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。     

多维度关注生物类似药的管理与临床应用

目的:为提高生物类似药的管理与临床应用水平提供参考。方法:检索国内外药品监管部门和世界卫生组织有关生物类似药审批和应用管理相关的政策法规,从药品全生命周期、通用名和处方、适应证外推、临床用药互换、药物警戒、医保支付体系、教育培训等多维度对生物类似药进行梳理。结果与结论:生物类似药是指在质量、安全性和有效性方面与已获准上市的参照药具有相似性的治疗性生物制品。在生物类似药的研发、生产、流通、使用、监管全生命周期系列环节中的管理在不同国家/地区/组织各有特点,其在研发阶段不需再独立验证安全性和有效性,只需用分析方法逐步从结构和功能上阐明其与参照药高度相似性即可;我国的生物类似药命名与原研药相同,采用通用名处方;美国FDA批准生物类似药的适应证外推需要基于其申请时的数据和信息、参照药的安全性和有效性信息及适应证相关科学要素的考量,需要经过评估,在监管下有条件地使用;美国FDA审批可替换生物类似物的标准严格,即实现互换的审批标准要高于生物相似的审批标准,但我国目前尚无这一概念;医药企业、监管机构、学术机构、医院药房之间需沟通交流,共同加强上市后风险控制和安全性监测;我国医疗保障部门需建立适宜的支付体系并通过支付制度鼓励生物类似药的使用;医务工作者要学习生物类似药的特点,才能在了解其技术审评的基础上,于实践中用好生物类似药。     

生物类似药质量分析方法研究进展

目的：为生物类似药的研发提供参考和借鉴。方法：通过查阅国内外大量文献,结合生物类似药相关法规,重点对生物类似药的理化特性、生物学活性、纯度与杂质、免疫学特性等药学特性进行梳理,并对相关分析方法进行汇总分析。结果与结论：生物类似药的研发需要采用先进的、敏感的技术和方法表征生物类似药的质量属性,评估生物类似药与参照药的生物相似性。通过对生物类似药的药学特性分析方法的相关研究进行综述,为生物类似药的研发和质量控制提供参考和借鉴。     

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。     

抗肿瘤生物类似药临床转换应用及管理的专家共识

为进一步规范生物类似药的临床转换应用,中国抗癌协会肿瘤临床药学专业委员会根据国内外生物类似药转换的法律法规,结合最新的研究数据及我国临床实践,组织相关领域专家讨论并制定共识。在转换的考量因素方面,提高疗效和减少不良反应是临床实践中由生物类似药反向转换到原研药的关键因素,而价格则是原研药主动转换到生物类似药的关键因素。在转换的态度立场方面,原抗肿瘤治疗药物控制良好的情况下应谨慎进行任何形式的转换;若原研药疗效未达预期时,不建议进行生物类似药转换,考虑直接换用其他治疗方案;在抗肿瘤生物类似药转换过程中,应符合药品的适应证且尊重并落实患者的知情权和自主选择权。在转换的管理措施方面,医疗机构应落实抗肿瘤生物类似药转换的药事监管及处方权限管理政策;在生物类似药临床转换后,应加强对患者的短期及长期的疗效及安全性监测。抗肿瘤生物类似药临床转换应用及管理专家共识的制定旨在为抗肿瘤生物类似药转换规则体系的建立及科学监管提供参考。     

欧盟生物类似药医保准入与使用政策对我国的启示

随着近些年生物类似药的研发与上市的不断踊现，生物类似药凭借其价格优势赢得了广大患者与各国医保部门的青睐。本文希望通过制度比较、案例分析及资料汇整方法对欧盟各国生物类似药的医保准入政策进行详细研究，以明晰欧盟各国在生物类似药的卫生技术评估、医保准入流程、定价支付标准等方面的先进经验，以期为我国生物类似药医保准入政策的制定提供参考和借鉴。通过在学习欧盟监管方法的基础上，我国应当扩大生物类似药的影响力、细化生物类似药相关医保准入规定、完善生物类似药医保准入配套政策。     

