Sowing confusion in the field: the interchangeable use of biosimilar terminology

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) created an abbreviated licensure pathway in the United States that allows for the development and approval of biologic products shown to be biosimilar to or interchangeable with a US Food and Drug Administration (FDA)-licensed reference product. FDA released the draft guidance for industry on Demonstrating Interchangeability with a Reference Product (hereafter referred to as the Draft Interchangeability Guidance) in January 2017. Despite FDA’s efforts, there continues to be a great deal of confusion and misinformation surrounding the topic of interchangeability. Here we discuss interchangeability, as well as substitution of biological products, with a focus on the US. Additionally, the separate topic of physician-mediated switching is covered and distinguished from interchangeability and substitution.     

Biosimilarity assessment of biosimilar therapeutic monoclonal antibodies

The concept of biosimilar was established in the early 2000s in EU. Currently, the regulatory framework for biosimilar has also been established in the US, Japan, and other countries. As of 2018, biosimilars for infliximab, adalimumab, rituximab, trastuzumab, and bevacizumab have been approved. During the development of a biosimilar, product quality should be evaluated and compared with those of the reference product extensively. Among the quality attributes of therapeutic antibodies, FcRn binding and related structures are well known to affect the pharmacokinetic profile of the product. Other quality attributes such as antigen binding, glycan structure, and isoelectric point are considered to have a potential impact on the pharmacokinetic profile of the product. Based on the high similarity of the quality attributes of the biosimilar to those of its reference product, comparative non-clinical and clinical studies are conducted. Comparable pharmacokinetic profile of the biosimilar and the reference product is important for biosimilar evaluation. In this review, the basic concept of biosimilar development as well as pharmacokinetic data obtained via non-clinical and clinical studies of biosimilar therapeutic antibody is introduced, and future perspective is discussed.     

利妥昔单抗及其生物类似药的杂质分析

目的  对利妥昔单抗原研药和类似药的产品相关杂质和工艺相关杂质进行分析。方法 用分子排阻高效液相色谱法（size-exclusion high-performance liquid chromatography,SE-HPLC）、毛细管电泳和离子交换高效液相色谱法（ion-exchange high-performance liquid chromatography,IEX-HPLC）对原研药和类似药的产品相关杂质进行分析。同时对类似药的电荷异质体进行纯度和生物活性鉴定。采用ELISA和定量PCR对原研药和类似药的工艺相关杂质进行分析。结果 SE-HPLC分析表明,原研药和类似药中抗体单体分别占98.9%和99.9%,聚合体分别占1.0%和0.1%。毛细管电泳显示,原研药中相对分子质量低的杂质占5.6%,类似药中占3.3%;原研药和类似药中非糖基化重链均占0.6%。IEX-HPLC分析表明,原研药酸性峰和碱性峰含量分别为21.0%和10.0%,类似药分别为17.7%和9.1%。类似药主峰组分的纯度和补体依赖的细胞毒性均高于酸性峰组分和碱性峰组分。原研药和类似药中的宿主细胞蛋白、宿主细胞DNA及蛋白A的残留量相似,且大多低于检测限。结论 利妥昔单抗原研药和类似药产品相关杂质和工艺相关杂质的类别和水平相似。     

Adjustment for unbalanced sample size for analytical biosimilar equivalence assessment

ABSTRACT

Large sample size imbalance is not uncommon in the biosimilar development. At the beginning of a product development, sample sizes of a biosimilar and a reference product may be limited. Thus, a sample size calculation may not be feasible. During the development stage, more batches of reference products may be added at a later stage to have a more reliable estimate of the reference variability. On the other hand, we also need a sufficient number of biosimilar batches in order to have a better understanding of the product. Those challenges lead to a potential sample size imbalance. In this paper, we show that large sample size imbalance may increase the power of the equivalence test in an unfavorable way, giving higher power for less similar products when the sample size of biosimilar is much smaller than that of the reference product. Thus, it is necessary to make some sample size imbalance adjustments to motivate sufficient sample size for biosimilar as well. This paper discusses two adjustment methods for the equivalence test in analytical biosimilarity studies. Please keep in mind that sufficient sample sizes for both biosimilar and reference products (if feasible) are desired during the planning stage.     

