Biosimilars have transformed treatment modalities across various medical fields such as oncology, rheumatology, and immunology. Despite their potential for reducing healthcare costs, concerns persist regarding their ability to induce an immune response, which could affect efficacy and safety. This review critically evaluates the current evidence on the immunogenicity of biosimilars and discusses the regulatory frameworks guiding their approval and monitoring.

This review includes studies from databases like Scopus, PubMed, Web of Science, and ScienceDirect, published up to April 2024. It explores the 'totality of the evidence' approach used by regulatory bodies like the FDA and EMA, detailing analytical, preclinical, and clinical assessments that ensure biosimilars' similarity to their reference products in terms of structure, function, and clinical outcomes. The review also addresses the challenges and limitations in current research methodologies and the implications of immunogenicity on therapeutic efficacy and patient safety.

While substantial evidence confirms the safety and efficacy of biosimilars, the review emphasizes the need for continuous regulatory vigilance and advanced methodologies in post-marketing surveillance to capture long-term immunogenicity data effectively. It advocates for integrating cutting-edge analytical techniques and personalized medicine to better manage immunogenic risks associated with biological therapies.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is a group of chronic, immune-mediated disorders of the gastrointestinal tract that present substantial clinical challenges owing to their complex pathophysiology and tendency to relapse. A treat-to-target approach is recommended, involving iterative treatment adjustments to achieve clinical response, reduce inflammatory markers and achieve long-term goals such as mucosal healing. Lifelong medication is often necessary to manage the disease, maintain remission and prevent complications. The therapeutic landscape for IBD has evolved substantially; however, a ceiling on therapeutic efficacy remains and surgery is sometimes required (owing to uncontrolled disease activity or complications). Effective IBD management involves comprehensive care, including medication adherence and a collaborative clinician-patient relationship. This Review discusses current therapeutic options for IBD, detailing mechanisms of action, efficacy, safety profiles and guidelines for use of each drug class. We also explore emerging therapies and the role of surgery. Additionally, the importance of a multidisciplinary team and personalized care in managing IBD is emphasized, advocating for patient empowerment and involvement in treatment decisions. By synthesizing current knowledge and emerging trends, this Review aims to equip healthcare professionals with a thorough understanding of therapeutic options for IBD, enhancing informed, evidence-based decisions in clinical practice.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease marked by inflammation of synovium and generation of autoantibodies. Bone and cartilage are frequently damaged along with weakening of tendons and ligaments resulting in disability. An effective RA treatment needs a multi-disciplinary approach which relies upon pathophysiology that is still partially understood. In RA patients, inflammation was induced by pro-inflammatory cytokines including IL-1, IL-6 & IL-10. The conventional dosage regimens for treating RA have drawbacks such as ineffectiveness, greater doses, frequent dosing, relatively expensive and serious adverse effects. To formulate an effective treatment plan for RA, research teams have recently focused on producing several nanoformulations containing anti-inflammatory APIs with an aim to target the inflamed area. Nanomedicines have recently gained popularity in the treatment of RA. Interestingly, unbelievable improvements have been observed in current years in diagnosis and management of RA utilizing nanotechnology. Various patents and clinical trial data have been reported in relevance to RA treatment.

Biosimilars are biologic medications designed to closely replicate the properties of previously approved biologic disease-modifying anti-rheumatic drugs (bDMARDs). They offer a cost-effective alternative once the original product's patent has expired.

In pediatric rheumatology, the use of biosimilars began in 2013 with the launch of the infliximab biosimilar. Since then, more biosimilars, including etanercept, rituximab, and adalimumab, have been introduced, providing additional treatment options for children with rheumatic diseases. This article explores the role of biosimilars in pediatric rheumatology, particularly in juvenile idiopathic arthritis, focusing on their development, safety, and efficacy, as well as the challenges associated with their clinical adoption. It also addresses the importance of education in improving understanding of biosimilars.

The article provides insights into their safety, effectiveness, and economic impact by reviewing current literature to help healthcare professionals make informed decisions for treating pediatric rheumatic diseases. Education for both patients and healthcare providers, effective communication, and expectation management play a critical role in ensuring appropriate treatment continuity.

Background/Objectives: CT-P13 is a biosimilar version of infliximab, a monoclonal antibody. In individuals with ankylosing spondylitis (AS), CT-P13 has been shown to be effective and to have a well-tolerated safety profile. The aim of this study was to evaluate the long-term drug persistence, safety, and efficacy of infliximab biosimilar CT-P13 in patients with AS undergoing first-line (1st-line) and later (≥2nd-line) treatment in clinical practice. Methods: We performed an observational cohort study that included AS patients based on the biological drug database in the TURKBIO Registry between 2014 and 2021. The patients were divided into two groups: those receiving CT-P13 as first-line treatment or as a switch (≥2nd-line) from another TNF inhibitor (TNFi). Standard disease activity metrics were used to assess the effectiveness of CT-P13, and drug retention rates were investigated. Results: There were 179 AS patients using CT-P13 (47.4% male, mean age: 42.9 ± 11.3 years). Of these patients, 123 (68.7%) were receiving CT-P13 as a first-line treatment. The mean length of treatment was 3.5 years. CT-P13 drug retention rates in the general patient population were 58.6% and 48.2% in the first-line and ≥second-line treatment, respectively, after 3 years of follow-up. The most common reason for CT-P13 treatment discontinuation was lack of efficacy. The first-line CT-P13 group had statistically substantially higher ASAS20/40 response rates at three and six months. Nonetheless, both groups' response rates at one year were comparable. Conclusions: In this real-world data analysis, AS patients who were TNFi naïve (1st-line) and subsequently treated (≥2nd-line) with CT-P13 showed encouraging drug retention rates with acceptable long-term effectiveness and safety.

