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Aims Methods Results Conclusions Biosimilar products have clinical characteristics similar to those of brand‐name products and can reduce medical costs. However, the use of biosimilar products for osteoporosis treatments remains limited due to concerns regarding its safety and efficacy. We aimed to clarify the effectiveness and safety of the biosimilar teriparatide compared with those of the reference product using the incidence of new fractures and osteosarcoma as outcomes in osteoporosis patients.This study used the DeSC database, which contains medical claims data for various insurers in Japan. We included patients with osteoporosis aged ≥65 years who newly received either biosimilar teriparatide or the reference products between April 2019 and November 2022. Competing risk analyses were performed with adjustments for patient characteristics. The primary and secondary outcomes were the occurrence of new fractures and osteosarcoma, respectively.Among 45 861 included patients, 3613 and 42 248 were in the biosimilar and reference product groups, respectively. The median follow‐up duration was 439 days. New fractures occurred in 6.7% of patients. Cumulative incidence function curves showed similar risks of new fractures over time in both groups. The cause‐specific hazard ratio for new fractures was 0.95 (95% confidence interval: 0.82–1.11) for the biosimilar group compared with that of the reference product group. The incidence of osteosarcoma did not differ significantly between the groups (P = .559).The biosimilar teriparatide showed effectiveness and safety comparable with those of the reference products in treating osteoporosis patients. Our results suggest that clinicians need not hesitate to prescribe biosimilar teriparatide for osteoporosis patients. [ABSTRACT FROM AUTHOR]

Objective: Spinal radiographic progression is an important outcome in radiographic axial spondyloarthritis (SpA). The objective of the phase IIIb SURPASS study was to compare spinal radiographic progression in patients with radiographic axial SpA treated with secukinumab (interleukin‐17A inhibitor) versus adalimumab biosimilar (Sandoz adalimumab [SDZ‐ADL]; tumor necrosis factor inhibitor). Methods: Biologic‐naive patients with active radiographic axial SpA, at high risk of radiographic progression (high‐sensitivity C‐reactive protein [hsCRP] ≥5 mg/L and/or ≥1 syndesmophyte[s] on spinal radiographs), were randomized (1:1:1) to secukinumab (150/300 mg) or SDZ‐ADL (40 mg). The proportion of patients with no radiographic progression (change from baseline [CFB] in modified Stoke Ankylosing Spondylitis Spinal Score [mSASSS] ≤0.5) on secukinumab versus SDZ‐ADL at week 104 (primary endpoint), mean CFB‐mSASSS, proportion of patients with ≥1 syndesmophyte(s) at baseline with no new syndesmophyte(s), and safety were evaluated. Results: Overall, 859 patients (78.5% male, mSASSS 16.6, Bath Ankylosing Spondylitis Disease Activity Index 7.1, hsCRP 20.4 mg/L, and 73.0% with ≥1 syndesmophyte[s]) received secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or SDZ‐ADL (n = 286). At week 104, the proportion of patients with no radiographic progression was 66.1%, 66.9%, and 65.6% (P = not significant, both secukinumab doses) and mean CFB‐mSASSS was 0.54, 0.55, and 0.72 in secukinumab 150 mg, secukinumab 300 mg, and SDZ‐ADL arms, respectively. Overall, 56.9%, 53.8%, and 53.3% of patients on secukinumab 150 mg, secukinumab 300 mg, and SDZ‐ADL, respectively, with ≥1 syndesmophyte(s) at baseline did not develop new syndesmophyte(s) by week 104. There were no unexpected safety findings. Conclusion: Spinal radiographic progression over two years was low with no significant difference between secukinumab and SDZ‐ADL arms. The safety of both treatments was consistent with previous reports. [ABSTRACT FROM AUTHOR]

Background and Aims: This study aimed to assess the comparative effectiveness of the etanercept (ETN) originator (Enbrel) and ETN biosimilar SB4 (Brenzys) as first‐line treatment in patients with rheumatoid arthritis (RA), while also exploring the potential cost‐savings associated with this approach in Australia. Methods: Clinical data were obtained from the Optimising Patient outcomes in rheumatoLogy Australian real‐world data set. Adult patients with RA who had initiated treatment with the ETN originator or biosimilar as their first‐recorded biologic or targeted synthetic disease‐modifying antirheumatic drug between 1 April 2017 and 31 December 2020 were included. Treatment persistence was analysed using survival analysis. Cost‐savings were estimated based on data reported by the Australian National Prescribing Service MedicineWise. Results: Propensity score matching followed by inverse probability of treatment weighting selected patients taking originator (n = 209) or biosimilar (n = 141) with similar baseline characteristics and eliminated small differences in baseline disease activity. The median time for 50% of the patients to stop treatment was 19.4 months (95% confidence interval [CI], 14.7–36.4 months) for the originator and 22.4 months (95% CI, 15.0–33.1 months) for the biosimilar (P = 0.95). As a result of pricing policies established by the Australian Government, introduction of the ETN biosimilar would have resulted in a cost‐savings of over AU$9.5 million for 1 year of treatment for the patients reported in this study. Conclusion: Treatment persistence using either ETN originator or biosimilar was similar. The cost of all brands of ETN markedly reduced upon listing of the ETN biosimilar, resulting in significant savings for the Australian Government. [ABSTRACT FROM AUTHOR]

Aggregates, in particular high molecular weight species (HMWs), have been linked to increased immunogenicity. The current understanding on the impact of HMWs is mainly based on in vitro and nonclinical studies and there are only limited data available associating differences in HMWs in marketed monoclonal antibodies (mAbs) to clinical outcomes. Biosimilars offer a unique opportunity to study the potential association between quality parameters and clinical outcomes. We performed a retrospective evaluation to investigate the association between HMW content and reported antidrug‐antibody (ADA) incidence in 30 full‐length biosimilar mAbs approved in the European Union and the United States. Information for HMW content and ADA incidence were collected from publicly available sources. Differences in HMW content between biosimilars and their reference products (RPs) ranged from −0.75 to 1.65% with slightly higher differences observed in antineoplastic products as compared with immunosuppressant products. The difference in the ADA incidence between the RP and the biosimilar for the programs studied ranged from −11.0 to 18.5%. No association was observed between differences in HMW content and reported ADA incidence, in neither phase I nor phase III studies. Our results show that the limited differences in the content of HMWs between marketed biosimilars and reference mAbs were not associated with differences in reported immunogenicity, determined as incidence of ADAs and neutralizing ADAs in comparative clinical studies. [ABSTRACT FROM AUTHOR]

Post‐marketing pharmacosurveillance is important to reduce harm to patients from marketed drugs. Oral adverse drug reactions (OADRs) are seldom reported and only few OADRs are listed scarcely in summary of product characteristics (SmPC) of drugs. Objective: Structured search for OADRs in the Danish Medicines Agencies database from January 2009 to July 2019. Results: Forty‐eight percent of OADRs were categorized as "serious" where oro‐facial swelling was reported 1041 times, medication‐related osteonecrosis of the jaw (MRONJ) 607 times and para‐ or hypoaesthesia 329 times. Four‐hundred‐eighty OADRs in 343 cases were related to biologic or biosimilar drugs where 73% affected the jawbone as MRONJ. Physician reported 44%, dentists 19% and citizens 10% of OADRs. Conclusions: Health care professionals had a sporadic reporting pattern that seemed to be influenced by the debate in the community and in professional circles but also by the information in the SmPC of the drugs. The results indicate some reporting stimulation of OADRs in relation to Gardasil 4, Septanest, Eltroxin and MRONJ. Eventually the knowledge of OADRs increases but there is a risk of skewed information if reporting is not systematic, reliable and consistent. All healthcare professionals must be educated in spotting and reporting all suspected adverse drug reactions. [ABSTRACT FROM AUTHOR]

