Policy measures and instruments used in European countries to increase biosimilar uptake: a systematic review.

Introduction: While biosimilar medicines can contribute to the sustainability of healthcare systems, their utilization rate varies across European countries. This study aims to identify and systematize policy measures and instruments used in European countries to increase biosimilar market share. Methods: A systematic review was conducted according to PRISMA 2020 recommendations. Medline-PubMed, Web of Science and ScienceDirect databases were searched using inclusion criteria that required full articles published in English between January 2006 and November 2023. Reviews, letters, reports, editorials and comments or opinion articles were excluded from this study. Results: Of the 1,137 articles, only 13 met the eligibility criteria for analysis, which covered a total of 28 European countries. Pricing regulation measures were found in 27 of these countries with tendering, price-linkage and internal reference price being the most used. Tendering was used by 27 countries to procure biosimilars in inpatient setting. Prescribing guidelines and recommendations were the widely used instrument. Some European countries adopted physician incentives, quotas, and prescription by international non-proprietary name. Conclusion: Automatic substitution was not commonly recommended or applied. Interchangeability and switching will become increasingly relevant issues. It is important that the positive results from some countries serve as an example for the future of these medicines in the European market. Systematic review registration: https://inplasy.com/, Identifier INPLASY2023120032.

Biosimilars Would Reduce Health Care Costs But Are Yet Poorly Known - Patient Survey Study Among Biological Medicine Users.

Background: From the beginning of the year 2024, gradually implemented amendment to the Medicines Act will enable interchange of biological medicines in pharmacies in Finland. The legislative change aims to reduce health care costs. Methods: Opinions of the biological medicine users regarding substitution in pharmacies and knowledge about biological medicines were determined by a patient survey in community pharmacies and via patient organizations in Finland. Results: In total, 199 users of biological medicines responded to the survey. The respondents did not always know which product they were using, an originator or a biosimilar. This was more prominent among patients with biosimilars determined according to brand names. The more recently the biological medicine had been prescribed, the more likely a biosimilar was in use. Only about 40% of the respondents would enable pharmacies to substitute their biological medicine to a lower cost product. The most common obstacle to the idea of interchange in pharmacies was that the respondents wanted to keep the product the doctor had prescribed for them. In general, biosimilar users were more accepting towards possible interchange than originator users. Conclusion: Although the most recent treatments appear to be initiated with biosimilars, interchange in pharmacies could enable an efficient way to lower health care costs. However, guidance and awareness regarding biosimilars and biological medicines in general would improve patients' willingness towards the change, but also help pharmacists and prescribing doctors in their meaningful role.

Evaluation of cost and infusion-related reactions among intravenous trastuzumab, subcutaneous trastuzumab, and trastuzumab biosimilars at an academic medical center.

INTRODUCTION: Trastuzumab is a vital treatment option for human epidermal growth factor 2 positive breast cancer. Since 2017, there have been 5 trastuzumab biosimilars approved for use. Despite hypotheses of infusion-related reactions among intravenous trastuzumab, subcutaneous trastuzumab, and trastuzumab biosimilars, there is minimal available literature comparing these agents. This evaluation will compare the rate of infusion-related reactions among these agents, evaluate our institution's utilization, and compare acquisition costs to determine if there is a potential cost savings by utilizing specific agents as our formulary preferred medication. METHODS: We retrospectively analyzed medical records to identify the incidence of infusion-related reaction after administration of intravenous or subcutaneous trastuzumab or trastuzumab biosimilars. Additionally, we conducted a cost analysis to identify potential cost savings by switching to an alternative institutional preferred agent. Infusion chair time was calculated to identify chair time savings with subcutaneous administration. RESULTS: There were 183 patients included in this study. Seven patients (3.8%) experienced an infusion-related reaction. The most utilized agent within our cohort was intravenous trastuzumab. During our study period, 181 patients received intravenous infusions, which could allow for substantial infusion chair savings by switching to trastuzumab/hyaluronidase, the subcutaneous formulation. Beyond the chair time, direct drug cost savings were also identified when comparing the costs of each of the evaluated medications. CONCLUSION: Subcutaneous trastuzumab or trastuzumab biosimilars do not pose a greater risk of infusion-related reactions compared to intravenous trastuzumab and may offer more affordable treatment options for breast cancer patients who qualify for trastuzumab therapy.