The aim of this article is to update evidence on the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) and provide information to the taskforce for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis (RA).

We searched various databases for randomised controlled trials on RA published until June 2022, with no language restriction. For each of the 15 clinical questions, two independent reviewers screened the articles, evaluated the core outcomes, and performed meta-analyses.

Subcutaneous injection of methotrexate (MTX) showed similar efficacy to oral MTX in MTX-naïve RA patients. Ozoralizumab combined with MTX improved drug efficacy compared to the placebo in RA patients with inadequate response (IR) to conventional synthetic DMARD (csDMARD). Rituximab with and without concomitant csDMARDs showed similar efficacy to other biological DMARDs (bDMARDs) in bDMARD-IR RA patients. Combined Janus kinase inhibitors and MTX achieved similar clinical responses and equal safety during a 4-year period compared to tumour necrosis factor inhibitors in MTX-IR RA patients. Biosimilars showed efficacy equivalent to that of the original bDMARDs in csDMARD-IR and bDMARD-IR RA patients.

This systematic review provides latest evidence for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for RA management.

The approval of biosimilars in the management of inflammatory bowel diseases (IBDs) has offered an answer to a growing concern about healthcare costs, and availability of treatments. Several studies have been conducted to demonstrate proof of biosimilars effectiveness as treatment in Crohn's disease (CD).

Since 2013, the European Medicines Agency has approved five biosimilars for infliximab and eight for adalimumab. Initial data leading to approval were extrapolated from studies conducted in patients with rheumatological or dermatological diseases, but recent studies filled the gap of clinical data among patients with IBD. In this review, 75 studies were included, with data from a total of 20 707 patients with CD. Clinical data on biosimilars in the treatment of CD show equivalence in terms of efficacy, either as induction or maintenance of treatment and regardless of previous exposure to originator or other biosimilar.

Since biosimilar market entry, utilization of infliximab increased by 89.9% and by 22.4% for adalimumab in European countries. With a 10-year insight since the first approval of biosimilar in Europe, biosimilars prescriptions should be implemented in routine clinical practice given the efficacy and safety profile.

Safety remains a significant concern for biologic drugs, and studies are needed to ensure a comparable safety profile for biosimilars and their legacy treatments. Using Canadian administrative health data from 2015-2019, we compared the incidence of serious infection between biosimilars and bio-originators initiators for etanercept and infliximab, two of the most commonly used biologics during this time.

We performed a retrospective cohort study using pan-Canadian data (except Quebec) from the National Prescription Drug Utilization Information System linked to hospitalization data. We studied new users of infliximab or etanercept (January/2015-December/2019) and compared incidence rates of serious infection, defined as those which required hospitalization, by using Cox regression models adjusted by biological sex, age at treatment initiation, prior corticosteroid or biologic, province, and calendar year.

We studied 6,583 etanercept users (mean age 62) and 7,202 infliximab users (mean age 45). Hospitalization with infections occurred in 7% of infliximab and 2% of etanercept users. Comparing the risk of infection between biosimilar to bio-originator, the adjusted hazard ratio (95% confidence interval) was 1.33 (0.77, 2.30) for etanercept and 0.93 (0.72, 1.18) for infliximab.

Our study found no clear difference between etanercept and infliximab biosimilars and their bio-originators for infection incidence, suggesting a similar safety profile.

The Veterans Health Administration (VHA) listed the infliximab (IFX) biosimilar, IFX-dyyb (Inflectra), on the Veterans Affairs National Formulary (VANF) in May 2017. In September 2018, biosimilar IFX-abda (Renflexis) became the VANF IFX product. The recommended formulary changes from one IFX biosimilar to another provided a unique opportunity to study IFX utilization patterns in IFX-naïve Veterans with Inflammatory Bowel Disease (IBD). This study aimed to describe IFX and healthcare utilization during the 365 days after initiation with IFX reference product (RP) or biosimilars IFX-dyyb and IFX-adba. This descriptive study was performed using the VHA Corporate Data Warehouse. All Veterans initiated on IFX-RP (Remicade) or biosimilars IFX-dyyb and IFX-adba between September 1, 2016 and December 30, 2019 were included and followed for 365 days. Veterans enrolled in the VHA for at least 365 days with no evidence of IFX before their index date were considered IFX-naïve. Continuous data on IFX use, laboratory measurements, and healthcare utilization were reported with means, 95% confidence interval (CI), medians, and interquartile ranges. Frequency, proportions, and 95% CIs were presented for categorical variables. Statistical tests included ANOVA and Kruskal-Wallis for continuous outcomes, Poisson regression for count-based outcomes (i.e., healthcare utilization visits), and Chi-square for dichotomous outcomes. The study identified 1763 IFX-naïve patients with IBD, and 785, 441, and 537 was indexed to RP, IFX-dyyb, and IFX-adba, respectively. Statistical differences were observed in IFX utilization measures related to dosing, adherence, and persistence. The proportion of days covered (PDC) during the 365-day follow-up period varied among the IFX groups: IFX-RP at 66%, IFX-dyyb at 60%, and IFX-abda at 69% (P value < .001). Persistence with the index IFX product during the 365-day follow-up period also varied: IFX-RP at 43%, IFX-dyyb at 32%, and IFX-abda at 51% (P value < .001). Healthcare utilization and laboratory findings were similar among the IFX groups. IFX utilization and laboratory patterns were clinically similar among the IFX biosimilars and RP groups, suggesting that providers did not modify their practice with biosimilars. Statistically significant differences in IFX utilization patterns are explained by formulary dynamics when the VANF product switched from IFX-dyyb to IFX-abda.

