking a summary-level evidence assessment, though limited by the quality of included studies
Kritzinger et al[23], 2025	Retrospective observational cohort	81, IBD (85.2% CD), Canada (McGill)	Ustekinumab biosimilar (non-medical switch from originator)	Complete response stable: 87%, 85.9%, 84.3%, 92.7% (week 8 before switch, baseline, week 12, week 24, not significant). Drug sustainability 96.3% at 12 weeks, 95% at 24 weeks. Discontinuation 4.9%	First real-world ustekinumab biosimilar switching data in IBD	Extends biosimilar evidence beyond anti-TNF therapy to the IL-12/23 pathway. The high short-term persistence observed despite substantial prior biologic exposure supports the feasibility of ustekinumab biosimilar switching, although longer-term data remain needed

¹The “contextual interpretation” column reflects the authors’ assessment and does not represent formal guideline recommendations.

RCT: Randomized controlled trial; IMDs: Immune-mediated diseases; IBD: Inflammatory bowel disease; CD: Crohn’s disease; IFX: Infliximab; ADA: Adalimumab; ED: Emergency department; TNF: Tumor necrosis factor; IL: Interleukin.

Randomized and comparative studies have been central to establishing clinical confidence. The landmark NOR-SWITCH trial, a 52-week, double-blind, randomized non-inferiority study of 482 patients with immune-mediated inflammatory diseases including IBD, demonstrated that switching from originator infliximab to CT-P13 was non-inferior to continued originator therapy, with disease worsening occurring in 30% of the switched group vs 26% in the originator group[13]. The pivotal randomized controlled trial further established the efficacy and safety of CT-P13 specifically in CD, confirming comparable clinical response and remission rates at week 6 and week 30 in a population of biologic-naive patients[14]. These findings were consolidated by systematic meta-analyses, including the comprehensive review, which demonstrated equivalent efficacy and safety of CT-P13 across IBD indications[15].

Large-scale real-world evidence has reinforced these trial findings. The Italian PROSIT-BIO cohort, a prospective multicenter study of 547 IBD patients treated with CT-P13, reported clinical response rates of 73.7% in biologic-naive patients and 78.9% in switched patients at 24 weeks, with no significant differences across treatment groups[16]. The prolonged PROSIT follow-up (n = 810, mean 345 days) confirmed sustained effectiveness with 71% of naive patients maintaining response at 12 months[17]. More recently, comparable remission maintenance with adalimumab biosimilars (ABP501 and SB5) was demonstrated in a propensity score-weighted IBD cohort[18], while no significant differences in clinical remission rates, hospitalizations, or emergency department visits between originator biologics and biosimilars were reported in a Canadian real-world registry[19].

Beyond traditional efficacy endpoints, persistence rates have emerged as a pragmatic measure of real-world effectiveness. Persistence reflects not only pharmacological performance but also patient trust, physician confidence, treatment satisfaction, and the absence of nocebo-driven discontinuation[19-21]. Available data indicate that persistence with adalimumab biosimilars in IBD reaches approximately 68.6% at 6 months and 60.4% at 12 months in patients switched from originators[22]. More recently, ustekinumab biosimilar switching data have demonstrated even higher drug sustainability, with 96.3% persistence at 12 weeks and 95% at 24 weeks despite a heavily pre-treated cohort[23]. These figures are broadly consistent with originator persistence rates reported in routine clinical practice. Collectively, both the American Gastroenterological Association 2024 guidelines for UC and the 2025 guidelines for CD now explicitly recognize biosimilars as appropriate alternatives to originator biologics, endorsing their use across clinical scenarios[24,25]. From a contemporary clinical perspective, the available literature increasingly suggests that biosimilars may be considered not only as acceptable switch options, but also as reasonable entry points into biologic care in selected settings[24,25]. These data support broader clinical use of biosimilars, while leaving important practical questions regarding patient selection, communication, and monitoring in routine care.

Switching strategies: From single switch to multiple transitions

The evidence on biosimilar switching in IBD has evolved through several categories of increasing clinical complexity. Single non-medical switching—the replacement of an originator biologic with a biosimilar in a patient in stable remission—is the most extensively studied scenario and is supported by the NOR-SWITCH trial and numerous real-world cohorts[13,16,17]. Systematic reviews and meta-analyses have confirmed that a single switch does not compromise efficacy, safety, or immunogenicity[15,26].