Cost-effectiveness and drug wastage of bevacizumab biosimilar with or without chemotherapy for platinum-resistant recurrent ovarian cancer.

INTRODUCTION: The cost-effectiveness of adding bevacizumab biosimilar with or without chemotherapy (CT) and drug wastage in treating platinum-resistant recurrent ovarian cancer (PRrOC) was assessed. METHODS: A three-state partitioned-survival model to compare the clinical and economic outcomes in the treatment of patients with PRrOC from a Taiwan healthcare prospective, extrapolated to two years based on data obtained from the JGOG3023 clinical trial. The primary outcomes of the model were incremental cost-effectiveness ratios (ICERs). RESULTS: In the base-case scenario, using vials of bevacizumab biosimilar (Bevbiol) plus chemotherapy, the ICER was (new Taiwan dollar) NT$ 4,555,878 per QALY gained. The incremental cost savings of an incremental 2.02 QALYs were NT$ 1,605,828 if weight-based Bevbiol plus chemotherapy were used, but the ICER remained high at the willingness-to-pay (WTP) threshold. If the cost of Bevbiol were reduced to 50% per vial, adding it to CT would be cost-effective at an acceptable WTP threshold of NTD 2,994,200, with an ICER of NT$ 2,975,484. CONCLUSIONS: Bevacizumab biosimilars in mg/kg dosage form with chemotherapy are still not cost-effective in Taiwan, but using weight-based dosing will reduce drug waste and save treatment costs.

Leveraging the holistic benefits of biosimilars in Europe - part 2: how payers can safeguard the future of a healthy biosimilar market environment.

INTRODUCTION: Biosimilars have improved access to biologic medicines; however, historical thinking may jeopardize the viability of future markets. AREAS COVERED: An expert panel of eight diverse European stakeholders provided insights about rethinking biosimilars and cost-savings, reducing patient access inequalities, increasing inter-market equity, and improving education. The insights reported here (Part 2) follow a study that provides perspectives on leveraging the holistic benefits of biosimilars for market sustainability based on independent survey results and telephone interviews of stakeholders from diverse biosimilar markets (Part 1). Directional recommendations are provided for payers. EXPERT OPINION: The panel's market maturity framework for biosimilars has three stages: 'Invest,' 'Expand' and 'Harvest.' Across market stages, re-thinking the benefits of biosimilars beyond cost-savings, considering earlier or expanded access/new indications, product innovations, and re-investment of biosimilar-generated cost-savings should be communicated to stakeholders to promote further engagement. During 'Expand' and 'Harvest' stages, development of efficient, forward-looking procurement systems and mechanisms that drive uptake and stabilize competition between manufacturers are key. Future biosimilars will target various therapy areas beyond those targeted by existing biosimilars. To ensure a healthy, accessible future market, stakeholders must align their objectives, communicate, collaborate, and coordinate via education, incentivization, and procurement, to maximize the totality of benefits.

Cost-effectiveness analysis of upadacitinib as a treatment option for patients with rheumatoid arthritis in the Kingdom of Saudi Arabia.