The infliximab biosimilar CT-P13 was the first biosimilar drug targeting tumor necrosis factor-α. However, its efficacy and safety in real-world clinical situations have remained insufficient. Therefore, we aimed to verify the efficacy and safety of CT-P13 in bio-naïve patients with Crohn's disease.

This retrospective multicenter study compared the remission rate at week 54 between patients with Crohn's disease who were treated with originator infliximab or CT-P13. Endoscopic and laboratory findings were assessed in both groups. A total of 184 (156 originator and 28 CT-P13) patients were analyzed. Of these, 138 originator users and 19 biosimilar users completed 54-week administration.

The clinical remission rates in patients taking originator infliximab of CT-P13 at week 54 were 92.5 % and 100 %, respectively. The endoscopic scores of each group significantly decreased from baseline at week 54 in both groups, and the mucosal healing rate at week 54 was 53 % and 64 %, respectively. Laboratory data including C-reactive protein, serum albumin, and hemoglobin significantly improved from baseline to week 14 and 54 in both groups. Adverse events were observed more frequently in the CT-P13 group (25 % vs. 4.5 %, p = 0.0015), but severe adverse events were rare in both groups.

The efficacy and safety of CT-P13 were comparable with those of originator infliximab in bio-naïve patients with Crohn's disease evaluated by clinical, endoscopic, and laboratory findings. This study establishes the needed groundwork for the development of a strategy for treatment with biologics in patients with Crohn's disease.

The introduction of anti-tumor necrosis factor α (TNFα) biologics significantly innovated inflammatory bowel disease (IBD) treatment and increased medical costs. The recent expiration of patents of some anti-TNFα biologics (such as infliximab and adalimumab) facilitated the development of biosimilars. Comparable pharmacokinetic, efficacy, safety, and immunogenicity profiles between anti-TNFα originators and biosimilars were demonstrated in different studies. Anti-TNFα biosimilars hold promise for reducing the high cost of biologics and increasing patient access to biologics. In this review, we outline the current data on the use of anti-TNFα originators and biosimilars in patients with IBD, with a focus on the efficacy, safety, and immunogenicity profiles of infliximab and adalimumab biosimilars. The potential benefits, challenges, and future directions of anti-TNFα biosimilars are also discussed in the review.

Among patients with rheumatoid arthritis (RA) who had an inadequate response to methotrexate, a treatment sequence initiated with biosimilar disease-modifying antirheumatic drugs (DMARDs) provides better clinical efficacy compared with conventional synthetic DMARDs recommended by current treatment guidelines; but its cost-effectiveness evidence remains unclear.

To evaluate the cost-effectiveness of the treatment sequence initiated with biosimilar DMARDs after failure with methotrexate vs leflunomide and inform formulary listing decisions.

This economic evaluation's cost-effectiveness analysis was performed at a Hong Kong public institution using the Markov disease transition model to simulate the lifetime disease progression and cost for patients with RA, using monetary value in 2022. Scenario and sensitivity analyses were performed to test the internal validity of the modeling conclusion. Participants included patients diagnosed with RA from 2000 to 2021 who were retrieved retrospectively from local electronic medical records to generate model input parameters. Statistical analysis was performed from January 2023 to March 2024.

The model assesses 3 competing treatment sequences initiated with biosimilar infliximab (CT-P13), biosimilar adalimumab (ABP-501), and leflunomide; all used in combination with methotrexate.

Lifetime health care cost and quality-adjusted life-years (QALYs) of the simulated cohort.

In total, 25 099 patients with RA were identified (mean [SD] age, 56 [17] years; 19 469 [72.7%] women). In the base-case analysis, the lifetime health care cost and QALYs for the treatment sequence initiated with leflunomide were US $154 632 and 14.82 QALYs, respectively; for biosimilar infliximab, they were US $152 326 and 15.35 QALYs, respectively; and for biosimilar adalimumab, they were US $145 419 and 15.55 QALYs, respectively. Both biosimilar sequences presented lower costs and greater QALYs than the leflunomide sequence. In the deterministic sensitivity analysis, the incremental cost-effectiveness ratio (US$/QALY) comparing biosimilar infliximab sequence vs leflunomide sequence and biosimilar adalimumab sequence vs leflunomide sequence ranged from -15 797 to -8615 and -9088 to 10 238, respectively, all below the predefined willingness-to-pay threshold (US $48 555/QALY gain). In the probabilistic sensitivity analysis, the probability of treatment sequence initiated with leflunomide, biosimilar infliximab, and biosmilar adalimumab being cost-effective out of 10 000 iterations was 0%, 9%, and 91%, respectively.