Biosimilars are biological drugs created from living organisms or that contain living components. They share an identical amino‐acid sequence and immunogenicity. These drugs are considered to be cost‐effective and are utilized in the treatment of cancer and other endocrine disorders. The primary aim of biosimilars is to predict biosimilarity, efficacy, and treatment costs; they are approved by the Food and Drug Administration (FDA) and have no clinical implications. They involve analytical studies to understand the similarities and dissimilarities. A biosimilar manufacturer sets up FDA‐approved reference products to evaluate biosimilarity. The contribution of next‐generation sequencing is evolving to study the organ tumor and its progression with its impactful therapeutic approach on cancer patients to showcase and target rare mutations. The study shall help to understand the future perspectives of biosimilars for use in gastro‐entero‐logic diseases, colorectal cancer, and thyroid cancer. They also help target specific organs with essential mutational categories and drug prototypes in clinical practices with blood and liquid biopsy, cell treatment, gene therapy, recombinant therapeutic proteins, and personalized medications. Biosimilar derivatives such as monoclonal antibodies like trastuzumab and rituximab are common drugs used in cancer therapy. Escherichia coli produces more than six antibodies or antibody‐derived proteins to treat cancer such as filgrastim, epoetin alfa, and so on. [ABSTRACT FROM AUTHOR]

This article discusses the price variability of TNF-α inhibitor biosimilars for the treatment of psoriasis across European countries. The study found that there is significant price variability, with lower prices in Italy and Spain compared to Germany, France, and Denmark. The pricing policies adopted by different countries, such as mandatory discounts, progressive price discounts, and tendering or direct contracting, contribute to this variability. The findings highlight the potential impact on healthcare costs and patient access to biological treatment. However, it is important to note that the study only included one center per country. [Extracted from the article]

Rituximab, the first monoclonal antibody approved for the treatment of lymphoma, eventually became one of the most popular and versatile drugs ever in terms of clinical application and revenue. Since its patent expiration, and consequently, the loss of exclusivity of the original biologic, its repurposing as an off-label drug has increased dramatically, propelled by the development and commercialization of its many biosimilars. Currently, rituximab is prescribed worldwide to treat a vast range of autoimmune diseases mediated by B cells. Here, we present a comprehensive overview of rituximab repurposing in 115 autoimmune diseases across 17 medical specialties, sourced from over 1530 publications. Our work highlights the extent of its off-label use and clinical benefits, underlining the success of rituximab repurposing for both common and orphan immune-related diseases. We discuss the scientific mechanism associated with its clinical efficacy and provide additional indications for which rituximab could be investigated. Our study presents rituximab as a flagship example of drug repurposing owing to its central role in targeting cluster of differentiate 20 positive (CD20) B cells in 115 autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background/Objectives: Recent literature highlights the potential of biologics in the management of inherited disorders of keratinisation. In this study, we conducted a systematic review of existing literature on treatment outcomes of inherited keratinisation disorders treated with biologics. Methods: Eligible records were retrieved through searches of the electronic databases MEDLINE, Embase, PubMed and Scopus. Databases were searched from inception to July 2023 for eligible records. A snowballing method was employed to search the references of the retrieved records for the identification of potentially relevant articles. Results: One hundred and four eligible studies consisting of a total of 166 patients with an inherited disorder of keratinisation were included. Patients had a median age of 19 years (range: 0.5 to 70 years). The most common disorders were Netherton syndrome (n = 63; 38%), autosomal recessive congenital ichthyoses (n = 27; 16%), CARD14‐associated papulosquamous eruptions (n = 17; 10%) and familial pityriasis rubra pilaris (PRP) (n = 15; 9%).Of the 207 times biologics were employed, the three most frequently employed biologics were secukinumab (n = 47; 23%), dupilumab (n = 44; 21%) and ustekinumab (n = 37; 18%). Complete remission was observed in 10 (5%) instances, partial remission in 129 (62%), no or limited response to biologic therapy in 68 (32%) cases, and results are still pending in one case. A total of 33 adverse events were reported. Conclusions: Whilst biologics may be considered in cases of inherited keratinisation disorders recalcitrant to standard therapy, definitive conclusions are prohibited by the low‐level of evidence and substantial heterogeneity in methodology across the included studies. Establishment of consensus definitions, and randomised clinical trials may help ascertain the efficacy and safety of biologic therapy in this context and establish the best agent and dosing protocol for each disorder. [ABSTRACT FROM AUTHOR]

Aim: To compare the efficacy and safety of trastuzumab biosimilars to reference trastuzumab in patients with breast cancer. Trastuzumab, a biologic pharmaceutical product, has improved survival in hormone‐oestrogen receptor 2 positive breast cancer. However, due to its high economic burden, 'highly similar' products known as biosimilars have been developed. Yet, concerns remain around the equivalency of efficacy and safety between biosimilars and their reference biologic. Data Sources: A systematic review with meta‐analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. MEDLINE, EMBASE, and Cochrane Central databases were searched from inception to 26 April 2021 to obtain all randomised control trial data reporting on safety and efficacy outcomes of patients with breast cancer treated with trastuzumab biosimilars. Study Selection: Studies were required to investigate and report on the safety and/or efficacy of trastuzumab. No restrictions were placed on study setting or intervention type and any study which reported at least one efficacy or safety outcome was included. A head‐to‐head comparison between the biosimilar and its reference biologic was not required for inclusion in the results. Only studies using randomised control trials were included. There was no restriction on the language the study was published in, and all abstracts, raw clinical trial data, and full‐text studies were eligible. Results: Forty‐one studies were identified to report on patients treated with trastuzumab. The odds of achieving an overall response rate in patients treated with a trastuzumab biosimilar compared to the reference over at least 24 weeks of treatment was 1.10 (95% confidence interval [CI] 0.94–1.29). The proportion of patients experiencing any treatment emergent adverse events were comparable between the two study arms, 1.07 (95% CI 0.87–1.32). The switching group contained one study with 342 patients in the meta‐analysis. Conclusion: Trastuzumab biosimilars have comparable efficacy and safety to reference trastuzumab in treatment‐naïve patients. However, evidence is lacking for switching patients from reference trastuzumab to biosimilars, so further work is required in the switch‐over population. [ABSTRACT FROM AUTHOR]

Objective: Transitions to biosimilars are common to reduce the cost burden of biologics. While brand changes can be daunting for patients, few studies have explored patients' experiences with the transitioning process. This study examined rheumatology patients' experiences with a mandatory nationwide brand change to an adalimumab biosimilar. Methods: People with rheumatic diseases involved in the adalimumab transition in Aotearoa New Zealand completed a nationwide online survey. Participants (n = 117, 48% with rheumatoid arthritis) reported their satisfaction with the biosimilar, logistics and supply, information and communication, and availability of support. They also reported what did and did not go well during the transition and provided recommendations for future transitions. Results: The mean [SD] satisfaction score with the transition was 6.2 [3.2] on a 0‐10 scale, with 10 indicating high satisfaction. Participants were the least satisfied with the support and information from patient support organizations, and training for the device during the transition. Participants were most satisfied with the biosimilar supply, support from pharmacists, and how early they were informed before the transition occurred. After the transition, participants were less satisfied with the device quality, patient support program, biosimilar safety and efficacy, and the provision of alcohol wipes and sharps bins (p < 0.05 for all). Satisfaction with training for the biosimilar device (B =.25, p =.036) predicted overall satisfaction. Participants appreciated less injection pain and the ease of the biosimilar device. The lack of alcohol wipes and loss of the bio‐originator support program were viewed negatively. Conclusion: Future biosimilar transitions should ensure the availability of alcohol wipes, sharps bins, and a comparable patient support program. Patient support organizations could be involved in providing information to patients about the change. [ABSTRACT FROM AUTHOR]