AIM: To evaluate cost-effectiveness of upadacitinib (targeted synthetic-disease modifying anti-rheumatic drug [ts-DMARD]) as first-line (1 L) treatment versus current treatment among patients with rheumatoid arthritis (RA) in the Kingdom of Saudi Arabia (KSA), who had an inadequate response to prior conventional-synthetic (csDMARDs) and/or biologic-DMARDs (bDMARDs). METHODS: This Excel-based model included patients with moderate (Disease Activity Score [DAS28]: >3.2 to ≤5.1) or severe RA (DAS28 > 5.1). Cost-effectiveness of current treatment (1 L: adalimumab-originator/biosimilar; second-line (2 L): other bDMARDs/tofacitinib) was compared against a new treatment involving two scenarios (1 L: upadacitinib, 2 L: adalimumab-biosimilar [scenario-1]/adalimumab-originator [scenario-2]) for a 10-year time-horizon from societal perspective. Model outcomes included direct and indirect costs, quality-adjusted life-years (QALYs), hospitalization days, number of orthopedic surgeries, and incremental cost-utility ratio (ICUR) per QALY. RESULTS: With the current pathway, estimated total societal costs for 100 RA patients over 10-year period were Saudi Riyal (SAR) 50,450,354 (United States dollars [USD] 13,453,428) (moderate RA) and SAR50,013,945 (USD13,337,052) (severe RA). New pathway (scenario-1) showed that in patients with moderate-to-severe RA, upadacitinib led to higher QALY gain (+8.99 and +15.63) at lower societal cost (cost difference: -SAR2,023,522 [-USD539,606] and -SAR3,373,029 [-USD899,474], respectively). Thus, as 1 L, upadacitinib projects "dominant" ICUR per QALY over current pathway. Moreover, in alternate pathway (scenario-2), upadacitinib also projects "dominant" ICUR per QALY for patient with severe RA (QALY gain: +15.63; cost difference: -SAR 164,536 [-USD43,876]). However, moderate RA was associated with additional cost of SAR1,255,696 (USD334,852) for improved QALY (+8.99) over current pathway (ICUR per QALY: SAR139,742 [USD37,264]). Both scenarios resulted in reduced hospitalization days (scenario-1: -14.83 days; scenario-2: -11.41 days) and number of orthopedic surgeries (scenario-1: -8.36; scenario-2: -6.54) for moderate-to-severe RA over the current treatment pathway. CONCLUSION: Upadacitinib as 1 L treatment in moderate-to-severe RA can considerably reduce healthcare resource burden in KSA, majorly due to reduced drug administration/monitoring/hospitalization/surgical and indirect costs.

Ex vivo comparative immunogenicity assessment (EVCIA) to determine relative immunogenicity in chronic plaque psoriasis in participants receiving Humira® or undergoing repeated switches between Humira® and AVT02.

Immunogenicity against biologic medicines is ubiquitous, and it is traditionally measured by the final humoral response. However, the onset of a sustained immunogenic response begins at the cellular level with activation of T cells and maturation of naïve B cells into plasma cells. Ex vivo comparative immunogenicity assessment (EVCIA) of cellular immunogenicity in participants with moderate-to-severe chronic plaque psoriasis in the AVT02-GL-302 study, who received either reference product (RP) alone (non-switching arm) or switched between RP and AVT02 (switching arm) after 1:1 randomization at week 12. Peripheral blood mononuclear cells (PBMCs) were collected and cryopreserved from 28 participants at: baseline (before treatment) (week 1); pre-randomization (week 12); and week 16 and week 28 in both switching and non-switching arms. PBMCs were thawed and re-exposed to either medium alone (negative control), RP, AVT02, keyhole limpet hemocyanin (KLH) (positive control), RP+KLH, or AVT02+KLH. Samples from 10 participants (predetermined average cell viability of 75% across all timepoints) from each arm were analyzed for cytokine release after 24 hours and for Th-cell proliferation, 6 days post-seeding. Until week 28, cytokine release and Th-cell proliferation was similar at all time points in both switching and non-switching arms. Overall cellular immune response was elevated post-KLH re-exposure at all timepoints. The comparable ex vivo cellular immunogenicity between switching and non-switching arms complements the confirmation of interchangeability in the main study. Given the sensitivity of novel EVCIA, detecting cellular immunogenicity could be a potential outcome in predicting the immunogenicity of biologic medicines.

Efficacy of an Indian Bevacizumab BIOSimilar (BEVATAS) for Type 1 and Aggressive Posterior Retinopathy of Prematurity (BIOS-ROP Study).