In this economic evaluation study, the treatment sequences initiated with biosimilar DMARDs were cost-effective compared with the treatment sequence initiated with leflunomide in managing patients with RA who experienced failure with the initial methotrexate treatment. These results suggest the need to update clinical treatment guidelines for initiating biosimilars immediately after the failure of methotrexate for patients with RA.

Studies have investigated the efficacy and safety of switching to the biosimilar infliximab (CT-P13) in patients with inflammatory bowel disease (IBD). However, there is limited research directly comparing the effectiveness, drug survival, and pharmacokinetic profiles of the reference infliximab (IFX) and CT-P13 in real clinical settings.

To compare the effectiveness and drug survival of CPT-13 and reference IFX at weeks 26 and 52, and to determine the pharmacokinetic profiles and safety profile in real-world settings.

A retrospective observational cohort analysis was conducted at a single center. The study compared the proportion of patients achieving clinical remission and experiencing poor clinical outcomes at weeks 26 and 52. The drug survival rate of CT-P13 and reference infliximab was also assessed during the follow-up period.

A total of 153 patients were included in the study, 39.2% receiving CPT-13 and 60.8% reference IFX. At week 26, clinical remission rates were 66.7% (CPT-13: 74.4% vs. reference IFX: 62.3%, p=0.178), and at week 52, they were 64% (CPT-13: 85.4% vs. reference IFX: 63.0%, p=0.012). Subgroup analysis with therapeutic drug monitoring (TDM) found no significant differences at week 26 (CPT-13: 74.4% vs. reference IFX: 58.8%, p=0.235) or at week 52 (CPT-13: 85.4% vs. reference IFX: 68.8%, p=0.153).

Our study demonstrates comparable efficacy, drug survival, pharmacokinetic profiles, and incidence of immunogenicity between both drugs in a real clinical setting. Further studies with greater statistical power are needed to validate these findings.

The Japanese biosimilar guideline requires that the sponsors conduct clinical studies such as comparative pharmacokinetic (PK), pharmacodynamic (PD), or efficacy studies. In each biosimilar development, the sponsors consider the clinical data package, and thus clinical data packages vary among biosimilar developments.

The aim of this study was to elucidate the clinical data packages for the biosimilars approved in Japan. The details of clinical data packages and sample size for the regulatory approvals of biosimilars in Japan was reported.

We surveyed the clinical data packages and sample size based on the Pharmaceuticals and Medical Devices Agency (PMDA) website review reports between 2009 and 2023.

Twenty-four biosimilars have been approved based on the comparative PK and efficacy studies, 10 biosimilars have been approved based on the comparative PK/PD study, and one biosimilar has been approved based on the comparative efficacy study. Regarding the sample size, comparative PK studies were conducted in healthy volunteers or patients for up to 300 cases, although the majority enrolled only 1-100 cases (68.1%, 32/47). Comparative PD studies enrolling 1-30, 31-60, and 61-90 cases totaled 4, 7, and 4 cases, respectively. Finally, comparative efficacy studies enrolling 1-300, 301-600, and 601-900 totaled 6, 10, and 11 cases, respectively. In particular, the oncology and rheumatology areas were the first and second disease areas recruiting 601-900 patients.

Large numbers of patients were enrolled to conduct a comparative efficacy study. Efficient biosimilar development should be considered on the basis of the accumulation of scientific understanding of comparable features of biosimilars and their development.

Biosimilars are biologic drugs that have the potential to increase the efficiency of healthcare spending and curb drug-related cost increases. However, their introduction into hospital formularies through initiatives such as non-medical switching must be carefully orchestrated so as not to cause treatment discontinuation or result in increased health resource utilization, such as additional visits or laboratory tests, among others. This retrospective cohort study aims to assess the impact of the introduction of CT-P13 on the healthcare expenditures of patients who were treated with originator infliximab or CT-P13.

Gastroenterology, immunoallergology and rheumatology patients treated between September 2017 and December 2020 at a university hospital in Western Switzerland were included and divided into seven cohorts, based on their treatment pathway (i.e., use and discontinuation of CT-P13 and/or originator infliximab). Costs in Swiss francs were obtained from the hospital's cost accounting department and length of stay was extracted from inpatient records. Comparisons of costs and length of stay between cohorts were calculated by bootstrapping.

Sixty immunoallergology, 84 rheumatology and 114 gastroenterology patients were included. Inpatient and outpatient costs averaged (sd) CHF 1,611 (1,020) per hospital day and CHF 4,991 (6,931) per infusion, respectively. The mean (sd) length of stay was 20 (28) days. Although immunoallergology and rheumatology patients had higher average costs than gastroenterology patients, differences in costs and length of stay were not formally explained by treatment pathway. Differences in health resource utilization were marginal.