More recently, attention has turned to multiple successive switches between different biosimilars or between biosimilars and originator products. Emerging data, including a prospective multicenter study, suggest that multiple switches (e.g., originator → CT-P13 → SB2) are effective and safe, with clinical remission rates of approximately 65%-77%, and treatment persistence rates of up to 87% maintained at 12 months across all switching groups[27]. Reverse switching (switch-back from biosimilar to originator) has been documented primarily in the context of perceived treatment failure or adverse events following the initial switch; however, distinguishing true pharmacological failure from nocebo-driven discontinuation remains a significant methodological challenge in these studies[28]. Recent prospective cohort data indicate that reverse switching from biosimilar SB2 to originator infliximab may be feasible without clear short-term detriment to efficacy, immunogenicity, or safety, although the evidence remains limited and potentially affected by selection bias[28].

Taken together, the totality of evidence supports the clinical use of biosimilars in IBD across the spectrum of treatment scenarios—from biologic-naive initiation to single and multiple switching. However, clinical perception has not fully aligned with this evidentiary strength. This perception gap—rather than the evidence itself—represents one of the most important barriers to optimal biosimilar adoption and warrants targeted intervention at the patient, physician, and system levels.

PERSISTENT CONTROVERSIES AND MULTI-LEVEL BARRIERS

Despite growing evidence supporting biosimilar use in IBD, important controversies remain. These barriers operate at the patient, physician, and system levels, and often influence adoption more than the evidence itself. In many settings, the key challenge is no longer whether biosimilars work, but why their uptake remains inconsistent.

Evidence-level controversies

Immunogenicity, interchangeability, and the role of therapeutic drug monitoring: Among the most persistent clinical concerns surrounding biosimilar use in IBD is immunogenicity—specifically, the potential for anti-drug antibodies (ADAs) to develop or amplify following a switch from originator to biosimilar, leading to secondary loss of response. However, systematic evaluation of the available evidence does not support this concern as biosimilar-specific. A comprehensive narrative review demonstrated that immunogenicity is a class-related phenomenon inherent to all biologic therapies, including originators, and that ADA profiles observed with biosimilars are quantitatively and qualitatively comparable to those of their reference products[29]. This finding has been further corroborated in the IBD-specific context by a 2025 review that confirmed that neither switching nor initiating biosimilar infliximab or adalimumab confers an incremental immunogenicity risk beyond that expected with the originator molecule[30].

We suggest that immunogenicity concerns may be more appropriately interpreted through the lens of therapeutic drug monitoring (TDM) rather than viewed as an inherent flaw of biosimilarity. Proactive TDM—measuring trough drug levels and ADAs at defined intervals—enables clinicians to identify and manage immunogenicity regardless of whether the patient is receiving an originator or biosimilar product. Current expert reviews have recommended that biosimilar stewardship programs incorporate TDM as a standard component of switching protocols, thereby transforming immunogenicity from a theoretical barrier into a manageable clinical variable[31,32].

Extrapolation in IBD: From regulatory principle to clinical acceptance

The regulatory principle of indication extrapolation—whereby biosimilar approval in one immune-mediated disease (typically rheumatoid arthritis) can be extended to IBD without requiring separate clinical trials—has been a source of enduring physician discomfort. The underlying concern is that the pathophysiology of IBD, the target tissue, and the disease-specific immune milieu differ sufficiently from rheumatoid arthritis to preclude direct extrapolation of efficacy and safety data. A balanced appraisal of this debate acknowledged the scientific rationale for extrapolation while noting that it relies on the assumption of shared mechanisms of action across indications, an assumption that, while supported by pharmacokinetic and structural comparability data, is not universally accepted by practicing gastroenterologists[33]. Importantly, however, the initial apprehension surrounding extrapolation has been substantially mitigated by the accumulation of post-marketing, IBD-specific evidence over the past decade. Prospective registries such as PROSIT-BIO and nationwide cohorts have generated a body of real-world IBD data that effectively validates the extrapolation framework, even if it was not originally designed for that purpose[16,34].