Purpose: To evaluate the role of an Indian bevacizumab biosimilar (Bevatas®), for the management of type 1 retinopathy of prematurity (ROP) and aggressive posterior ROP (APROP) over 24-weeks. Patients and Methods: A retrospective, single-center, interventional study of 144 eyes of type 1 (100 eyes) and APROP (44 eyes). All eyes received a single dose of 0.625mg Bevatas injection, and were advised additional laser therapy for suboptimal response. Results: The study population had a mean gestational age of 28.94 (±2.32) weeks, an average birth weight of 1.2 (±0.34) kg, and modest male predominance (52.05%). Complete regression of ROP was seen in 65.97% of 144 eyes after 24 weeks of bevacizumab monotherapy, and in 97.22% of eyes (140 eyes) after adding laser photocoagulation. The remaining four eyes (all had APROP) developed Stage 4 ROP and needed vitreous surgery. After monotherapy with bevacizumab biosimilar, type 1 ROP eyes had significantly higher rate of complete ROP regression than APROP eyes (87% vs 18.18%; P<0.00001). All eyes with type 1 ROP, and 90.91% of eyes with APROP, regressed after receiving additional laser therapy. The study population experienced no ocular or systemic adverse effects. Conclusion: The BIOS-ROP study demonstrates that intravitreal bevacizumab biosimilar monotherapy offers significant benefit for type 1 ROP, but not APROP. Low-cost biosimilars can help sustain healthcare systems in lower-middle income countries (LMICs) with escalating healthcare expenditures. They can also improve healthcare equity by making vision-saving therapies like bevacizumab more affordable and accessible.

[90Y]Yttria Alumino Silicate Glass Microspheres: A Biosimilar Formulation to "TheraSphere" for Cost-Effective Treatment of Liver Cancer.

Background: Selective internal radiation therapy (SIRT) using a suitable ß--emitting radionuclide is a promising treatment modality for unresectable liver carcinoma. Yttrium-90 (90Y) [T1/2 = 64.2 h, Eß(max) = 2.28 MeV, no detectable γ-photon] is the most preferred radioisotope for SIRT owing to its favorable decay characteristics. Objective: The present study describes indigenous development and evaluation of intrinsically radiolabeled [90Y]yttria alumino silicate ([90Y]YAS) glass microsphere, a formulation biosimilar to "TheraSphere" (commercially available, U.S. FDA-approved formulation), for SIRT of unresectable liver carcinoma in human patients. Methods: YAS glass microspheres of composition 40Y2O3-20Al2O3-40SiO2 (w/w) and diameter ranging between 20 and 36 µm were synthesized with almost 100% conversion efficiency and >99% sphericity. Intrinsically labeled [90Y]YAS glass microspheres were produced by thermal neutron irradiation of cold YAS glass microspheres in a research reactor. Subsequent to in vitro evaluations and in vivo studies in healthy Wistar rats, customized doses of [90Y]YAS glass microspheres were administered in human patients. Results: [90Y]YAS glass microspheres were produced with 137.7 ± 8.6 MBq/mg YAS glass (∼6800 Bq per microsphere) specific activity and 99.94% ± 0.02% radionuclidic purity at the end of irradiation. The formulation exhibited excellent in vitro stability in human serum and showed >97% retention in the liver up to 7 d post-administration when biodistribution studies were carried out in healthy Wistar rats. Yttrium-90 positron emission tomography scans recorded at different time points post-administration of customized dose of [90Y]YAS glass microspheres in human patients showed near-quantitative retention of the formulation in the injected lobe. Conclusions: The study confirmed the suitability of indigenously prepared [90Y]YAS glass microspheres for clinical use in the treatment of unresectable hepatocellular carcinoma.

Cost-effectiveness analysis of continuing bevacizumab plus chemotherapy versus chemotherapy alone after first progression of metastatic colorectal cancer.