The introduction of CT-P13 and the disruption of patient treatment management were not associated with differences in average outpatient and inpatient costs and length of stay, in contrast to the results reported in the rest of the literature. Future research should focus on the cost-effectiveness of non-medical switching policies and the potential benefits for patients.

Biosimilar-originator equivalence has been demonstrated in phase 3 trials in a few indications of infliximab, etanercept and adalimumab. The objective of our study was to compare the persistence and safety of biosimilars versus originators in all the licensed indications of these molecules.

We used data from the French National Health Data System (SNDS), covering 99% of the French population, to identify infliximab, etanercept and adalimumab initiators from biosimilar launch (January 2015, May 2016 and October 2018, respectively) to 30 June 2021. Patients were then followed for 1 year. Treatment persistence (duration without treatment discontinuation or modification) and safety (including severe infections, all-cause hospitalisation and death) were compared between originator and biosimilar users by Cox regressions weighting the populations on the inverse probability of treatment. Analyses were performed by molecule, by disease and by biosimilar product.

From January 2015 to June 2021, 86 776 patients were included in the study: 22 670, 24 442 and 39 664 patients had initiated infliximab, etanercept and adalimumab, respectively; 49 752 (53%) were biosimilar initiators. We did not find any risk of discontinuation (HRs were below or around 1, here all pathologies and products together: infliximab 0.88 (0.80-0.97), etanercept 0.85 (0.81-0.90) and adalimumab 0.96 (0.91-1.00)) or safety event (infection: infliximab 0.97 (0.78-1.21), etanercept 1.04 (0.81-1.33) and adalimumab 0.98 (0.83-1.16); hospitalisation: infliximab 1.08 (0.96-1.23), etanercept 0.99 (0.87-1.11) and adalimumab 0.91 (0.83-0.99)) associated with biosimilar versus originator use.

Our study shows reassuring results regarding the persistence and safety of biosimilar tumour necrosis factor-alpha inhibitors compared with originators in all licensed indications.

Favourable clinical data were published on the efficacy of CT-P13, the first biosimilar of infliximab (IFX), in pediatric inflammatory bowel disease (IBD); however, few studies have compared the effect on endoscopic healing (EH) and drug retention rate between the IFX originator and CT-P13. Therefore, we aimed to compare EH and the drug retention rate between the IFX originator and CT-P13.

Children with Crohn's disease (CD) and ulcerative colitis (UC)/IBD-unclassified (IBD-U) at 22 medical centers were enrolled, with a retrospective review conducted at 1-year and last follow-up. Clinical remission, EH and drug retention rate were evaluated.

We studied 416 pediatric patients with IBD: 77.4% had CD and 22.6% had UC/IBD-U. Among them, 255 (61.3%) received the IFX originator and 161 (38.7%) received CT-P13. No statistically significant differences were found between the IFX originator and CT-P13 in terms of corticosteroid-free remission and adverse events. At 1-year follow-up, EH rates were comparable between them (CD: P=0.902, UC: P=0.860). The estimated cumulative cessation rates were not significantly different between the two groups. In patients with CD, the drug retention rates were 66.1% in the IFX originator and 71.6% in the CT-P13 group at the maximum follow-up period (P >0.05). In patients with UC, the drug retention rates were 49.8% in the IFX originator and 56.3% in the CT-P13 group at the maximum follow-up period (P >0.05).

The IFX originator and CT-P13 demonstrated comparable therapeutic response including EH, clinical remission, drug retention rate and safety in pediatric IBD.

To evaluate which American College of Rheumatology (ACR) response definition (ACR20, 50 or 70) should primarily be used for efficacy claims in future drug approval trials of rheumatoid arthritis (RA).

We systematically searched EMBASE, Medline and the Cochrane Library for randomised controlled RA drug approval trials of biological and targeted synthetic disease-modifying antirheumatic drugs (DMARDs). We included full-text articles reporting ACR response rates for multiple time points over a 24-week placebo-controlled period and visualised normalised response trajectories over time in different patient populations. Using mixed-effect logistic regression, we calculated the proportion of ACR responders per outcome and time point, and compared the discriminant validity of these metrics at multiple time points.

We screened 12 680 records and included 45 in the final analysis. Discriminative capacity of the ACR20 was high across all time points, whereas ACR50 and ACR70 showed highest discrimination towards the end of the placebo-controlled periods. This effect could be observed in all patient populations and compound groups. Faster response to treatment was observed in DMARD naïve patient populations when compared with DMARD insufficient responders.

ACR20 remains the most powerful discriminator between active treatment and placebo, especially when early discrimination is of primary interest. At the same time, our results support the selection of more stringent thresholds if later time points shall be evaluated, given their comparable discriminant but higher clinical face validity.

We aimed to evaluate clinical efficacy, biomarker activity, therapeutic drug monitoring (TDM), adverse events (AEs), and nocebo effect in inflammatory bowel disease (IBD) patients who underwent non-medical biosimilar switching.

A prospective observational study of consecutive IBD patients who underwent biosimilar switch. Disease activity, biomarkers, TDM, and AEs, including the nocebo effect were captured 8 weeks before switch, at the time of switch (baseline),12 and 24 weeks after the switch.