Non-medical switching and switch-back dilemmas

Non-medical switching—defined as the replacement of an originator biologic with a biosimilar for economic or policy reasons rather than clinical indication—raises distinct ethical and practical concerns. When switching is mandated by formulary decisions or institutional cost-containment directives, patients and physicians may perceive a loss of therapeutic autonomy, which can erode trust and amplify negative expectations[35]. Healthcare providers frequently cite ambiguity in incentive structures, inadequate education, and medicolegal uncertainty as barriers to embracing non-medical switches, even when the evidence supports their safety[36]. The switch-back dilemma—whether and when to revert to the originator following perceived treatment failure after a biosimilar switch—further complicates clinical decision-making. A substantial proportion of biosimilar discontinuations in real-world practice are attributable to subjective symptoms rather than objective evidence of disease worsening, making it difficult to determine whether switch-back is clinically warranted or merely reinforces nocebo-driven perceptions[37].

Patient-level barriers: The nocebo effect and beyond

The nocebo effect—defined as the occurrence of adverse events or perceived treatment failure driven by negative expectations rather than pharmacological properties—represents one of the most clinically significant yet under-addressed barriers to biosimilar adoption in IBD. While the landmark consensus report established the conceptual and practical framework for understanding the nocebo effect in the biosimilar switching context[20], real-world observational studies have subsequently quantified its clinical burden, estimating that approximately 13% of patients experience nocebo-related phenomena rather than true pharmacological failure[38,39]. Further elucidation of the mechanistic pathways of the nocebo effect in medication switching identified three principal non-pharmacological triggers: The delivery of negatively framed information during the consent process, a prevailing lack of biosimilar knowledge among stakeholders, and inconsistent messaging across members of the healthcare team[35].

In evaluating adverse events, a conceptual framework distinguishing between subjective and objective nocebo responses is highly valuable. As established in prior allergy challenge studies, a subjective nocebo response consists of symptoms solely perceived by the patient (e.g., nausea, headache, or malaise), whereas an objective nocebo response involves measurable clinical manifestations (e.g., tachycardia, changes in blood pressure, or skin rashes) triggered by negative expectations rather than a pharmacological agent[40]. Applying this distinction to biosimilar transition in IBD, the NOCE-BIO consensus group emphasizes that nocebo-related complaints predominantly align with the subjective profile, occurring without objective deterioration in disease activity markers[12]. This distinction has critical implications for clinical management: While true objective pharmacological failures—distinct from nocebo, such as ADA formation or elevated inflammatory markers—may warrant dose adjustment or switching protocols, subjective nocebo responses are optimally managed through structured communication and psychological support. Supporting this framework, real-world clinical data confirm that nocebo-driven discontinuation persists for up to six months following a non-medical switch. The highest attrition rates occur in the first 12 weeks, which represents the critical window during which patient confidence is most vulnerable[38].

Beyond the nocebo effect per se, patient-level barriers extend to health literacy, trust in the healthcare system, and the increasingly pervasive influence of social media misinformation[41]. In many contexts, patients equate “biosimilar” with “generic” or “inferior copy”, a misconception that can be amplified by unregulated online narratives and peer testimonials[42]. These factors converge to create a psychological environment in which even well-informed patients may harbor residual doubt about their treatment, undermining both adherence and persistence (Figure 1)[21].

Figure 1 Conceptual model of the nocebo effect in biosimilar-treated inflammatory bowel disease. This figure illustrates how negative information framing during informed consent, knowledge gaps among stakeholders, and inconsistent messaging across healthcare team members may trigger adverse psychological mediators, including anxiety, negative expectations, and loss of trust. These mediators may contribute to both objective nocebo manifestations, such as measurable adverse events without a clear pharmacological basis, and subjective nocebo manifestations, such as perceived symptom worsening in the absence of objective inflammatory activity, ultimately leading to treatment discontinuation, switch-back requests, or reduced adherence.

Physician-level barriers: Knowledge, confidence, and cognitive bias

Despite the strength of the evidence base, physician hesitation remains a substantial impediment to biosimilar uptake. Survey data consistently reveal a paradox: While the majority of gastroenterologists acknowledge the scientific validity of biosimilar approval, a significant proportion express reluctance to prescribe or switch in practice[10,11]. Significant physician resistance to non-medical switching has been documented, with 84% of surveyed providers opposing the practice for stable patients. Rather than a single overriding issue, physicians cited a convergence of concerns, predominantly anticipating negative impacts on office management, patient mental health, treatment efficacy, and overall patient safety. In this context, policies that circumvent the physician-patient relationship or erode clinical decision-making autonomy are viewed highly unfavorably, as they may introduce perceived risks of adverse clinical outcomes and raise concerns about physician liability[43]. This concern, while understandable, is not supported by the current evidence on switching safety and may reflect cognitive biases—specifically, omission bias (the preference for inaction over action when outcomes are uncertain) and status quo bias (the preference for the familiar originator over the less familiar biosimilar).