BACKGROUND: Continuation of bevacizumab plus second-line chemotherapy has significantly improved overall and progression-free survival in patients with metastatic colorectal cancer (mCRC). However, the cost-effectiveness of such high cost therapy is still uncertain in China; so this analysis was performed to evaluate the cost-effectiveness of these treatment options from the Chinese health care system perspective. METHODS: A cost-effectiveness analysis was conducted using data from the ML18147 trial (ClinicalTrials.gov identifier NCT00700102) by modeling a partitioned survival model. Main evaluation indicators were quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) with a willingness to pay (WTP) threshold of $38,201 per QALY. One-way and probabilistic sensitivity analyses were conducted to assess the robustness and stability of the model. Subgroup and scenario analyses were also performed to make our study more relevant. RESULTS: Bevacizumab plus chemotherapy increased 0.12 QALYs and an incremental cost of $22,761.62 compared with chemotherapy, resulting in an ICER of $188,904.09 per QALY. The model was most sensitive to the utility of progression-free survival and the cost of bevacizumab. Compared with chemotherapy, bevacizumab plus chemotherapy had a 0% cost-effectiveness probability, and no cost-effectiveness in subgroups at the WTP threshold of $38,201 per QALY. The scenario analysis found that bevacizumab biosimilar gained an ICER of $126,397.38 per QALY when assuming the cost of drugs was calculated at the most affordable price. CONCLUSIONS: At the WTP threshold of $38,201 per QALY, continuation of bevacizumab plus chemotherapy is unlikely considered cost-effective for patients after first progression of mCRC.

The impact of an 'evergreening' strategy nearing patent expiration on the uptake of biosimilars and public healthcare costs: a case study on the introduction of a second administration form of trastuzumab in The Netherlands.

In this paper, we explore dynamic market share and public healthcare costs of trastuzumab's evergreening (subcutaneous) variant during introduction of trastuzumab's competitive biosimilar variants in the Netherlands. We used a time series design to assess dynamic market share of trastuzumab's evergreening variant after introducing trastuzumab's biosimilar variants, focusing on the number of treatments and patients. The public healthcare costs of this evergreening strategy were estimated using administrative claims data. Our results show that the original trastuzumab was completely replaced by the subcutaneous and biosimilar variants. The uptake of the subcutaneous form peaked at 50% market share but after the introduction of biosimilars progressively reduced to a market share of 20%, resulting in a more competitive market structure. The public healthcare costs for trastuzumab significantly decreased after the introduction of the biosimilars. After the introduction of the biosimilars, a substantial price drop is visible, with the subcutaneous version, still under patent, also falling sharply in price but less strongly than the iv/biosimilar version. As the costs are publicly funded, we recommend a more explicit societal debate to consider if the potential benefits of subcutaneous Herceptin® (and other similar medicines) are worth the additional costs, and at which price it should be reimbursed as the part of the benefit package.

Achieving white blood cell equity: are the safety profiles of biosimilar and reference pegfilgrastims comparable?

Biosimilars can provide choices for patients and may provide cost savings; however, their uptake has been slow in the USA, in part due to limited knowledge. To provide additional confidence in US pegfilgrastim biosimilars, this narrative review compared the safety profiles of biosimilar pegfilgrastims, currently approved or filed for approval in the USA, with the EU- and US-approved reference pegfilgrastims. Headache and bone pain were common to biosimilars and reference products and occurred at a similar incidence. Clinical trial data on the safety profiles of biosimilar pegfilgrastims and reference products have demonstrated similarity and comparability, with no unexpected safety outcomes. Overall, the safety profiles of biosimilar pegfilgrastims and reference pegfilgrastims demonstrated a high degree of similarity and comparability.