210 patients were included [81.4% had Crohn's disease (CD), the median age at inclusion: 42 years (IQR 29-61)]. There was no significant difference in the rates of clinical remission at week 8 before switch, baseline, week12, and 24 after switch: 89.0%,93.4%,86.3%,and 90.8%,p = 0.129. The biomarker remission rates were not significantly different; CRP:81.3%,74.7%,81.2%,73.0%,p = 0.343; fecal calprotectin: 78.3%,74.5%,71.7%,76.3%,p = 0.829. The rates of maintaining therapeutic levels (84.7%,83.9%,83.0%,85.3%,p = 0.597) and prevalence of positive anti-drug antibodies remained unchanged. Drug persistence at 12 week of switch was 97.1%, regardless of disease phenotype and originator. The nocebo effect was observed in 13.3%. The discontinuation rate was 4.8%.

Despite a significant number of early nocebo complaints within the first 6 months after the biosimilar switch, no significant changes were found in clinical efficacy, biomarkers, therapeutic drug level, or anti-drug antibodies.

Biosimilar CT-P13 was approved with limited data from clinical trials compared to the originator infliximab in biologic-naïve patients with rheumatoid arthritis. Three prospective post-marketing surveillance studies have been conducted in Japanese biologic-naïve patients and switched patients from biologics including the originator infliximab.

We performed an integrated analysis of final data from three post-marketing studies to provide long-term safety and efficacy data of CT-P13 in a real-world clinical setting.

A total of 1816 patients consisting of 987 patients with rheumatoid arthritis, 342 patients with Crohn's disease, 322 patients with ulcerative colitis, and 165 patients with psoriasis were evaluated for safety. Efficacy was assessed in 1150 patients whose disease parameter values were serially collected.

Adverse drug reactions were reported in 24.2% of all patients. The incidence of adverse drug reactions differed by the prior treatment status with biologics: 30.5% in patients naïve to biologics, 17.0% in patients switched from the originator infliximab, and 33.5% in patients switched from other biologics. Infusion reactions were the most frequent adverse drug reactions (8.2%), and its incidence was significantly higher in patients with ulcerative colitis and an allergy history in a multivariable Cox regression analysis. Infection was the second most frequent (6.1%), but tuberculosis only occurred in four patients (0.2%). The incidence of infection was low in patients with Crohn's disease and psoriasis, and significant risk factors were an allergy history, comorbidities, and concomitant steroid use. Interstitial lung disease occurred in 16 patients (0.9%), including 11 patients with rheumatoid arthritis. With CT-P13 therapy, disease activity parameters decreased similarly in all four diseases, although long-term drug discontinuation rates because of inefficacy varied by disease. In naïve patients, the disease activity parameters decreased rapidly and the proportion of patients in remission increased. Patients switched from infliximab maintained lowered parameter levels with infliximab pretreatment. Decreases were also observed in patients switched from other biologics, but discontinuations were most often because of insufficient efficacy.

The integrated analysis of a large number of patients detected no new safety signals with long-term CT-P13 treatment. Efficacy in rheumatoid arthritis, psoriasis, Crohn's disease, and ulcerative colitis cases was confirmed in biologic-naïve patients and switched patients from the originator infliximab or other biologics.

To improve knowledge about biosimilar medicines and to generate a consensus framework on their use.

Qualitative study. A multidisciplinary group of experts in biosimilar medicines was established (1dermatologist, 1hospital pharmacist, 1rheumatologist, and 1gastroenterologist) who defined the sections and topics of the document. A narrative literature review was performed in Medline to identify articles on biosimilar medicines. Systematic reviews, controlled, pre-clinical, clinical, and real-life studies were selected. Based on the results of the review, several general principles and recommendations were generated. The level of agreement was tested in a Delphi that was extended to 66 health professionals who voted from 1 (totally disagree) to 10 (totally agree). Agreement was defined if at least 70% of the participants voted ≥7.

The literature review included 555 articles. A total of 10 general principles and recommendations were voted upon. All reached the level of agreement established. The document includes data on the main characteristics of biosimilar medicines (definition, development, approval, indication extrapolation, interchangeability, financing, and traceability); published evidence (biosimilarity, efficacy, effectiveness, safety, immunogenicity, efficiency, switch); barriers and facilitators to its use; and data on information for patients.

Authorized biosimilar medicines meet all the characteristics of quality, efficacy, and safety. They also significantly help improve patient access to biological therapies and contribute to health system sustainability.

Background: The infliximab biosimilar CT-P13 was approved in Thailand in 2015. Methods: This open-label, multicenter, post-marketing surveillance study evaluated the safety (events of special interest [ESIs]; primary end point) and effectiveness of 46 weeks of CT-P13 treatment according to routine practice in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), or psoriatic arthritis (PsA), with 1 year follow-up post-treatment. Results: 30 patients were enrolled (16 RA, 8 AS and 6 PsA). Infections were the most frequently reported study drug-related ESIs (2 RA and 2 AS). One patient with RA and one with PsA experienced infusion-related reactions. No cases of tuberculosis, malignancy (as expected, given 1 year follow-up), or drug-induced liver disease were reported. Disease activity improved across indications. Conclusion: CT-P13 was well tolerated and effective across indications.

The optimal first-line treatment in early rheumatoid arthritis (RA) is debated. We compared clinical and radiographic outcomes of active conventional therapy with each of three biological treatments with different modes of action.