Compounding these cognitive factors is a genuine knowledge deficit. Many healthcare providers lack confidence in their understanding of interchangeability designations, the distinction between biosimilarity and interchangeability, and the regulatory basis for extrapolation[36]. To effectively address these barriers, continuous education and the regular updating of healthcare providers are vital; this ensures that clinicians are equipped to provide appropriate, confident information to patients regarding biosimilar therapies[21,41].

System-level barriers: Policy, reimbursement, and institutional readiness

At the system level, the architecture of health policy, reimbursement structures, and institutional protocols exert a decisive influence on biosimilar adoption—often independently of the evidence. Mandatory switching policies, while effective in driving rapid uptake, may paradoxically undermine long-term confidence if implemented without concomitant communication strategies and robust regulatory guidance[43,44]. Furthermore, current payer-driven contracting models often fail to provide adequate financial incentives for biosimilar adoption. These models frequently prioritize short-term cost savings, which are driven by established rebate structures and deep discounts, rather than investing in the administrative facilitation and structured implementation programs essential for a sustainable transition[36]. Similarly, international Delphi consensus guidelines emphasize that successful biosimilar integration relies on coordinated institutional frameworks. Such frameworks must strategically align formulary decisions with clinician education, patient communication, and post-switch monitoring, which are essential elements that are frequently absent in resource-constrained settings[12,20].

The interaction between these three levels of barriers—patient, physician, and system—is bidirectional and synergistic (Figure 2). Physician uncertainty amplifies patient anxiety; inadequate system support leaves physicians without the tools to communicate effectively; and patient dissatisfaction, expressed through social media or complaints, reinforces institutional caution about implementing switching programs. Breaking this cycle requires interventions that address all three levels simultaneously, a principle that underpins the clinical framework proposed in the following section.

Figure 2 Multi-level barriers to biosimilar adoption in inflammatory bowel disease. This figure summarizes the interacting barriers to biosimilar implementation at the patient, physician, and system levels. Patient-level barriers include the nocebo effect, low health literacy, trust deficits, and social media misinformation. Physician-level barriers include knowledge gaps, cognitive bias, medicolegal concerns, risk aversion, and limited biosimilar experience. System-level barriers include mandatory switching policies without communication support, reimbursement structures focused on short-term savings, formulary constraints, and limited monitoring infrastructure. These barriers interact bidirectionally and may reinforce one another.

A PROPOSED FRAMEWORK FOR EQUITABLE CLINICAL ADOPTION

In practice, biosimilar adoption requires more than a simple product switch; it also requires appropriate patient selection, structured communication[12], and objective follow-up[32,45]. We therefore propose a pragmatic 5-step framework, informed by recent global surveys and updated regulatory consensuses[11,30,46], to support clinical decision-making during biosimilar initiation or switching. This framework is intended as an author-proposed practical model rather than a formally validated algorithm (Figure 3).

Figure 3 Pragmatic 5-step framework for biosimilar initiation or switching in inflammatory bowel disease. This figure presents an author-proposed clinical framework for structured biosimilar integration in routine inflammatory bowel disease care. The model includes scenario classification, risk stratification, structured communication, objective monitoring, and outcome assessment. It also identifies clinical situations in which switching may reasonably be deferred until treatment stability is achieved. This framework is intended as a practical decision-support model rather than a formally validated algorithm or guideline. TDM: Therapeutic drug monitoring; CD: Crohn’s disease.

Step 1: Identification of the clinical scenario

The first step requires explicit identification of the clinical context in which a biosimilar is being considered, as each scenario carries distinct clinical and psychological implications[47,48] (Table 2). Three principal scenarios should be distinguished: (1) Biologic-naive patients initiating their first biologic therapy, for whom the biosimilar can be offered as the default first-line agent on pharmacoeconomic grounds[47,48]; (2) Patients in stable remission on an originator biologic, for whom a non-medical switch is being considered; and (3) Patients with a prior switching history or previous biologic exposure, who may carry residual concerns or immunogenicity risk[47,48]. The distinction between these scenarios is clinically meaningful: Biologic-naive patients have no prior reference point and are therefore less susceptible to the nocebo effect, whereas patients being switched from a familiar originator require more intensive communication and expectation management[12].