Charge heterogeneity of monoclonal antibodies is considered a critical quality attribute and hence needs to be monitored and controlled by the manufacturer. Typically, this is accomplished via separation of charge variants on cation exchange chromatography (CEX) using a pH or conductivity based linear gradient elution. Although an effective approach, this is challenging particularly during continuous processing as creation of linear gradient during continuous processing adds to process complexity and can lead to deviations in product quality upon slightest changes in gradient formation. Moreover, the long length of elution gradient along with the required peak fractionation makes process integration difficult. In this study, we propose a novel approach for separation of charge variants during continuous CEX chromatography by utilizing a combination of displacement mode chromatography and salt‐based step elution. It has been demonstrated that while the displacement mode of chromatography enables control of acidic variants ≤26% in the CEX eluate, salt‐based step gradient elution manages basic charge variant ≤25% in the CEX eluate. The proposed approach has been successfully demonstrated using feed materials with varying compositions. On comparing the designed strategy with 2‐column concurrent (CC) chromatography, the resin specific productivity increased by 95% and resin utilization increased by 183% with recovery of main species >99%. Further, in order to showcase the amenability of the designed CEX method in continuous operation, the method was examined in our in‐house continuous mAb platform. [ABSTRACT FROM AUTHOR]

Complications related to wound healing pose substantial obstacle in the management of colorectal cancer (CRC), specifically in the field of anorectal medicine. Biosimilars of bevacizumab have emerged as crucial therapeutic agents in the management of these complications. With the particular emphasis on effects of Bevacizumab Biosimilar Plus on wound healing among patients diagnosed with CRC, this review underscores the potential of this anorectal medication to improve patient outcomes and was aimed to assess the safety and efficacy of Bevacizumab Biosimilar Plus in relation to complications associated with wound healing in patients with CRC. The assessment centers on its therapeutic potential and safety profile within the domain of anorectal medicine. In accordance with the PRISMA guidelines, a comprehensive literature search was performed, resulting in the identification of 19 pertinent studies out of an initial 918. Priority was given to assessing the safety and adverse effects of Bevacizumab Biosimilar Plus in conjunction with its effectiveness in wound healing. The extracted data comprised the following: study design, patient demographics, comprehensive treatment regimens, wound healing‐specific outcomes and adverse effects. The evaluation of study quality was conducted utilizing the instruments provided by the Cochrane Collaboration and the Newcastle‐Ottawa Scale (NOS). Bevacizumab Biosimilar Plus demonstrates efficacy in the management of wound healing complications among patients with CRC, with a safety and efficacy profile similar to that of the original Bevacizumab, according to the analysis. Notably, several studies reported improved rates of wound healing in relation to the biosimilar. The safety profiles exhibited similarities to the anticipated anti‐VEGF agent effects. In wound management, the biosimilar also demonstrated advantages in terms of prolonged efficacy. In addition, analyses of cost‐effectiveness suggested that the use of biosimilars could result in cost reductions. Bevacizumab Biosimilar Plus exhibited potential as an anorectal medication for the effective management of wound healing complications in patients with CRC. This has substantial ramifications for improving the quality of patient care, encompassing the affordability and effectiveness of treatments. [ABSTRACT FROM AUTHOR]

This article explores the legislation and guidelines surrounding the approval of biosimilars in the United States, with a focus on the role of the FDA in determining testing criteria. The author argues against the use of clinical efficacy testing in patients, citing its low sensitivity and the potential risk of approving products that may not meet analytical and clinical pharmacology assessments. Instead, the article suggests alternative methods such as PD biomarkers and computational modeling. The author concludes that clinical efficacy testing is less effective than analytical assessment and clinical pharmacology profiling in establishing biosimilarity, and that clinical trial data are not necessary to address uncertainties about biosimilar quality. The article also discusses the use of pharmacodynamic biomarkers and receptor binding assays as alternative evaluation methods, while raising ethical concerns about testing biosimilars in patients. [Extracted from the article]

Objective: Transitioning patients to biosimilars has become common to reduce costs and improve access. However, it is unclear how the transition process impacts health care providers at the frontline of the brand change. This study explores health care providers' experiences of a mandatory brand change to an adalimumab biosimilar. Methods: A cross‐sectional study was conducted in Aotearoa New Zealand with 164 providers involved in the nationwide adalimumab brand change. Rheumatologists (n = 39), rheumatology nurses (n = 16), and pharmacists (n = 109) completed a survey that assessed their satisfaction with logistics and supply, information and education, support, and administrative workload and reported what did and did not go well during the transition. Results: The mean satisfaction score (0‐10) with the transition was 5.7 (SD = 2.6). Providers were the least satisfied with training for the biosimilar device, information from government agencies, and administrative workload during the transition. Satisfaction with adalimumab safety, efficacy and device quality, and the availability of sharps bins, alcohol wipes, and patient support was lower following the transition. Satisfaction with administrative workload (B = 0.37, P < 0.001) and training for the device (B = 0.20, P = 0.020) predicted overall satisfaction. Providers reported that a poorly implemented initial authorization process, loss of a patient support program, and insufficient communication between providers complicated the transition. The citrate‐free preservative and longer authorization duration after the transition were viewed positively. Conclusion: Providers experienced an increased workload and reported less satisfaction with the biosimilar following the transition. Experiences may be improved by ensuring training for the device, a high‐quality patient support program, and functioning authorization processes throughout the transition. [ABSTRACT FROM AUTHOR]

Immunogenicity is critical for biologics. However, reference biologics labeling documents do not necessarily mention immunogenicity impact, rendering the development of biosimilars more challenging. We aimed to investigate the comparative assessment of immunogenicity profiles between biosimilars and their respective reference biologics in the review reports of the biosimilar monoclonal antibody applications approved by the Center for Drug Evaluation and Research (CDER), US Food and Drug Administration (FDA) as of March 13, 2022, covering 22 applications approved between April 5, 2016, and December 17, 2021. The maximum differences in anti‐drug antibody (ADA) and neutralizing antibody (NAb) incidences between biosimilars and reference products mostly fell within ± 15% (−13.6% to 12%) and ± 20% (−17.4% to 17.1%, except extreme values of −23.4% and 66.7%), respectively. In comparison with antineoplastic agents, more immunosuppressants had ADA‐positive (11/11, 100.0% vs. 8/10, 80.0%)/NAb‐positive (11/11, 100.0% vs. 3/10, 30.0%) subjects, and the distribution of the aforementioned incidence differences was wider. The investigated biosimilars with available data for analysis demonstrated a high degree of consistency with their reference products in terms of the impact on pharmacokinetic parameters. No increase in immunogenicity was found in available switching studies. Most (16/22, 72.7%) biosimilars were issued post‐marketing requirements that were not directly related to immunogenicity concerns. The FDA considered the totality of evidence assessing clinical consequences of immunogenicity differences, if any. Additional information on titers and subgroup analysis may be warranted to elucidate the critical attributes of immunogenicity impact and to aid in forming cost‐effective strategies for biosimilar development. [ABSTRACT FROM AUTHOR]

Key points: Between January 2005 and January 2023, the average selling price of omalizumab increased by nearly 60%.Between 2016 and 2021, Medicare Part B and D spending on omalizumab totaled over $3.7 billion.Between 2016 and 2021, Medicare Part B and D utilization of omalizumab increased by approximately 30%. [ABSTRACT FROM AUTHOR]

Health systems encourage switching from originators to biosimilars as biosimilars are more cost‐effective. The speed and completeness of biosimilar adoption is a measure of efficiency. We describe the approach to biosimilar adoption at a single hospital Trust and compare its efficiency against the English average. We additionally follow up patients who reverted to a previously used biologic, having switched to a biosimilar, to establish whether they benefitted from re‐establishing prior treatment. The approach we describe resulted in a faster and more complete switch to biosimilars, which saved an additional £380 000 on drug costs in 2021/2022. Of patients who reverted to their original biologic, 87% improved short‐term, and a time on treatment analysis showed the benefit was retained long term. Our approach to biosimilar adoption outperformed the English average and permits patients to revert to their original biosimilar post‐switch if appropriate. [ABSTRACT FROM AUTHOR]