Pegfilgrastim is a biologic drug (one made in living cells such as bacteria) that is given to some patients being treated for cancer. Pegfilgrastim is prescribed to reduce a patient's risk of infection due to a weakened immune system caused by various chemotherapy treatment plans. A biosimilar is a type of biologic medicine that is highly similar to a US FDA-approved reference biologic, and is often cheaper, making it more widely available to patients. As of March 2023, there are eight pegfilgrastim biosimilars (six approved and two awaiting approval by the FDA). This review compared the side effects for the reference pegfilgrastim with the biosimilar pegfilgrastims. The side effects in general and the side effects from treatment were similar for the reference pegfilgrastim and for the biosimilar pegfilgrastims, with the most common side effects being headache and bone pain. Serious side effects such as allergic reactions or problems with the spleen were very low and were also similar between the reference pegfilgrastim and the biosimilar pegfilgrastims. These results show that the safety of the biosimilar pegfilgrastims was similar to the reference pegfilgrastim, with no unexpected side effects. With comparable safety to their reference product, biosimilars have the potential to improve patient access to more affordable treatment options.

Combined analytical assays for the characterization of drugs binding to human IgE: Applicability to omalizumab-bearing biosimilar candidates assessment.

Analytical and functional comparison is key for substantiating the level of convergence (essential sameness) or divergence between versions or variants of a given biological medicine. Accordingly, an overlapping biological activity between products meant to be equal probably reflects a highly similar structure and anticipates a comparable pharmacodynamic behavior. We developed an orthogonal approach to compare the human IgE binding features of different lots and versions of Xolair® (omalizumab), an anti-human IgE monoclonal antibody. The IgE binding affinity and kinetics were measured by surface plasmon resonance. Ability to prevent mast cell activity was assessed in vitro and in vivo in mast cell-based models. The variability of monoclonal antibodies with identical amino acid sequences produced either in Chinese hamster ovarian cells or in human HEK293 cells, was compared. Monoclonal antibodies from the two sources exhibited slightly different human IgE binding and neutralizing features. A known variant exhibiting a three amino acid replacement in the Fab region had lower IgE binding affinity than the original omalizumab. The lower binding affinity translated into reduced IgE neutralizing capacity and, in turn, a difference in the ability to prevent mast cell activation in vitro and in vivo. The proposed set of analytical and functional assays was sensitive enough to detect Fab-linked differences between anti-IgE antibody versions exhibiting an identical aminoacid sequence. In addition to add value to the comparative assessment of biosimilar candidates bearing omalizumab, these methods can aid pre-assessments of new anti-IgE agents that aim to improve therapeutic performance.

Cost minimization analysis of subcutaneous trastuzumab versus intravenous biosimilar trastuzumab: policy recommendations for breast cancer treatment in Malaysia.

PURPOSE: Current clinical practice recommends switching innovator intravenous trastuzumab (IV-TZMi) to subcutaneous trastuzumab (SC-TZM) to save healthcare resources. However, with the availability of biosimilar intravenous trastuzumab (IV-TZMb), there is a need to re-evaluate the recommendation. Hence, this study aims to compare the cost and resource use of SC-TZM and IV-TZMb in a Malaysian public healthcare facility. METHODS: This activity-based costing study consists of (1) a retrospective medical record abstraction to determine patient details to estimate drug costs and (2) a time-motion study to quantify personnel time, patient time, and consumables used. The total cost of both SC-TZM and IV-TZMb were then compared using a cost-minimization approach, while differences were explored using an independent t-test. A sensitivity analysis was also conducted to determine the impact of uncertainties in the analysis. RESULTS: The mean total cost of SC-TZM and IV-TZMb was USD 13,693 and USD 5,624 per patient respectively. The cost difference was primarily contributed by savings in drug cost of IV-TZMb, a reduction of USD 8,546 (SD = 134), p < 0.001 compared to SC-TZM. Interestingly, SC-TZM had a significantly lower cost than IV-TZMb for both the consumable and personnel cost, a reduction by USD 300 (SD = 17.6); p < 0.001 and USD 176 (SD = 7.3); p < 0.001 respectively. The sensitivity analysis demonstrated that the total cost difference between the formulation was mainly driven by drug costs. CONCLUSION: The study evidenced that IV-TZMb was a more economically viable option in Malaysian public healthcare currently compared to SC-TZM.

Cost effectiveness of using trastuzumab biosimilars compared to trastuzumab original drugs to treat breast cancer in a hospital setting.