Investigator-initiated, randomised, blinded-assessor study. Patients with treatment-naïve early RA with moderate-severe disease activity were randomised 1:1:1:1 to methotrexate combined with (1) active conventional therapy: oral prednisolone (tapered quickly, discontinued at week 36) or sulfasalazine, hydroxychloroquine and intra-articular glucocorticoid injections in swollen joints; (2) certolizumab pegol; (3) abatacept or (4) tocilizumab. Coprimary endpoints were week 48 Clinical Disease Activity Index (CDAI) remission (CDAI ≤2.8) and change in radiographic van der Heijde-modified Sharp Score, estimated using logistic regression and analysis of covariance, adjusted for sex, anticitrullinated protein antibody status and country. Bonferroni's and Dunnet's procedures adjusted for multiple testing (significance level: 0.025).

Eight hundred and twelve patients were randomised. Adjusted CDAI remission rates at week 48 were: 59.3% (abatacept), 52.3% (certolizumab), 51.9% (tocilizumab) and 39.2% (active conventional therapy). Compared with active conventional therapy, CDAI remission rates were significantly higher for abatacept (adjusted difference +20.1%, p<0.001) and certolizumab (+13.1%, p=0.021), but not for tocilizumab (+12.7%, p=0.030). Key secondary clinical outcomes were consistently better in biological groups. Radiographic progression was low, without group differences.The proportions of patients with serious adverse events were abatacept, 8.3%; certolizumab, 12.4%; tocilizumab, 9.2%; and active conventional therapy, 10.7%.

Compared with active conventional therapy, clinical remission rates were superior for abatacept and certolizumab pegol, but not for tocilizumab. Radiographic progression was low and similar between treatments.

NCT01491815.

Current guidelines recommend tapering biological disease-modifying antirheumatoid drugs (bDMARDs) in rheumatoid arthritis (RA) if the disease is under control. However, guidelines on tapering are lacking. Assessing cost-effectiveness of different tapering strategies might provide broader input for creating guidelines on how to taper bDMARDs in patients with RA. The aim of this study is to evaluate the long-term cost-effectiveness from a societal perspective of bDMARD tapering strategies in Dutch patients with RA, namely 50% dose reduction (tapering), discontinuation and a 50% dose reduction followed by discontinuation (de-escalation).

Using a societal perspective, a Markov model with a life-time horizon of 30 years was used to simulate 3-monthly transitions between Disease Activity 28 (DAS28)-defined health states of remission (<2.6), low disease activity (2.63.2). Transition probabilities were estimated through literature search and random effects pooling. Incremental costs, incremental quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs) and incremental net monetary benefits for each tapering strategy were compared with continuation. Deterministic, probabilistic sensitivity analyses and multiple scenario analyses were performed.

After 30 years, the ICERs were €115 157/QALY lost, €74 226/QALY lost and €67 137/QALY lost for tapering, de-escalation and discontinuation, respectively; mainly driven by bDMARD cost savings and a 72.8% probability of a loss in quality of life. This corresponds to a 76.1%, 64.3% and 60.1% probability of tapering, de-escalation and discontinuation being cost-effective, provided a willingness-to-accept threshold of €50 000/QALY lost.

Based on these analyses, the 50% tapering approach saved the highest cost per QALY lost.

What is the impact of switching between biologics and biosimilars of adalimumab, etanercept, and infliximab on efficacy and safety for rheumatoid arthritis? A systematic review and network meta-analysis were performed to compare switching and non-switching groups of treatments. Pooled Risk Relative (RR) or standardised mean differences (SMD) with 95% credible intervals (95% CrIs) were obtained. Seventeen randomized trials with a switching phase involving 6,562 patients were included. Results showed that a single switch from biologics to biosimilars compared to continuing biologics had comparable effects for primary and co-primary outcomes, the American College of Rheumatology criteria with 20% response (ACR20) (7 trials, 1,926 patients, RR 0.98, 95% CrIs 0.93 to 1.03) and the Health Assessment Questionnaire-Disability Index (HAQ-DI) (5 trials, 1,609 patients, SMD - 0.07, 95% CrIs - 0.23 to 0.1), and within the equivalence margins: ACR20 [RR 0.94, 1.06] and HAQ-DI [SMD - 0.22, 0.22]. The risk of treatment-emergent adverse events, discontinuation, and positive anti-drug antibodies were comparable after switching. Safety results were imprecise, and the follow-up period might not be sufficient to evaluate long-term effects, especially malignancies. Overall, the practice of single switching between approved biologics and biosimilars of Tumour Necrosis Factor inhibitors is efficacious and safe for rheumatoid arthritis.

As of May 2023, 19 and 18 biosimilars have been approved for the treatment of rheumatoid arthritis (RA) by the European Medicines Agency (EMA) and United States Food and Drug Administration (US FDA) respectively.

Pharmacokinetic results of phase 1 studies of approved biosimilars were reviewed by systematic literature search. The impact of immunogenicity on the pharmacokinetic data and clinical response was assessed, and the potential benefit of monitoring serum concentrations of biologic drugs is discussed. The advantage of subcutaneous CT-P13 (an infliximab biosimilar) in clinical practice is reviewed.