Objective: Biosimilars represent cost‐effective alternatives to reference biologic disease‐modifying antirheumatic drugs. Our objective was to compare drug effectiveness and drug persistence in the treatment of rheumatoid arthritis (RA), assessing the etanercept biosimilar SB4 in efficacy and safety compared with reference etanercept in a Phase III, randomized controlled trial. We applied EULAR Points to Consider for Comparative Effectiveness Research in a retrospective database study of etanercept and SB4 in patients treated in clinical practice in Norway. Methods: Patients with RA (n = 1,455) treated with etanercept or SB4 between 2010 and 2018 at 5 centers in Norway with ≥1 year of follow‐up were included. Disease outcomes (Disease Activity Score in 28 joints [DAS28] at week 52) and drug persistence were compared between unmatched etanercept (n = 575) and SB4 (n = 299) cohorts and matched analyses (n = 172, both cohorts) using propensity score (PS) matching to adjust for confounders. Results: In unmatched analyses, the difference in change from baseline between etanercept (n = 221) and SB4 (n = 106) for DAS28 at week 52 was mean –0.02 (95% confidence interval [95% CI] –0.32, 0.27), demonstrating equivalence by the predetermined equivalence margin (±0.6). In PS‐matched analyses, the difference between etanercept (n = 49) and SB4 (n = 49) was 0.03 (95% CI –0.46, 0.52), within the predefined equivalence margin. Persistence using the drug at week 52 was similar between etanercept (0.62 [95% CI 0.57, 0.65]) and SB4 (0.66 [95% CI 0.60, 0.71]) cohorts in the unmatched analysis; in PS‐matched cohorts, persistence at week 52 was 0.52 (95% CI 0.44, 0.59) for etanercept and 0.68 (95% CI 0.61, 0.75) for SB4. Conclusion: Outcomes for disease status/drug persistence at week 52 were similar between patients with RA treated with etanercept or SB4. [ABSTRACT FROM AUTHOR]

A letter to the editor discusses the safety and efficacy of bevacizumab biosimilar (bevacizumab-awwb) in the treatment of retinopathy of prematurity (ROP). The use of anti-vascular endothelial growth factor (VEGF) drugs, such as bevacizumab, is preferred for treating aggressive ROP. Biosimilar drugs, which are similar to the original drug but not identical, are being developed as a more cost-effective alternative. A retrospective study of neonates treated with bevacizumab-awwb found no ocular adverse events or immunogenic complications. The authors suggest that bevacizumab-awwb can be a substitute treatment for severe ROP if the original drug is withdrawn from the market. [Extracted from the article]

SAL001, a recombinant form of parathyroid hormone, is a biosimilar drug to teriparatide and is planned to be used in osteoporosis treatment. A single‐dose, randomized, open‐label, 2‐way crossover trial was conducted in healthy subjects to compare the pharmacokinetics (PK) and safety between SAL001 and the reference drug. Sixty‐four subjects were enrolled in the study, and 61 subjects completed the study. In each period, 20 μg of the test or reference formulation was administered subcutaneously. SAL001 was administered by autoinjector pen, whereas the reference drug was administered by a self‐matched injection pen. Serial blood samples were obtained for the analyses of PK and serum calcium concentration. Geometric mean ratios with 90%CIs for the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) were estimated. The safety of these 2 formulations was also evaluated. Overall, the 90%CIs for the geometric mean ratios of Cmax, AUC from time 0 to the last quantifiable time point, and AUC from time 0 extrapolated to infinity of the test or reference product were within 80.0%–125.0% of biosimilarity criteria. Other PK parameters, serum calcium concentration, and safety profiles had no significant differences between the 2 formulations. SAL001 demonstrated PK similarity to the reference drug, and the serum calcium concentration and safety profiles of SAL001 were also considered comparable to the reference drug. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration (FDA) Biosimilars Guidance describes how biosimilars may be approved based on clinical pharmacokinetic and pharmacodynamic (PD) biomarker data, without comparative clinical studies with efficacy end points. This type of clinical development program, however, has only been implemented for a small number of FDA‐approved biosimilar products over the last decade. To encourage the use of PD biomarkers in biosimilar development and approval, the Duke‐Margolis Center for Health Policy collaborated with the FDA to host a two‐day virtual public workshop entitled "Pharmacodynamic Biomarkers for Biosimilar Development and Approval" on September 20–21, 2021. The public workshop was a forum for global regulators, biopharmaceutical developers, and academic researchers to discuss the current and future role of PD biomarkers in improving the efficiency of biosimilar development and approval. The workshop objectives included: (i) discuss the current and potential future state of leveraging PD biomarkers for biosimilar development and approval; (ii) summarize the FDA's initiatives to advance biosimilar development; (iii) describe stakeholders' experience with PD biomarkers in biosimilar development; and (iv) explain research efforts to promote broader application of PD biomarkers in biosimilar development. This document summarizes presentations and panel discussions from each session of the two‐day September 2021 public workshop covering the application of PD biomarkers for biosimilar development. [ABSTRACT FROM AUTHOR]

Biosimilar development has a well‐documented foundation of product quality and extensive comparative analytics providing the bulk of the "totality of the evidence" that a proposed product is biosimilar to its reference product. This work provides a retrospective evaluation of a single critical quality attribute—high mannose glycans for monoclonal antibody biosimilars. Given the well‐established conclusion that high mannose glycans can impact pharmacokinetic (PK) profile, we performed a retrospective evaluation of 21 monoclonal antibody biosimilar programs (those licensed before April 2022), their levels of glycans, and the methods used to study them. We provide herein a summary of the methods used and their relative performance. We also present a subset analysis for seven biosimilar products with levels of high mannose that differ from the corresponding reference product (and where other differences in quality attributes between the two that may influence PK profile were not observed or considered minor) and compared the PK profiles. Critically, this analysis has demonstrated that the measurement of glycan profiles is highly precise, reproducible within and across programs, and can detect differences in mannose levels, even those that do not impact PK. These results provide support that analytics rather than pharmacokinetic data may be sufficient to predict whether differences within a certain magnitude of this attribute are likely to impact PK. This work enhances the Agency's understanding of this issue allowing for better understanding of challenges faced by the biotechnology industry developing biosimilars. [ABSTRACT FROM AUTHOR]

Objectives: Erythropoiesis‐stimulating agents (ESA) have an established role in treating anemia in hematological malignancies. However, their role, particularly biosimilar ESA (B‐ESA), in myelofibrosis (MF) is not well established. Methods: This study retrospectively collected data on 96 MF patients treated with B‐ESA (alpha/zeta) for the management of anemia to assess safety, efficacy (anemia response [AR]), and survival. Results: Seventy‐seven patients (80%) obtained AR. The median time to AR was 2.5 months. In multivariate analysis, significant predictive factors of AR were transfusion independency (p =.006) and ferritin levels <200 ng/ml (p =.009) at baseline. After a median follow‐up of 43.8 months from diagnosis, 38 patients (39%) died, 11 (28.9%) from leukemic evolution. Only two patients (2.5%) stopped B‐ESA for toxicity. The 24‐month survival was significantly affected by response to B‐ESA (70.8% in AR vs. 55.3% in non‐responder patients, p =.016). In multivariate analysis, age ≤ 70 years (p =.029) and Hb > 8.5 g/dl (p =.047) at baseline were significantly associated with improved survival, with a trend for longer survival in AR patients (p =.06). Conclusions: B‐ESA seems to be an effective and well‐tolerated option for anemia treatment in the MF setting. This strategy deserves further clinical investigation. [ABSTRACT FROM AUTHOR]