INTRODUCTION: Subcutaneous (SC) drug administration, such as the Herceptin® in an oncology day hospital reduces the administration time of trastuzumab. In the context of combination therapy administration, this time-saving may be called into question. The challenge posed by the deployment of much less expensive IV biosimilar forms raises questions about the cost-effectiveness of SC administration. METHODS: Using data from a french Diagnostic Related Groups regarding prescriptions of intravenous Herceptin® (HIV), Herceptin® biosimilar IV (BSIV), and Herceptin® subcutaneous (HSC), we conducted two simulations. This simulation involved replacing all HSC with BSIV in combination therapy administration (Simulation 1) and subsequently substituting IV forms with SC forms only when prescribed as monotherapy (Simulation 2). A cost-benefit analysis was conducted based on these two simulations, from the hospital's perspective, for Normandy's population over a 1-year timeframe. RESULTS: In Simulation 1, there was an average cost-saving of €12 per patient per year, but it resulted in a loss of 10140 min, equivalent to 10 min per patient per year when compared to the current situation. Simulation 2 yielded average cost-savings for the hospital amounting to €51 per patient per year, along with a time-saving of 67 min per patient per year compared to the current situation. CONCLUSIONS: The development of a program aimed at optimizing the prescription of Trastuzumab holds the potential to deliver significant cost-savings to hospitals while enhancing the quality of service provided to the patients. This optimization involves using H SC in monotherapy and BS IV in combination therapy administration.

Recent advances in structural mass spectrometry methods in the context of biosimilarity assessment: from sequence heterogeneities to higher order structures.

Biotherapeutics and their biosimilar versions have been flourishing in the biopharmaceutical market for several years. Structural and functional characterization is needed to achieve analytical biosimilarity through the assessment of critical quality attributes as required by regulatory authorities. The role of analytical strategies, particularly mass spectrometry-based methods, is pivotal to gathering valuable information for the in-depth characterization of biotherapeutics and biosimilarity assessment. Structural mass spectrometry methods (native MS, HDX-MS, top-down MS, etc.) provide information ranging from primary sequence assessment to higher order structure evaluation. This review focuses on recent developments and applications in structural mass spectrometry for biotherapeutic and biosimilar characterization.

An international comparative analysis and roadmap to sustainable biosimilar markets.

Background: Although biosimilar uptake has increased (at a variable pace) in many countries, there have been recent concerns about the long-term sustainability of biosimilar markets. The aim of this manuscript is to assess the sustainability of policies across the biosimilar life cycle in selected countries with a view to propose recommendations for supporting biosimilar sustainability. Methods: The study conducted a comparative analysis across 17 countries from North America, South America, Asia-Pacific, Europe and the Gulf Cooperation Council. Biosimilar policies were identified and their sustainability was assessed based on country-specific reviews of the scientific and grey literature, validation by industry experts and 23 international and local non-industry experts, and two advisory board meetings with these non-industry experts. Results: Given that European countries tend to have more experience with biosimilars and more developed policy frameworks, they generally have higher sustainability scores than the other selected countries. Existing approaches to biosimilar manufacturing and R&D, policies guaranteeing safe and high-quality biosimilars, exemption from the requirement to apply health technology assessment to biosimilars, and initiatives counteracting biosimilar misconceptions are considered sustainable. However, biosimilar contracting approaches, biosimilar education and understanding can be ameliorated in all selected countries. Also, similar policies are sometimes perceived to be sustainable in some markets, but not in others. More generally, the sustainability of the biosimilar landscape depends on the nature of the healthcare system and existing pharmaceutical market access policies, the experience with biosimilar use and policies. This suggests that a general biosimilar policy toolkit that ensures sustainability does not exist, but varies from country to country. Conclusion: This study proposes a set of elements that should underpin sustainable biosimilar policy development over time in a country. At first, biosimilar policies should guarantee the safety and quality of biosimilars, healthy levels of supply and a level of cost savings. As a country gains experience with biosimilars, policies need to optimise uptake and combat any misconceptions about biosimilars. Finally, a country should implement biosimilar policies that foster competition, expand treatment options and ensure a sustainable market environment.