Table 2 Clinical scenarios and suggested approaches for biosimilar use in inflammatory bowel disease.

Clinical scenario1	Risk profile	Suggested approach	Monitoring	Key considerations
Biologic-naive initiation	Generally low	Biosimilar as default first-line biologic on pharmacoeconomic grounds	Standard protocol (CRP, FCP at 4-6 weeks, 12-week, 6-month)	Lowest nocebo risk (no prior reference point). Cost savings most impactful at population level. Shared decision-making still recommended
Stable remission on originator	Low to moderate	Non-medical switch with structured communication (positive framing, one voice)	Standard protocol + clinical reassessment at 4-6 weeks	Highest nocebo risk. Communication quality is the key determinant of success. One voice strategy essential. Most extensively studied scenario (NOR-SWITCH, PROSIT-BIO)
Prior switching history	Moderate	Individualized assessment; consider TDM at baseline and 12 weeks	Enhanced: TDM + biomarkers at closer intervals	Prior immunogenicity signals may warrant proactive TDM. Distinguish prior pharmacological failure from nocebo-driven discontinuation before deciding approach
Complex disease (fistulizing CD, extensive colitis, EIM)	High	Caution advised; biosimilar initiation feasible but switching should be deferred during active disease	Enhanced: TDM + endoscopy/imaging as indicated	Treatment stability takes precedence over cost optimization. If switching, ensure that disease is in remission with objective confirmation before transition
Special populations (pregnancy, pediatric, postoperative)	High (context-dependent)	Defer switching; maintain current effective therapy. Biosimilar initiation in naive patients may be considered case-by-case	Standard + disease-specific monitoring	Limited data on switching during pregnancy or postoperative period. Stability and continuity of care are priorities. Pediatric data emerging but still limited

¹This table represents a pragmatic author-proposed framework and does not constitute formal guideline recommendations. Clinical judgment should be exercised for individual patients.

CD: Crohn’s disease; EIM: Extraintestinal manifestations; TDM: Therapeutic drug monitoring; CRP: C-reactive protein; FCP: Fecal calprotectin.

Step 2: Risk stratification

Within each clinical scenario, patients should be stratified according to their individual risk profile. High-risk patients, including those with prior immunogenicity (documented ADAs or secondary loss of response), severe or complicated disease phenotype (stricturing or penetrating CD, extensive colitis), or a history of multiple treatment failures, warrant a more cautious approach, with closer monitoring intervals and proactive TDM[32,49]. A recent meta-analysis demonstrated that post-switch remission rates are consistently high across risk categories but that patients with prior switching history may exhibit modestly lower persistence, reinforcing the value of risk-adapted monitoring[50]. Conversely, low-risk patients, those in stable deep remission with no prior immunogenicity signals, can be transitioned with standard monitoring protocols[46,50]. Real-world data, including prospective cohorts evaluating multiple successive switches, have confirmed that patients maintain favorable clinical and biochemical outcomes without incremental safety signals[51].

We suggest that biosimilar introduction is often most feasible in settings where baseline disease assessment, patient education, and follow-up are well established. By contrast, switching may warrant greater caution, and may often be deferred, in patients with active disease flare, complex perianal or fistulizing CD, pregnancy or planned conception, or the immediate postoperative period, where treatment stability and clinical continuity may reasonably take precedence over cost considerations[49,52]. This more cautious approach reinforces the principle that biosimilar integration should remain individualized, context-sensitive, and patient-centered.

Step 3: Shared decision-making and communication precision

Effective communication should not be viewed merely as an adjunct to biosimilar implementation, but as a central component of the intervention itself. The manner in which a physician introduces, explains, and contextualizes the transition determines the patient’s psychological response and, by extension, their clinical outcomes[12,21]. A comprehensive framework for shared decision-making in the context of IBD biologic therapy has emphasized that patients who actively participate in treatment decisions report higher satisfaction, better adherence, and lower rates of nocebo-driven discontinuation[21,53].