There is over a hundred years of clinical experience with insulin for the treatment of diabetes. The US Food and Drug Administration (FDA) approved the first insulin biosimilar interchangeable product in 2021 for improving glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Several recombinant insulin products are available in the United States, including the recently approved biosimilar insulins. The approval of the biosimilar insulin products was based on comparative analytical characterizations and comparative pharmacokinetic (PK) and pharmacodynamic (PD) data. The primary objective of this review is to discuss the scientific considerations in the demonstration of biosimilarity of a proposed insulin biosimilar to a reference product and the role of clinical pharmacology studies in the determination of biosimilarity and interchangeability. Euglycemic clamp studies are considered a "gold standard" for insulin PK and PD characterization and have been widely used to determine the time‐action profiles of rapid‐acting, intermediate‐acting, and long‐acting insulin products. Clinical pharmacology aspects of study design, including selection of appropriate dose, study population, PK, and PD end points, are presented. Finally, the role of clinical pharmacology studies in the interchangeability assessment of insulin and the regulatory pathways used for insulin and the experience with follow‐on insulins and the two recently approved biosimilar insulin products is discussed. [ABSTRACT FROM AUTHOR]

The World Health Assembly resolution on access to biotherapeutics in 2014 urges WHO and Member States to facilitate access to biotherapeutics while ensuring their quality, safety, and efficacy. While efforts to date have contributed to increased availability and better access to biotherapeutics, including biosimilars, huge gaps still remain, with lack of product access identified as a problem in many countries. A thorough review of the WHO guidelines on biosimilars issued in 2009 in view of technical developments, accumulated and emerging scientific evidence as well as experience in biosimilar evaluation since the release of the guidelines provided an opportunity to introduce greater flexibility and to reduce regulatory requirements in biosimilar development where possible. Based on the identification, draft revisions of the WHO guidelines were prepared with input from extensive consultation with various stakeholders and the broader public. The move toward a greater emphasis on quality and functional in vitro assessment enables the reduction of cost and timelines of development and supports streamlined regulatory approval as a first critical step toward product availability. This article includes the key updates that have been incorporated in the revised guidelines but are not restricted to these alone and should be read in conjunction with the guidelines. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration (FDA) has taken steps to bring efficiency to the development of biosimilars, including establishing guidance for the use of pharmacokinetic and pharmacodynamic (PD) similarity study data without a comparative clinical study with efficacy end point(s). To better understand the potential role for PD biomarkers in biosimilar development and inform best practices for biomarker selection and analysis, we conducted a randomized, double‐blinded, placebo‐controlled, single‐dose, parallel‐arm clinical study in healthy participants. Eighty‐four healthy participants (n = 12 per dose arm) received either placebo or one of three doses of either interferon β‐1a (7.5–30 μg) or pegylated interferon β‐1a (31.25–125 μg) to evaluate the maximum change from baseline and the baseline‐adjusted area under the effect curve for the biomarkers neopterin in serum and myxovirus resistance protein 1 in blood. Both PD biomarkers increased following product administration with clear separation from baseline (neopterin: 3.4‐fold and 3.9‐fold increase for interferon β‐1a and pegylated interferon β‐1a, respectively; myxovirus resistance protein 1: 19.0‐fold and 47.2‐fold increase for interferon β‐1a and pegylated interferon β‐1a, respectively). The dose–response curves support that therapeutic doses were adequately sensitive to detect differences in both PD biomarkers for consideration in a PD similarity study design. Because baseline levels of both biomarkers are low compared with on‐treatment values, there was little difference in using PD measures adjusted to baseline compared with the results without baseline adjustment. This study illustrates potential methodologies for evaluating PD biomarkers and an approach to address information gaps when limited information is publicly available for one or more PD biomarkers. [ABSTRACT FROM AUTHOR]

Analytical and functional characterization of batches of biologics/biosimilar products are imperative towards qualifying them for pre‐clinical and clinical investigations. Several orthogonal strategies are employed to characterize the functional attributes of these drugs. However, the use of conventional techniques for online monitoring of functional attributes is not feasible. Liquid chromatography is one of the crucial unit operations during the downstream processing of biopharmaceuticals. In this work, we have demonstrated the utility of FcγRIIIA affinity chromatography as an independent quantitative functional characterization tool. FcγRIIIA affinity chromatography aided in sequential elution of Rituximab glycoform mixtures, based on varying levels of galactosylation, and thereby the affinity for the receptor protein. The predominant glycans present in the three Rituximab glycoform mixture peaks were G0F, G1F, and G2F, respectively. Dissociation rate constants were derived from the chromatographic elution profiles by the peak profiling method, for the control and glucose stress conditions. The glucose stress conditions did not result in unfavorable binding kinetics of Rituximab and FcγRIIIA. The dissociation rate constants of the glycoform mixture 2, predominantly consisting of G1F, were similar to the dissociation rate constants obtained by surface plasmon resonance. Moreover, the glycosylation profiles obtained from chromatographic estimation can be corroborated with the ADCC activity. However, the ex vivo ADCC reporter assay indicated that there was an increase in the effector activity with increasing glucose stress. Thus, FcγRIIIA affinity chromatography permitted three independent assessments via a single analysis. Such approaches can be utilized as potential process analytical technology (PAT) tools in the biosimilar development process. [ABSTRACT FROM AUTHOR]

Broader discussions around use of PD biomarkers occurred at an FDA and Duke Margolis Center for Health Policy public workshop in 2021, which is summarized by Florian I et al i .[2] The workshop identified opportunities for investing in PD biomarker research and clarifying regulatory expectations for PD biomarker acceptability. Biologic medicines have revolutionized the treatment options for many diseases and typically carry favorable benefit-risk profiles compared with small molecule drugs. Evaluating the utility of proteomics for the identification of circulating pharmacodynamic biomarkers of IFNbeta-1a biologics. Considerations for use of pharmacodynamic biomarkers to support biosimilar development - (III) a randomized trial with interferon Beta-1a products. [Extracted from the article]

Biosimilar monoclonal antibodies (mAbs) have been approved in the European Union since 2013 and have been demonstrated to reduce healthcare costs and to expand patient access. Biosimilarity is mainly established on the basis of demonstrated similarity of relevant quality attributes (QAs), determined by comprehensive physiochemical and functional analyses, and demonstration of bioequivalence. In addition, comparative efficacy/safety studies have been requested for all approved biosimilar mAbs so far, although the European Medicines Agency (EMA) Guidelines state that such confirmatory clinical trials may not be necessary in specific circumstances. In order to evaluate the degree of analytical similarity, how residual uncertainty regarding biosimilarity was resolved, and the value of clinical data, we analyzed the quality and clinical data packages for authorized adalimumab (7 products) and bevacizumab (5 products) biosimilars. The percentage of biosimilar batches meeting the similarity range for QAs, as defined by the biosimilar manufacturer based on a comprehensive characterization of the EU reference product (RP), was determined and clinical data were reviewed. Our analyses show that QAs of approved adalimumab and bevacizumab biosimilars have varying concordance with the EU‐RP similarity range. In this study, we found that clinical efficacy data played a limited role in addressing quality concerns. Therefore, we encourage a regulatory review of the standards for clinical data requirements for mAb and fusion protein biosimilars. This study outlines a quality data driven approach for facilitating tailored clinical programs for biosimilars. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from a US Food and Drug Administration (FDA)‐approved reference product. The development and approval of biosimilars is critical to enhancing the availability of safe, effective, and affordable treatment options for patients. Utilization of pharmacodynamic (PD) biomarkers can help streamline biosimilar development programs as the current process can be costly and time‐consuming. Whereas PD biomarkers have not been prominently used across biosimilar approvals to date, moving forward, there is ample opportunity to increase the use of PD biomarkers in biosimilar development programs in place of comparative clinical studies with efficacy end point(s). This includes utilizing PD biomarkers that were not used as surrogate end points in approval of reference products. This mini‐review summarizes how PD biomarkers have been used in biosimilar development programs to date and then discusses evidentiary considerations for PD biomarkers. In addition, study design considerations for clinical pharmacokinetic and PD assessment of proposed biosimilars are discussed. Finally, the FDA's applied regulatory science activities related to PD biomarkers for biosimilars conducted in support of the FDA's Biosimilars Action Plan are reviewed. This included conducting three clinical studies to address information gaps about PD biomarkers for biosimilars and inform general methodological best practices. In summary, enhancing our understanding of key evidentiary considerations and optimal study designs for incorporating PD biomarkers in the evaluation of proposed biosimilars can help bring more treatment options to patients faster. [ABSTRACT FROM AUTHOR]