韩国生物类似药的研究进展

随着多个"重磅炸弹"级原研生物药的专利逐渐到期,全球生物类似药的研发呈现出蓬勃发展的态势,各个国家及地区的监管机构也逐步明确了技术指南要求,生物类似药的发展也因各国监管方式及监管理念的不同而各具特色。介绍韩国生物类似药的批准上市情况和临床在研状况,对韩国生物类似药的研究进展进行综述。     

Improving the understanding of originator and biosimilar biologics among healthcare providers in Saudi Arabia

The loss of patentability of many originator biologics has led to the rapid introduction of biosimilar agents. The anticipated economic benefit of introducing such agent has been accompanied by vagueness surrounding their biotechnology, approval requirements, positioning in treatment paradigms and potential for adverse events. The Second Symposium on Biologics and Biosimilars “Beyond Clinical Practice” was held on 24th-26th January 2020 aiming at improving the understanding of these new agents in a diverse interactive conference and to guide stakeholders how to introduce biosimilars into clinical practice. The symposium consisted of 4 tracks and 3 workshops. A total of 217 participants attended the meeting. The majority were pharmacists (78.8%) followed by physicians (18.9%) and other healthcare providers (2.3%). The workshops covered the following topics: basics of pharmacoeconomics, pharmacovigilance and patients’ perspective toward biosimilar biologics. While, the 4 main tracks included: Introduction to biosimilars, challenges in clinical practice, regulatory and pharmacoeconomic aspects and Challenges in biosimilar pharmacovigilance.     

Recommendations and requirements for the design of bioanalytical testing used in comparability studies for biosimilar drug development

With the imminent expiry of patents on a number of biological products on the market, the development of biosimilars (or 'follow-on biologics') creates an increasing opportunity in the biotechnology industry. Although general guidelines on the quality and safety of biological products also apply to biosimilars, there is a need to address specific requirements for developing biosimilar drugs. Since it is critical to show comparability of the biosimilar products to their reference (or innovator) products, developing the appropriate bioanalytical methods to support such preclinical and clinical comparability studies is of great importance. The present work recommends the requirements for the development and validation for both pharmacokinetic and immunogenicity assays to support the biosimilar drug development.     

各国生物类似药参照药管理比对研究及完善我国生物类似药参照药管理的建议

参照药是生物类似药研发的标杆,对参照药进行规范管理,有利于保证生物类似药的研发质量。通过对美欧日韩等国家以及WHO对于生物类似药参照药的相关要求进行对比研究,提炼管理要素;结合我国参照药的现状、设计问卷、开展调研和专家研讨;综合对比研究、调研和研讨,提出完善我国生物类似药参照药管理的建议及建议的考量。     

Non-clinical safety studies on biosimilar recombinant human erythropoietin

Recombinant human erythropoietin (rhEPO) is widely used for the treatment of patients with anaemia and its loss of patent protection has stimulated the development of cheaper biosimilar products. However, the quality and comparability of rhEPO products recently marketed in several developing countries is questionable. Paying attention to quality in its isolation, purification and analytical characterization, it has been possible to produce a biosimilar rhEPO that is comparable with the originator product. Non-clinical safety testing was initially carried out in the absence of a regulatory framework and contributed to the receipt of marketing approval for biosimilar rhEPO in Eastern Europe. Subsequently, this non-clinical testing was extended to take into account the recent guidelines for similar biological medicinal products published by the European regulatory authorities, which were markedly influenced by the intervening occurrence of pure red cell aplasia in patients taking what proved to be an impure rhEPO product. This Mini Review discusses the challenges faced, approaches taken and lessons learned in developing a biosimilar rhEPO product, both before and after the publication of the regulatory guidelines.     

Safety concerns of biosimilar hormone products

Background: Currently, biotherapeutic medicines are the most effective options for the treatment of many severe and chronic diseases. For faster market entry of biotherapeutic products and their cost reduction, the principles of “biosimilarity” have been developed. Development and licensing of biosimilars is allowed only after the end of patent exclusivity of the original preparation period.

Purpose: Characteristics of the main safety parameters of biosimilar hormone preparations licensed by EMA.

Methods: This paper analyzes the results demonstrating the similarities and differences between biosimilar and reference hormone products indicated in the EPAR (public assessment report) for the examination of materials presented for the licensing of biosimilar products.