We suggest a structured communication approach built on three principles: (1) Positive framing: The conversation should emphasize the validated equivalence of the biosimilar and the regulatory rigor of its approval, rather than dwelling on theoretical risks or differences[21]; (2) The “one voice” strategy: Every member of the healthcare team—gastroenterologist, nurse, pharmacist, and infusion center staff—must deliver a consistent, aligned message[44]. Divergent opinions or equivocal language from any team member can seed doubt and amplify nocebo responses[35]. This principle has been reinforced from a regulatory perspective, with calls for strengthened one voice messaging as a cornerstone of biosimilar implementation[44]; and (3) Expectation management: Patients should be counseled that transient subjective symptoms (mild fatigue, injection site discomfort) may occur during any treatment transition and do not indicate treatment failure[12,21]. Innovative approaches, including digital educational tools and gamification-based training for healthcare professionals, have shown promise in standardizing communication quality and reducing nocebo incidence[54]. Public deliberation studies have further demonstrated that patients value transparency, consistent messaging, and the opportunity to ask questions as the most important elements of the switching conversation[55].

Step 4: Monitoring strategy

Post-switch monitoring should be systematic, time-defined, and anchored in objective biomarkers rather than subjective symptom reporting alone[45]. Early follow-up should focus on both objective inflammatory control and the patient’s experience of the transition; discordance between symptoms and objective markers should prompt careful reassessment before attributing deterioration to biosimilar inefficacy[21,35]. We suggest a standardized protocol comprising clinical reassessment and inflammatory marker measurement (C-reactive protein and fecal calprotectin) at 4-6 weeks, 12 weeks, and 6 months following the switch[45,51]. Endoscopic evaluation (colonoscopy, with magnetic resonance enterography or computed tomography enterography for small bowel CD) should be performed when clinically indicated or when objective biomarkers suggest disease flare[45,49]. TDM, including trough drug levels and ADA assessment, should be considered at baseline and at 12 weeks for high-risk patients. This approach aligns with established proactive TDM consensuses[32,56], and has been effectively implemented in real-world biosimilar switch protocols[51]. In low-risk patients, routine biomarker-based follow-up may be sufficient, and TDM can be reserved for cases with suspected loss of response or discordance between symptoms and objective inflammatory markers[32,49]. Critically, the monitoring framework must be designed not only to detect treatment failure but also to distinguish true pharmacological failure from nocebo-driven symptom reporting—a distinction that has profound implications for subsequent management decisions[12,21].

Step 5: Defining persistence, switch-back, or escalation criteria

The final step establishes explicit criteria for the three possible trajectories following a biosimilar switch: Persistence (continuation of the biosimilar), switch-back (reversion to the originator), or escalation (transition to an alternative mechanism of action). Persistence may be considered the preferred trajectory when objective disease markers remain stable, even in the presence of transient subjective symptoms[12,21,45]. Switch-back should be reserved for patients with documented objective evidence of disease worsening (rising calprotectin, endoscopic inflammation, or confirmed ADAs) that cannot be attributed to intercurrent factors and should be preceded by a structured reassessment to exclude nocebo as the primary driver[12,45,56]. Escalation to an alternative therapeutic class is appropriate when both the biosimilar and originator have failed, as determined by objective criteria[49].

Taken together, this framework is intended to support clinical reasoning and implementation, not to replace individualized judgment or formal guideline recommendations. Its value lies in shifting biosimilar use from a simplistic substitution model toward a context-sensitive clinical strategy grounded in evidence, communication, and implementation quality.

EQUITABLE ACCESS AND IMPLEMENTATION IN RESOURCE-LIMITED SETTINGS

Access and economic constraints

The global discourse on biosimilars has been dominated by the experience of high-income healthcare systems in Europe and North America, where biosimilar adoption is primarily framed as a cost-optimization strategy[57]. However, for the majority of IBD patients worldwide—particularly those in low- and middle-income countries (LMICs) across Asia, Latin America, and Africa—the significance of biosimilars extends far beyond cost savings[5,58]. In these settings, originator biologics are frequently unaffordable or unavailable, and biosimilars represent the only realistic pathway to biologic therapy for patients with moderate-to-severe disease[59]. Compounding this challenge, IBD in many LMICs is characterized by low disease awareness, significant diagnostic delays, and a consequently higher burden of complicated disease phenotypes at presentation. The IBD-Emerging Nations’ Consortium, a multicenter study of over 10000 patients across 15 countries in South Asia, South-East Asia, and the Middle East, reported a median diagnostic delay of 12 months for CD, with biologic use remaining strikingly low at 4% for UC and 13% for CD despite substantial rates of stricturing and penetrating disease[60]. These findings suggest that, in resource-limited settings, biosimilars may represent more than a cost-optimization strategy and may help support access to guideline-concordant biologic therapy in populations that might otherwise remain undertreated. Biosimilar adoption in LMICs typically generates price reductions of approximately 30% relative to originators, creating savings that can be reinvested to expand the availability of biologic medicines[61]. Beyond competitive pricing, optimizing biosimilar access requires streamlined regulatory pathways and equitable reimbursement policies tailored to the unique pharmacoeconomic context of resource-limited settings[62].