In some adalimumab BS products "Hefiya/Hyrimoz", "Idacio", "Hukyndra/Libmyris", and "Yusimry" and the etanercept BS product "Erelzi", approved in the European Union / United States, comparative efficacy studies using the psoriasis area and severity index (PASI) as the primary end point were conducted in patients with plaque psoriasis. REFERENCE PRODUCT AS A COMPARATOR One of the differences between Japan and the European Union / United States lies in the reference products used for development. Worldwide activity of the development of biosimilar products has increased since the first biosimilar product somatropin was approved in the European Union (EU) in 2005. Bridging with analytical data only is allowed in Japan, but clinical PK bridging data for the proposed biosimilar, the EU-licensed reference product, and the US-licensed reference product are also required for the European Union / United States application. [Extracted from the article]

After market exclusivity ends for biologic drugs, biosimilars—follow‐on versions made by other manufacturers—can compete with lower prices. Biosimilars have modestly reduced prescription drug spending for US payers, but it is unclear whether patients have directly experienced any savings. In this study we assessed whether availability of biosimilar infliximab was associated with lower out‐of‐pocket (OOP) costs, using claims from a national data set of commercially insured patients from 2014 to 2018. We used two‐part models, adjusting for patient demographics, clinical characteristics, insurance plan type, and calendar month. Compared with the reference biologic, there was no difference in the percentage of biosimilar claims with OOP costs (30.1% vs. 30.8%; adjusted odds ratio (aOR) 0.98, 95% confidence interval (CI), 0.84–1.15, P = 0.84) or the average nonzero OOP cost (median $378 vs. $538, adjusted mean ratio (aMR) 0.97, 95% CI, 0.80–1.18, P = 0.77). The percentage of claims with OOP costs was lower after biosimilar competition (30.7% vs. 35.0%, aOR 0.96, 95% CI, 0.94–0.99, P = 0.003), but average nonzero costs increased (median $534 vs. $520, aMR 1.04, 95% CI, 1.01–1.07, P = 0.004). Thus, early biosimilar infliximab competition did not improve affordability for patients. Policymakers need to better assure that competition in the biosimilar market translates to lower costs for patients using these medications. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration (FDA) guidance describes how pharmacodynamic (PD) biomarkers can be used to address residual uncertainty and demonstrate no clinically meaningful differences between a proposed biosimilar and its reference product without relying on clinical efficacy end point(s). Pilot studies and modeling can inform dosing for such PD studies. To that end, we conducted a randomized, double‐blinded, placebo‐controlled, single‐dose, parallel‐arm clinical study in healthy participants to evaluate approaches to address information gaps, inform best practices for analysis of biomarker samples and study results, and apply emerging technologies in biomarker characterization. Seventy‐two healthy participants (n = 8 per arm) received either placebo or 1 of 4 doses of the interleukin‐5 inhibitors mepolizumab (3–24 mg) or reslizumab (0.1–0.8 mg/kg). A clinical study using doses lower than approved therapeutic doses was combined with modeling and simulation to evaluate the dose–response relationship of the biomarker eosinophils. There was no dose–response relationship for eosinophil counts due to variability, although the mepolizumab 24 mg and reslizumab 0.8 mg/kg doses showed clear effects. Published indirect‐response models were used to explore eosinophil data across doses from this study and the unstudied therapeutic doses. Simulations were used to calculate typical PD metrics, such as baseline‐adjusted area under the effect curve and maximum change from baseline. The simulation results demonstrate sensitivity of eosinophils as a PD biomarker and indicate doses lower than the approved doses would have PD responses overlapping with variability in the placebo arm. The simulation results further highlight the utility of model‐based approaches in supporting use of PD biomarkers in biosimilar development. [ABSTRACT FROM AUTHOR]

The potential for pharmacodynamic (PD) biomarkers to improve the efficiency of biosimilar product development and regulatory approval formed the premise for the virtual workshop Pharmacodynamic Biomarkers for Biosimilar Development and Approval hosted by the US Food and Drug Administration (FDA) and Duke Margolis, September 2021. Although the possibility of PD biomarkers replacing the to‐date routine comparative phase III confirmatory study currently expected by the FDA was discussed, the motivation and feasibility for biosimilar sponsors developing such markers and the regulatory risks entailed largely were not. Even more fundamental is the already established greater comparative value of the pharmacokinetic (PK) study as the most sensitive clinical assay for detecting subtle differences between two products. Consequently, the comparative analytical assessment and the head‐to‐head PKs will have already answered the core questions as to the biosimilarity of the candidate product to its reference. No further actionable information is obtained with either a PD study or a comparative clinical phase III study even as they may provide some reassurance of what is already known. When a suitable PD biomarker is available for the originator reference product they have already been used for biosimilar development. We must carefully consider the core requirements and timelines inherent in biosimilar development and how they occur in parallel rather than in the series we see for originator products. In order to improve the efficiency of biosimilar development, we need to ask the right questions based on a full understanding of how biosimilars have been developed to date and can be in the future. [ABSTRACT FROM AUTHOR]

Over the past 2 decades, biosimilars have created an opportunity for access to affordable medicines globally. The development process includes robust analytical and functional comparability, equivalent pharmacokinetic profile, and demonstration of lack of any meaningful clinical differences. In this brief opinion article, we offer an overview of the major aspects that are involved in biosimilar development and regulatory requirements in Asia in order to facilitate a standardized process that can enable cost‐effective development of biosimilars. [ABSTRACT FROM AUTHOR]

This study applied modeling and simulation (M&S) approaches to evaluate the sensitivity of pegfilgrastim pharmacokinetics (PKs) and pharmacodynamics (PDs) to changes in dose amount, and linear or nonlinear clearance (CL) over pegfilgrastim subcutaneous dose of 2–6 mg. A previously published model was adapted to better describe pegfilgrastim PK and PD data in healthy subjects and used in simulation. Nonlinear CL accounts for 98% and 77%, respectively, of the total CL of pegfilgrastim at 2 and 6 mg. The sensitivity analyses showed: (i) PK of 2 and 6 mg doses are similarly sensitive to detect differences for a 5% change in dose; (ii) PK of 2 mg dose is more sensitive to changes in receptor binding affinity, a model parameter for nonlinear CL, and a product quality attribute characterized with orthogonal methods as part of demonstrating analytical similarity between products; (iii) PK of approved 6 mg dose is more sensitive to changes in linear CL, which has not been associated with any specific product quality attributes, and (iv) the PDs are not sensitive to changes in linear or nonlinear CL. Taken together, our analyses support that the approved pegfilgrastim dose of 6 mg is appropriate for detecting differences between a biosimilar and the reference products in pegfilgrastim PK and PD similarity studies. The described M&S approaches can be adopted to support dose selection for biosimilars with nonlinear PK and complex PK–PD interplay. [ABSTRACT FROM AUTHOR]

The article discusses the introduction of biosimilars as competition to the blockbuster drug Humira (adalimumab), which has been a top-selling drug for the past decade. It examines the potential impact of biosimilars on lowering drug prices and addresses the challenges in biosimilar market competition, including patent issues and financial incentives in the supply chain.