Cost-effectiveness of granulocyte colony-stimulating factors (G-CSFs) for the prevention of febrile neutropenia (FN) in patients with cancer.

PURPOSE: Clinical practice guidelines recommend the use of all approved granulocyte colony-stimulating factors (G-CSFs), including filgrastim and pegfilgrastim, as primary febrile neutropenia (FN) prophylaxis in patients receiving high- or intermediate-risk regimens (in those with additional patient risk factors). Previous studies have examined G-CSF cost-effectiveness by cancer type in patients with a high baseline risk of FN. This study evaluated patients with breast cancer (BC), non-small cell lung cancer (NSCLC), or non-Hodgkin's lymphoma (NHL) receiving therapy who were at intermediate risk for FN and compared primary prophylaxis (PP) and secondary prophylaxis (SP) using biosimilar filgrastim or biosimilar pegfilgrastim in Austria, France, and Germany. METHODS: A Markov cycle tree-based model was constructed to evaluate PP versus SP in patients with BC, NSCLC, or NHL receiving therapy over a lifetime horizon. Cost-effectiveness was evaluated over a range of willingness-to-pay (WTP) thresholds for incremental cost per quality-adjusted life year (QALY) gained. Sensitivity analyses evaluated uncertainty. RESULTS: Results demonstrated that using biosimilar filgrastim as PP compared to SP resulted in incremental cost-effectiveness ratios (ICERs) well below the most commonly accepted WTP threshold of €30,000. Across all three countries, PP in NSCLC had the lowest cost per QALY, and in France, PP was both cheaper and more effective than SP. Similar results were found using biosimilar pegfilgrastim, with ICERs generally higher than those for filgrastim. CONCLUSIONS: Biosimilar filgrastim and pegfilgrastim as primary prophylaxis are cost-effective approaches to avoid FN events in patients with BC, NSCLC, or NHL at intermediate risk for FN in Austria, France, and Germany.

Assessment of structural and functional similarity of biosimilar products: Bevacizumab as a case study.

The antiangiogenic drug bevacizumab is a blockbuster therapeutic pharmaceutical product that is used to treat many different types of cancer including kidney, colon, rectum, lung, and breast cancer. As a result, multiple biosimilars have been approved across the various regulatory jurisdictions in India (>20 in number till date). The rapidly growing market and acceptance of biosimilars was the motivation to perform comparability study of bevacizumab biosimilars that are presently available in the Indian market. A comprehensive analytical and functional biosimilarity assessment has been performed to examine and compare innovator product of bevacizumab (Avastin-innovator product, Roche Products (India) Pvt Ltd) and six biosimilars that are being marketed in India (Abevmy from Mylan Pharmaceuticals Pvt Ltd, Bevazza from Lupin Ltd, Bryxta from Zydus Cadila, Krabeva from Biocon, Ivzumab from RPG Life Sciences Ltd, and Advamab from Alkem Laboratories Ltd). Physiochemical characterization of drug products was performed with respect to their primary structure (intact mass, reduced mass, peptide mapping by LC-MS), higher order structure (secondary structure by FTIR, Far-UV-CD, and tertiary structure by Near-UV-CD, intrinsic fluorescence spectroscopy), impurity profile (SE-HPLC, SEC-MALS, extrinsic fluorescence: size heterogenicity, degradation, stability; DLS: hydrodynamic radius; WCX-HPLC: charge variants analysis) and post-translational modifications by measuring reduced glycans through fluorescence dye analysis. Functional characterization was performed by SPR and cell proliferation assay. Further, chemometrics based quantitative evaluation of biosimilarity has been performed by combining the data obtained from analytical characterization platform. The analysis of the analytical, functional and chemometric results revealed significant levels of similarity, with biosimilar4 being the sole exception. Despite being within product specifications, Biosimilar4 displayed significant deviations with respect to critical quality attributes, including a lower proportion of monomer content, a larger percentage of basic charge variant species, and a lower proportion of aglycosylated glycoform.