Health system and infrastructure barriers

The implementation of biosimilar programs in resource-limited settings faces infrastructure barriers that are qualitatively distinct from those encountered in high-income countries[59]. Specifically, many healthcare systems across resource-limited regions in Asia lack routine access to TDM, fecal calprotectin assays, and advanced imaging modalities, which are considered standard tools for biologic monitoring in Western practice[58]. Without these objective monitoring capabilities, clinicians must rely more heavily on clinical assessment alone, which increases vulnerability to nocebo-driven discontinuation (where subjective symptom worsening is misattributed to biosimilar failure) and delays the detection of true treatment failure[12,21]. Furthermore, specific barriers in East Asia exacerbate these challenges, including diagnostic delays, constrained biologic access, and significant variability in physician training and familiarity with biosimilar evidence[63]. These systemic deficiencies compound patient-level and physician-level barriers, creating an environment in which biosimilar adoption is simultaneously more needed and more difficult to implement successfully.

Nocebo-prone environments: A proposed explanatory framework

We propose the concept of the “nocebo-prone environment” to describe healthcare settings in which structural conditions may amplify the risk of nocebo-driven adverse outcomes following biosimilar initiation or switching. This concept is intended as a pragmatic explanatory lens rather than a formally validated construct. Several structural conditions may contribute to this vulnerability. At the system and provider levels, these include short consultation times that preclude shared decision-making, policy-driven non-medical switching without proper communication strategies, and insufficient physician training in biosimilar science[12]. At the patient and societal levels, the risk may be further compounded by limited health literacy, the pervasive influence of social media misinformation, and a low baseline trust in non-originator medications, which is often rooted in historical experiences with substandard generic products[37]. In many developing healthcare systems, these factors do not operate in isolation but may converge to create a self-reinforcing cycle: Inadequate communication leads to negative patient expectations, which manifest as subjective adverse events. These, in turn, erode physician confidence in the biosimilar, further reducing institutional commitment to biosimilar programs[12,21].

If useful, this concept may offer practical implications for implementation in resource-limited settings. Whereas high-income settings can mitigate nocebo through dedicated biosimilar stewardship programs, nurse-led education, and routine TDM[12,56], resource-limited settings require adapted strategies—including community-based peer support, simplified patient education materials, and telemedicine-assisted follow-up—that account for the structural realities of the local healthcare environment (Table 3)[58,59].

Table 3 Comparison of biosimilar adoption challenges: High-income vs resource-limited settings.

Factor	High-income setting	Resource-limited setting1
TDM availability	Routine and proactive; integrated into standard switching protocols	Limited or unavailable in most centers; reliance on clinical assessment alone[58]
Consultation time	15-30 minutes; dedicated IBD clinics with multidisciplinary teams	5-10 minutes; general GI outpatient setting without dedicated IBD infrastructure[37]
Patient education resources	Nurse-led programs, digital tools, IBD helplines, patient associations	Limited; no dedicated IBD nurse specialist role in most settings[59]
Fecal calprotectin access	Standard of care; point-of-care testing increasingly available	Often unavailable or unaffordable; not routinely reimbursed[58]
Physician biosimilar training	Integrated into CME; supported by peer networks and professional societies	Variable; limited formal exposure; knowledge gaps regarding extrapolation and interchangeability[63]
Reimbursement structure	Established biosimilar incentive programs; gainsharing models	Restricted formularies; predominantly out-of-pocket payment; biosimilar-specific incentives rare[61]
Switching policy framework	Structured programs with shared decision-making; institutional protocols	Often policy-driven without concomitant communication support or monitoring infrastructure[12]
Nocebo risk environment	Moderate; mitigated by dedicated stewardship programs and infrastructure	High; structural amplification due to convergence of short consultations, low health literacy, social media misinformation, and low baseline trust[12,37]

¹Reference numbers correspond to the manuscript reference list. This comparison is intended to highlight structural differences that may influence biosimilar adoption outcomes; it does not imply that resource-limited settings are uniformly disadvantaged across all domains.