For regulatory approval of a biosimilar product, extensive evaluations should be performed by rigorous clinical trials to establish the similarity between the reference product and the proposed biosimilar in terms of both efficacy and safety. Existing designs for biosimilar trials often use a single primary efficacy endpoint in trial monitoring, and then separately evaluate the safety of the biosimilar product in a secondary analysis at the trial completion. However, ignoring the safety endpoint and the correlation between safety and efficacy in trial monitoring may lead to a high false positive rate, or it may delay the termination of the trial when dissimilarity in safety is early detected. We propose a Bayesian optimal design for biosimilar trials by incorporating both safety and efficacy endpoints in a unified framework. Based on a Bayesian joint safety and efficacy model, we sequentially use a so‐called Bayesian biosimilar probability to make go/no‐go decisions. We calibrate the Bayesian design to maximize the statistical power while maintaining the frequentist type I error rate at the nominal level. We carry out extensive simulation studies to show that the design has desirable performance in terms of the false positive rate and the average sample size. We also apply the proposed design to a biosimilar trial evaluating a ranibizumab product. [ABSTRACT FROM AUTHOR]

Aim: To compare the efficacy and safety of rituximab biosimilars to reference rituximab in patients with cancer. Data Sources: A systematic review and meta‐analysis was conducted in accordance with PRISMA guidelines. MEDLINE, EMBASE, and Cochrane Central databases were searched from inception to 12 January 2022 to obtain all randomised control trial (RCTs) reporting on the safety and efficacy outcomes of patients with cancer treated with rituximab biosimilars. Study Selection: All RCTs comparing the reference rituximab with a biosimilar, conducted in inpatient and outpatient settings, were included in the systematic review. Results: Twenty‐nine RCTs were identified to report on patients treated with rituximab. The odds of achieving overall response rate in patients treated with a rituximab biosimilar compared to the reference over at least 24 weeks of treatment was 1.06 (95% confidence interval [CI] 0.88–1.26). The proportion of patients experiencing any treatment emergent adverse events were comparable between the two study arms (OR 1.20 [95% CI 0.98–1.49]). Conclusion: Biosimilars for rituximab have comparable efficacy and safety profiles in treatment naïve patients; however, evidence for efficacy and safety of switching patients from reference biologic to biosimilar is lacking, and further research is required. Plain language summary: Rituximab is a genetically engineered monoclonal antibody. Rituximab has improved the treatment outcome of many cancers, such as non‐Hodgkin's lymphoma. However, the original medication, referred to as reference rituximab, is expensive, so less expensive versions, called rituximab biosimilars, are now available. Yet concern remains around the similarity between rituximab reference and biosimilars. We performed a comprehensive literature review and summarised the results of 29 RCTs involving 8850 participants from 41 countries. These studies involved experiments in which participants were randomly assigned to receive interventions, including either rituximab biosimilar or reference biologic, for the treatment of cancer, and the results were compared. Rituximab biosimilars had treatment response (efficacy) and side effects (safety) comparable to those of reference rituximab. However, efficacy and safety data are lacking in populations that switched from rituximab reference to a rituximab biosimilar. Thus, additional studies investigating treatment outcomes following the switch from the reference rituximab to rituximab biosimilar are required. [ABSTRACT FROM AUTHOR]

Background: Comparative efficacy randomized controlled trials (RCTs) compare two active interventions in a head‐to‐head design. They are useful for informing clinical practice guidelines, but the degree to which such trials inform clinical practice guidelines in rheumatology is unknown. Methods: The American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) websites were searched from January 1, 2017, to June 12, 2021, for clinical practice guidelines. RCTs referenced by each guideline were identified, and information regarding design and outcomes were extracted. Clinical practice recommendations from each guideline were also analyzed. Results: Fifteen ACR‐ and nine EULAR‐endorsed guidelines were included, which cited 609 RCTs and provided 481 recommendations. Referenced RCTs enrolled an average of 418 patients (SD 985), most commonly evaluated biologic/targeted synthetic disease‐modifying antirheumatic drugs (70.1%), and infrequently used a head‐to‐head design (28%). A minority of recommendations received a high level of evidence (LOE) by the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology (2.9%) or an "A" grade by the Oxford Centre for Evidence based Medicine Standards (OCEBM) methodology (28.9%). LOE was higher for recommendations informed by RCTs (P < 0.001) or head‐to‐head RCTs (P = 0.008). Many recommendations received a strong recommendation despite low (8 [2.6%]) or very low (25 [8.3%]) LOE. Conclusion: Less than one in six rheumatology guideline recommendations are informed by head‐to‐head RCTs. Recommendations that were informed by head‐to‐head RCTs were more likely to have a high LOE by both GRADE and OCEBM. Efforts to introduce more comparative efficacy RCTs should be undertaken. [ABSTRACT FROM AUTHOR]

To date, two infliximab biosimilar brands have been approved for use in Australia. In 2020, Queensland Health encouraged biosimilar use by removing the infliximab originator from their state formulary and left only one infliximab biosimilar (Renflexis®; Samsung Bioepis, Sydney, NSW, Australia). The aim was to conduct a quality assurance study examining the incidence of infusion reactions after switching all patients to the one approved biosimilar brand of infliximab. This was a retrospective study of medical charts of all patients who received an infliximab dose at a tertiary hospital between 10 June to 30 September 2020. The number of infusion reactions to the first dose of Renflexis® (Samsung Bioepis) was compared to the two doses immediately prior to the switch with an alternative brand. The study received ethics exemption (2020100904CM). A total of 370 doses of infliximab were dispensed to 139 patients, of which 320 doses (86.5%) were Renflexis® (Samsung Bioepis). There were three patients excluded from the study. A total of 119 patients (88%) were switched to the Renflexis® (Samsung Bioepis) brand and two of these patients (1.7%) experienced a true infusion reaction. When compared to doses prior to the switch, three of 116 patients (2.6%) with data available experienced an infusion reaction for the dose immediately prior, and one of 113 patients (0.9%) for two doses prior. No treatment‐naïve patients (n = 17) initiated on Renflexis® (Samsung Bioepis) experienced an infusion reaction. The use of a biosimilar infliximab, in both treatment‐naïve patients and those and switching from alternative brands, does not appear to have an increased incidence of infusion reactions. [ABSTRACT FROM AUTHOR]

This phase 1 study compared the pharmacokinetic (PK) and glucose pharmacodynamic (PD) characteristics of biosimilar SAR342434 insulin lispro and Japan‐reference Humalog insulin lispro. This was a randomized, double‐blind, 2‐period, crossover study. Thirty‐six healthy Japanese male subjects underwent a 10‐hour euglycemic clamp following a single subcutaneous 0.3‐U/kg dose of SAR342434 or Humalog. Insulin lispro concentration and blood glucose were measured, and the glucose infusion rate (GIR) was adjusted to maintain the target blood glucose level. Primary PK end points were maximum plasma insulin lispro concentration and area under the plasma insulin concentration–time curve (AUC) from time 0 to the last quantifiable concentration. Primary PD end points were area under the GIR–time curve from time 0 to 10 hours and maximum GIR. PK exposure (maximum plasma concentration and AUC from time 0 to the last quantifiable concentration) and PD activity (GIR‐AUC from time 0 to 10 hours and maximum GIR) were similar between treatments. Geometric mean ratios were close to 1, and the corresponding 90% and 95%CIs (PK and PD activity, respectively) were within the 0.80 to 1.25 equivalence range. SAR342434 and Humalog were well tolerated. In healthy Japanese males, SAR342434 and Humalog showed similar PK exposure profiles and PD potency, in support of SAR342434 use as a biosimilar product. [ABSTRACT FROM AUTHOR]