Results: During the development of biosimilar hormone medicines, differences in the glycosylation profile between biosimilar and reference preparations are revealed. As biotherapeutical preparations are produced by cells, the differences in glycosylation profile between biosimilar and referent preparation are predictable. While carrying out clinical studies, a high similarity of biosimilar and reference product effectiveness is shown, but some differences between them in the safety profile are revealed.

Conclusions: The study of biosimilar product safety has shown the necessity of further improvement in safety and standard approaches for the assessment of the immunogenicity of biosimilar products.     

Knowledge,attitudes, and practices of pharmacists toward biosimilar medicines in Nigeria

BackgroundBiopharmaceutical medicines have transformed the treatment of various long-term diseases, despite their high cost and limited availability. Due to their cost saving potentials, biosimilar medicines represent a new wave of therapy for several diseases in the next few years. Thus, pharmacists are uniquely placed to promote and enhance their uptake.ObjectivesThe objectives of this study were to assess Nigerian pharmacists’ biosimilar medicine knowledge, attitudes, and practices.MethodsThis was a cross-sectional, national online survey of conveniently sampled pharmacists in Nigeria. Data were collected with a validated 31-item biosimilar medicine knowledge, attitude, and practice questionnaire. The Pearson correlation (r) analysis was conducted to investigate the association among knowledge, attitude, and practice. A P value of < 0.05 was considered statistically significant.ResultsOf the 600 pharmacists who were invited to participate in the survey, 411 completed the questionnaire giving a response rate of 68.5%. The mean knowledge score was 6.2 ± 3.0 out of a maximum score of 14. Most of the participants (n = 268, 65.2%) had overall knowledge scores of 1 to 7. The mean attitude score was 35.0 ± 8.8 out of a maximum score of 55, whereas that of practice was 18.7 ± 5.3 out of a maximum score of 30. Knowledge was significantly positively correlated with practice (r = 0.360).ConclusionMost of the surveyed pharmacists had poor knowledge of biosimilar medicines, while their reported fair attitude did not translate to good practice.     

液相色谱-质谱技术对利妥昔单抗及其类似药结构表征和相似性的研究

目的 应用液相色谱-质谱法(liquid chromatography-mass spectromety,LC/MS)和液相色谱-非数据依赖二级质谱数据采集技术(liquid chromatography-data independent acquisition mass spectromety,LC/MSE)对利妥昔单抗及其类似药进行结构表征和相似性研究.方法 用LC/MS对利妥昔单抗及其类似药的完整蛋白及轻链和重链的相对分子质量进行测定;用基于LC/MSE的肽图分析确定利妥昔单抗及其类似药的氨基酸全序列;用LC/荧光检测法分析利妥昔单抗的糖基化修饰结构及相对含量.结果 LC/MS可准确测定利妥昔单抗的相对分子质量.基于LC/MSE的肽图分析显示,利妥昔单抗的氨基酸序列覆盖率＞99％.LC/荧光检测法对利妥昔单抗的糖谱分析具有较好的重复性.利妥昔单抗类似药与原研药的相对分子质量和糖型信息相符、氨基酸序列完全一致、糖谱相似.结论 LC/MS和LC/MSE可用于利妥昔单抗及其类似药的结构表征和相似性比较,这为今后其他单克隆抗体结构表征平台的建立提供了依据.     

FDA对生物类似药说明书的要求

美国食品药品监督管理局（FDA）于2018年7月发布了"供企业用生物类似药说明书指导原则"。该指导原则提出了起草生物类似药说明书的一般原则，并对生物类似药说明书的内容提出了许多具体建议。而我国目前尚无类似的指导原则。详细介绍FDA的该指导原则主要内容，对我国撰写、阅读和监管生物类似药说明书有重要的参考价值。     

各国生物类似药适应症外推技术要求的比对研究及完善我国生物类似药适应症外推技术要求的建议

生物类似药的适应症外推,需要满足科学的前提条件。通过对美国、欧盟等国家以及WHO生物类似药适应症外推技术要求进行比对研究,提炼生物类似药适应症外推的前提条件,设计问卷、开展调研和研讨;结合对比研究、调研及专家研讨,提出完善我国生物类似药适应症外推技术要求考量的建议。     

EU pharmacovigilance regulatory requirements of anticancer biosimilar monoclonal antibodies

An increasing number of innovative oncology monoclonal antibodies (mAbs) have been introduced into the global market, and biosimilar versions have now also been approved in Europe. Being complex to develop and difficult to manufacture, the biosimilar is a drug similar but not identical in physicochemical characteristics, efficacy, and safety to an original biological drug already approved in the European Union, for which marketing exclusivity rights have expired. Generally, the safety monitoring of biosimilars follows the same requirements that apply to all biologicals, even if specific pharmacovigilance measures exist and some of them are still being debated. The manufacturing process, immunogenicity, traceability, and extrapolation of indication are keywords which may impact on the achievement of additional knowledge about the safety of a biosimilar mAb. In this article, we aim to discuss elements that play a central role in the pharmacovigilance legislation of biosimilar mAbs.     