TDM: Therapeutic drug monitoring; CME: Continuing medical education; GI: Gastroenterology; IBD: Inflammatory bowel disease.

Policy and implementation needs

Translating the potential of biosimilars into more equitable access will likely depend on coordinated action at multiple policy and health-system levels. At the regulatory level, strengthened pharmacovigilance systems and more harmonized biosimilar approval pathways may help facilitate timely market entry without compromising safety standards[59]. At the institutional level, biosimilar formulary integration may be strengthened by physician education programs and standardized communication protocols—the “one voice” strategy adapted to local contexts[44]. At the healthcare delivery level, innovative models such as telemedicine-assisted monitoring, community health worker engagement, and simplified patient education materials can extend the reach of biosimilar stewardship programs beyond tertiary referral centers[59,64]. The experience of countries such as Brazil and India, where proactive biosimilar policies have expanded biologic access despite resource constraints, provides instructive precedents for other LMICs embarking on this transition[59,64].

In our view, the value of biosimilars in resource-limited settings lies not only in reducing costs, but also in their potential to expand access to biologic therapy for patients who might otherwise remain untreated or undertreated. In this sense, biosimilars may be viewed not only as cost-containment tools, but also as one potential means of reducing inequities in access to biologic therapy. However, expanded access should not come at the expense of informed decision-making, pharmacovigilance, or patient trust. Lower cost alone does not guarantee successful implementation; the potential benefits of biosimilars are more likely to be realized when affordability is accompanied by appropriate communication, monitoring capacity, and institutional readiness.

FUTURE DIRECTIONS

Toward pragmatic interchangeability and switching studies

While the existing evidence base supports the safety and efficacy of biosimilar switching in IBD, important gaps remain[50]. Most switching data derive from single-switch scenarios in stable patients; the evidence on multiple successive switches, reverse switching, and switching in complex disease phenotypes remains limited[51,65]. Future studies should therefore move beyond simple equivalence questions and prioritize pragmatic, cluster-randomized or real-world comparative designs that evaluate both treatment persistence and the impact of structured communication on nocebo-related discontinuation[66]. Long-term phase IV registries with immunogenicity monitoring across multiple biosimilar products will also be important for assessing interchangeability in IBD-specific populations over clinically meaningful time horizons[33].

Communication interventions to reduce the nocebo effect

The nocebo effect has been extensively described, yet surprisingly few interventional studies have tested specific communication strategies to mitigate it. The NOCE-BIO consensus group identified this as a priority research gap[12], and international Delphi experts have likewise emphasized that communication quality should be considered a core component of biosimilar implementation rather than an optional adjunct[11]. Future work should therefore focus on developing and validating structured communication toolkits, including patient education materials, healthcare professional training modules, and adaptable “one voice” implementation frameworks[44].

Region-specific implementation science

Because biosimilar adoption occurs across highly heterogeneous healthcare systems, implementation strategies must be tailored to local contexts. Approaches developed in well-resourced systems may not translate directly to Southeast Asia, Latin America, or sub-Saharan Africa. Region-specific implementation research is therefore needed to define the minimal effective package of patient education, physician training, monitoring intensity, and policy support required for safe and trusted biosimilar use in resource-limited settings[59,66]. Harmonized real-world registries, similar to the Canadian CAN-AIM initiative, may help capture the health-system and epidemiological factors shaping biosimilar outcomes across different regions[19].

CONCLUSION

Biosimilars in IBD have reached a level of clinical maturity supported by randomized trials, real-world evidence, and endorsement from major professional societies. In this review, we argue that the persistent gap between evidence and adoption is driven less by pharmacology than by trust, communication, and health-system design. To address this gap, we propose a structured 5-step framework for biosimilar integration and introduce the proposed concept of the “nocebo-prone environment” as a lens that may help explain why implementation can be especially challenging in resource-limited settings. Looking ahead, an important priority may be not only to generate additional comparative data, but also to improve implementation. In this context, the value of biosimilars may extend beyond cost reduction, particularly when they help support access to biologic therapy for patients who might otherwise remain untreated.