Biosimilars are approved based on the totality of evidence including comparable physiochemical properties, PK / PD profiles, and clinical efficacy and safety to the originator. To utilize biosimilars more effectively, physicians should be aware of the utility of combination DMARD therapy to reduce immunogenicity and maintain efficacy and PK profile. PK monitoring, however, is not currently recommended in clinical practice. CT-P13 subcutaneous (SC) is the first SC infliximab used for treatment of RA patients. Based on data from clinical studies and the real world, SC-infliximab is an attractive therapeutic option compared to IV formulations of infliximab based on its efficacy, pharmacokinetics, patient-reported outcomes, and safety profile.

TNF inhibitors (TNFi) are in widespread use to treat a range of immune-mediated inflammatory diseases. However, the use of less expensive, biosimilar versions of these costly agents varies considerably around the world. Along with other Scandinavian countries, Norway has been successful in implementing the consistent clinical use of biosimilars rather than originator compounds.

We discuss the implementation of biosimilar TNFi in Norway, explain how this work was carried out over the past 10 years and highlight factors that have been key in securing their acceptance and use. This implementation is discussed in relation to the situation in other countries.

The Norwegian tender and procurement system has been important to lower the cost of TNFi. Importantly, the emergence of biosimilar alternatives has lowered the cost not just of biosimilar TNFi but also originators due to competition. The involvement of the clinical communities through expert advisory boards has been important in securing acceptance of biosimilars early on. We suggest that the Norwegian procurement and tender system for biologic drugs may serve as a model for other countries, but has to be adjusted and modified according to specific national health-care systems and national contextual factors.

The objective of this non-interventional, observational prospective cohort study (CONNECT-IBD) was to assess the use of CT-P13 (Inflectra®) in the treatment of patients with Crohn's disease (CD) and ulcerative colitis (UC) in the context of treatment with reference infliximab (IFX; Remicade®).

Patients (recruited April 2015 to October 2018) at 150 sites across 13 European countries were followed for up to 2 years. Primary outcomes were safety, population characteristics, and drug utilization patterns. Secondary outcomes included clinical assessment of disease activity. Data were analyzed descriptively.

Overall, 2543 patients (CD, n = 1676; UC, n = 867) were included. In the CT-P13 cohort (n = 1522), median disease duration was 63 (0-579) months and 30% of patients were IFX naïve; median duration of prior IFX treatment was 5 months. During the observation period, median duration of drug exposure was 14 (0-28) months. 41% of patients reported 912 all-causality treatment-emergent adverse events (TEAEs); 24% experienced treatment-related TEAEs. Most TEAEs were of mild-to-moderate severity. Treatment-emergent serious adverse events were reported by 17% of patients.

Safety information for CT-P13 in this large study was consistent with the known safety profile for IFX and did not alter the established benefit-risk profile of CT-P13.

The approval and adoption of biosimilar products are essential to contain increasing healthcare costs and provide more affordable choices for patients. Despite steady progress in the number of the US Food and Drug Administration (FDA) biosimilar approvals over the years, biosimilar adoption in the United States has been slow and gradual, largely driven by payers rather than clinicians. In order to better understand the barriers to biosimilar adoption in the clinic, the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI) and the FDA jointly hosted a virtual workshop on April 13, 2022, titled "Biosimilars: A Decade of Experience and Future Directions - Strategies for Improving Biosimilar Adoption and the Potential Role of Clinical Pharmacology." This summary documents the experiences of four leading academic clinicians with specialties in oncology, rheumatology, gastroenterology, and endocrinology and their perspectives on how to increase biosimilar adoption, including the role of clinical pharmacology. Besides systemic changes in pricing and reimbursement, there is a need for additional education of a broad range of providers, including advanced care practitioners, and patients themselves. Educational efforts highlighting the rigor of the studies that support the approval of biosimilars-including the clinical pharmacology studies-and the benefits of biosimilars, can play a major role in improving biosimilar acceptance.

Crohn's disease (CD) is a relapsing and progressive condition characterized by diarrhea, abdominal pain, weight loss, and hematochezia that results in serious complications such as perforations, fistulas, and abscesses. Various medications, interventions, and surgical treatments have been used to treat CD. The Korean guidelines for CD management were distributed in 2012 and revised in 2017 by the Inflammatory Bowel Disease (IBD) Research Group of the Korean Association for the Study of Intestinal Diseases. Substantial progress in mucosal immunologic research has elucidated the pathophysiology of IBD, leading to development of biological agents for treatment of CD. The first developed biologic agent, tumor necrosis factor-α agents, were shown to be efficacious in CD, heralding a new era in management of CD. Subsequently, vedolizumab, a monoclonal antibody against integrin α4β7, and ustekinumab, a human monoclonal antibody that inhibits the common p40 subunit of interleukin-12 and interleukin-23, were both approved for clinical use and are efficacious and safe for both induction and maintenance of remission in moderate-to-severe CD patients. Moreover, a recent study showed the non-inferiority of CT-P13, an infliximab biosimilar, compared with infliximab in CD patients. The third Korean guidelines for CD management provide updated information regarding treatment of moderate-to-severe CD patients with biologic agents.