Addressing the health technology assessment of biosimilar pharmaceuticals

Abstract

The growing number of biosimilars presents challenges to regulatory and health technology assessment (HTA) systems. This paper illustrates these challenges by focusing on biosimilars used in the oncological setting. In particular, discordances between data required by regulatory and HTA authorities potentially deprive patients of effective treatments and hinder optimal resource allocation. Regulatory and HTA authorities need to harmonize requirements to foster the development and widespread use of biosimilars, which potentially release considerable resources. The authors believe that often-inappropriate methodology creates a very real chance that HTA authorities will reject some biosimilars. This would effectively extend patent protection and, in the absence of competitor pressure from biosimilars, result in prices remaining unnecessarily high. The authors propose that HTA organizations should accept pharmacokinetic and pharmacodynamic equivalence between the brand and the biosimilar as a proxy of biological comparability. HTA organizations should then adopt, in the absence of compelling reasons otherwise, cost-minimization analysis (CMA) as the basis of the cost-effectiveness deliberations. In the absence of adequate studies demonstrating equivalent efficacy, a prerequisite of CMA, HTA organizations should require threshold analysis. Once approved, biosimilar manufacturers and regulators should maintain rigorous pharmacovigilance to exclude immunoreactivity or other rare adverse events. Furthermore, cancer centres and trusts should regularly audit and publish the impact of biosimilars on clinical outcomes and resource use. When appropriate, regulatory and HTA authorities should demand revised cost-effectiveness analyses from biosimilar manufacturers. This approach would hone the accuracy of the cost-effectiveness analyses, protect patients and allow health services rapid access to low cost treatments.     

关于生物仿制药临床评价的探讨

我国已上市和正在申报的生物制品绝大多数都是生物仿制药（biosimilar products）,关于此类药物的临床研究如何评价,目前国内尚未制定相关的指导原则和技术要求,本文期望通过借鉴国外最新相关指导原则的内容和观点,结合国情为我所用。     

各国生物类似药说明书管理的比对研究及完善我国生物类似药说明书管理的建议

对生物类似药的说明书进行规范管理,对指导医生合理用药、保证用药安全至关重要。通过对美欧日加等国家及我国生物类似药说明书管理要求进行比对研究,提炼管理要素;结合我国说明书的现状、设计问卷、开展调研和专家研讨;综合对比研究、调研和研讨,提出完善我国生物类似药说明书管理要求的建议和建议的考量。     

Assessing awareness and attitudes of healthcare professionals on the use of biosimilar medicines: A survey of physicians and pharmacists in Ireland

Increasing numbers of biosimilar medicines are becoming available. The objective of this survey was to assess awareness of and attitudes to biosimilars amongst physicians (medical specialists and General Practitioners (GPs)) and community pharmacists in Ireland. Physicians were invited to complete an online questionnaire during April and May 2016. Community pharmacists received a postal questionnaire in August 2015. Responses from 102 medical specialists, 253 GPs and 125 community pharmacists were analysed. The majority of medical specialists (85%) and pharmacists (77%) claimed to be either very familiar or familiar with the term biosimilar, whereas many GPs (60%) were unable to define or had never heard of the term. One in five (21%) healthcare professionals responded that biosimilars were the same as generic medicines. The majority of medical specialists opposed pharmacist-led substitution of biological medicines but some thought it could be appropriate if agreed with the clinician in advance. Medical specialists who prescribe biosimilars (n = 43) were more likely to do so on treatment initiation (67%), than switch a patient from an originator medicine to a biosimilar (28%). The findings will aid the design of educational initiatives for healthcare professionals and highlight attitudes of healthcare professionals to biosimilars, so informing regulators, policy makers and industry.