Glycosylation can be a critical quality attribute in biologic manufacturing. In particular, it has implications on the half‐life, immunogenicity, and pharmacokinetics of therapeutic monoclonal antibodies (mAbs), and must be closely monitored throughout drug development and manufacturing. To address this, advances have been made primarily in upstream processing, including mammalian cell line engineering, to yield more predictably glycosylated mAbs and the addition of media supplements during fermentation to manipulate the metabolic pathways involved in glycosylation. A more robust approach would be a conjoined upstream–downstream processing strategy. This could include implementing novel downstream technologies, such as the use of Fc γ‐based affinity ligands for the separation of mAb glycovariants. This review highlights the importance of controlling therapeutic antibody glycosylation patterns, the challenges faced in terms of glycosylation during mAb biosimilar development, current efforts both upstream and downstream to control glycosylation and their limitations, and the need for research in the downstream space to establish holistic and consistent manufacturing processes for the production of antibody therapies. [ABSTRACT FROM AUTHOR]

Biosimilars are highly similar follow‐on products for biologics that can foster biologics competition. Questionnaire studies have attempted to gauge the patient perspective on biosimilars, but none have delved deeper into how patients view biologics and switching of these. Considering Denmark has one of the highest biosimilar uptakes worldwide, the aim of this study was to investigate how Danish patients with psoriasis, arthritic diseases or inflammatory bowel disease perceive biosimilars. Twelve participants were semi‐structurally interviewed in either a focus group or an internet‐based, individual interview between May 2019 and July 2019. Content analysis was inductively applied. Participants on originators voiced more reluctance towards using biosimilars than those already using them. Both participants using originator and biosimilar products expressed concerns about reoccurrence of disease symptoms due to differences in effectiveness and safety. Participants generally struggled with understanding biosimilarity, and they voiced a need to be well‐informed about switching. They were all aware of and accepted how healthcare budget restrictions played a role in the push to use biosimilars. To improve biosimilar uptake and willingness to switch to a biosimilar, patient‐centred information on efficacy and safety and explanation of the societal benefits of the savings from using biosimilars must be carefully communicated. [ABSTRACT FROM AUTHOR]

Aims: The objective of this retrospective cohort study was to provide an overview of the utilization of originator and biosimilar infliximab in the Netherlands. Methods: All infliximab dispensings were selected from the PHARMO In‐patient Pharmacy Database from 2002–2018. Descriptive analyses were performed in order to characterise initiators and to describe switching patterns over time. Results: Overall, 3840 patients with 61 274 infliximab dispensings were identified. 2496 patients initiated an originator infliximab and 777 patients initiated a biosimilar infliximab. Overall, 57% of the patients was female and mean age was 43.2 years. Both originators and biosimilars were mostly prescribed by gastroenterologists, followed by internists and rheumatologists. After market authorisation of the first biosimilar, the proportion of new patients initiating the biosimilar increased from 39% in 2015 to 91% in 2018. Out of 704 patients eligible for switching 34% switched. Among switchers, the proportion of females was 60% and mean age at index was 45.1 years. Among nonswitchers, 55% were female and mean age was 39.8 years. The median time to switch was 1.7 years and switchers were most frequently initiated on infliximab by a rheumatologist (42%), while nonswitchers were most frequently initiated by a gastroenterologist (42%). Conclusion: The results of this large population‐based cohort show an increase in biosimilar initiation in daily clinical practice. The number of switchers remains relatively low as nonmedical switch is not encouraged in the Netherlands. [ABSTRACT FROM AUTHOR]

Aims: Adalimumab is a biological therapy used to treat different chronic inflammatory diseases. At present, there is an increasing number of adalimumab biosimilars. To assume the acceptability of interchangeability between reference adalimumab and biosimilars, there should be evidence about efficacy and safety of this switching. Regulation of this practice falls under the authority of individual European Union Member States. The aim of this study is to systematically review the evidence on the efficacy, safety and immunogenicity of switching between reference adalimumab and biosimilars in different chronic immune‐mediated inflammatory diseases. Methods: Studies presenting data about switching between reference adalimumab and biosimilars were identified by sensitive search strategies in Medline and EMBASE from 1 January 2004 to 30 June 2021. Results: A total of 471 references were obtained and 21 finally included in the analysis (total number of patients switching: 2802). Eight different adalimumab biosimilars were tested after receiving reference adalimumab. Eight articles included rheumatoid arthritis (RA), one miscellaneous rheumatic disease, six psoriasis (PSO) and six inflammatory bowel disease (IBD) patients. Overall, the efficacy results in the switching groups were comparable to those obtained in the arms of continuous biosimilar and continuous reference adalimumab. There were no significant differences in treatment emergent adverse events, anti‐drug or neutralising antibodies among the three groups. Conclusions: Switching between reference adalimumab and biosimilars has no impact on efficacy, safety and immunogenicity in patients with RA, PSO and IBD. This finding was consistent for the different adalimumab biosimilars analysed. These conclusions could probably be extended to other rheumatic diseases such as psoriatic arthritis and ankylosing spondylitis. [ABSTRACT FROM AUTHOR]

Although, when a PK/PD study cannot be conducted in HVs due to ethical considerations or an anticipated pharmacological effect, PK/PD studies should be conducted in the patient population. This narrative review summarizes Health Canada's perspective on the clinical development of biosimilars and related scientific and regulatory challenges on the use of pharmacodynamic (PD) markers, and what we may have learned from using them. [Extracted from the article]

Aims: The pharmacokinetic (PK) similarity between MB02, a proposed bevacizumab biosimilar, and reference bevacizumab approved from the USA (US‐bevacizumab) and European Union (EU‐bevacizumab) was evaluated. Safety and immunogenicity were also assessed. Methods: In this phase 1, randomized, double blind, single dose, parallel group study, 114 healthy male volunteers were randomized 1:1:1 to receive a 3 mg/kg intravenous dose of MB02, US‐bevacizumab or EU‐bevacizumab, and evaluated for 100 days. PK similarity between MB02 and reference bevacizumab was determined using the standard bioequivalence criteria (0.80–1.25) for the area under the serum concentration–time curve from time 0 extrapolated to infinity (AUC(0‐∞)) and the maximum observed serum concentration (Cmax). Results: Baseline demographics were similar across treatment groups. All study drugs exhibited similar PK profile. The 90% confidence interval for the geometric lead square means ratios for the primary parameters AUC(0‐∞) and Cmax for MB02, US‐bevacizumab and EU‐bevacizumab were fully contained within the pre‐defined bioequivalence limits for the 3 pairwise comparisons: AUC(0‐∞) (MB02:US‐bevacizumab 0.998 [0.944 to 1.05]; MB02:EU‐bevacizumab 1.07 [1.00 to 1.14]; and US‐bevacizumab:EU‐bevacizumab 0.934 [0.884 to 0.988]) and Cmax (MB02:US‐bevacizumab 0.983 [0.897 to 1.08]; MB02:EU‐bevacizumab 1.06 [0.976 to 1.16]; and; US‐bevacizumab: EU‐bevacizumab 0.926 [0.851 to 1.01]). Treatment emergent adverse events were reported in 87 subjects (76.3%), most being mild and with comparable incidence among treatment groups. Thirty‐three subjects (28.9%) reported 56 possibly related treatment emergent adverse events with comparable incidence across treatments, the most frequent being headache (10.5%) and fatigue (3.5%). Anti‐drug antibody incidence was low and similar between treatment groups. Conclusions: This study demonstrates the PK similarity and bioequivalence of MB02 to the reference bevacizumab, whether approved from USA or EU. The safety and immunogenicity profile of MB02 was shown also to be similar to the bevacizumab reference product (NCT 04238663). [ABSTRACT FROM AUTHOR]