抗体类生物类似药命名管理及其影响分析

目的 规范我国抗体类生物类似药命名,完善其全生命周期管理体系。方法 深入研究世界卫生组织（World Health Organization,WHO）、欧盟、美国、日本及我国关于抗体类生物类似药的命名要求,分析不同命名方式对药品全生命周期管理的影响。结果 目前,国内外抗体类生物类似药的命名原则不尽相同,但总体遵循WHO的国际非专利药名系统不同的命名方式将对处方安全性、药物警戒、医保准入与支付等方面产生影响。结论 建议药品监管部门逐步与国际接轨,基于国际非专利药名系统并结合我国实际情况尽快出台生物类似药命名相关文件,以明确抗体类生物类似药命名。此外,建议加强药物警戒管理、制定科学审慎的生物类似药医保支付决策,从而构建生物类似药尤其是抗体类药物的全生命周期管理体系。     

各国生物类似药沟通交流机制及生物类似药可互换性对比研究及建议

药品注册中的沟通交流对于控制风险、提高研发注册效率具有重要作用。对美国、欧盟、日本、韩国等国家生物类似药沟通交流机制进行对比研究,结合我国沟通交流的现状,问卷调研和专家研讨,提出完善我国生物类似药沟通交流机制的建议。各国对生物类似药的"可互换性"有着不同的界定和管理。对美欧等国家生物类似药的"可互换性"进行研究,结合问卷调研和专家研讨,提出完善我国生物类似药可互换性的建议。     

FDA对少于参照药适应症生物类似药许可证申请的建议

美国食品药品监督管理局（FDA）于2020年2月发布了“供企业用生物类似药和可互换的生物类似药：少于已许可的参照药所有使用条件的许可证指导原则（草案）”。该指导原则主要对少于参照药适应症的生物类似药申报注册类别和说明书的内容提出了建议。介绍该指导原则的内容，期望能扩大我国对这类药物研发和监管的视野。     

低分子量肝素生物类似药的免疫原性及监管

低分子量肝素(LMWHs)是临床常用抗凝药物,其生物类似药在近年来得到不断发展。作为大分子生物制剂,LMWHs结构及制备工艺复杂,且部分结构难以表征,其潜在免疫原性成为安全性重点关注问题。本文对LMWHs及其生物类似药复杂性、免疫原性、监管规范进行综述,以期推动我国LMWHs生物类似药合理应用。     

Biosimilares: balance de eficacia,seguridad y coste

A biosimilar medicinal product is a successor to a biological medicinal product for which patent protection no longer applies. Manufactured by recombinant DNA technology (insertion of gene into the host cell to produce the protein). Comparable with the selected comparator, reference product, in terms of quality, safety and efficacy. The biosimilar product is usually approved for the same indications as the comparator reference product given that they share the same mode of actions.     

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.     

Are biosimilars patentable?

Introduction: This paper explores whether, and under what circumstances, a biosimilar approved in the United States under the Biologics Price Competition and Innovation Act (hereafter ‘BPCIA’) can be patented. The possibility that a biosimilar product could have meaningful patent protection arises from specific requirements for biosimilarity under the BPCIA, which account for the fact that manufacturing processes of biologics are inherently imprecise. The requirements for biosimilar approval may provide sufficient leeway to a biosimilar applicant to patent structural or formulation differences that provide non-clinical but business-relevant advantages over the reference molecule, such as improved shelf-life or ease of manufacture, without compromising clinical biosimilarity.

Areas covered: Examination of the BPCIA and related Acts, Food and Drug Administration (FDA) guidance papers, case law, patent database searching, and relevant scholarly articles.

Expert opinion: Legislative and regulatory requirements for the approval of a biosimilar under the BPCIA are focused on clinical results and allow a degree of leeway for differences to exist between a biosimilar’s structure and non-clinical components and those of the biosimilar’s reference molecule. This leeway can be exploited to provide the biosimilar with potentially patentable business-relevant advantages over its reference product while maintaining clinical biosimilarity to the reference product.     

Systematic Verification of Bioanalytical Similarity Between a Biosimilar and a Reference Biotherapeutic: Committee Recommendations for the Development and Validation of a Single Ligand-Binding Assay to Support Pharmacokinetic Assessments

For biosimilar drug development, it is critical to demonstrate similar physiochemical characteristics, efficacy, and safety of the biosimilar product compared to the reference product. Therefore, pharmacokinetic (PK) and immunogenicity (antidrug antibody, ADA) assays that allow for the demonstration of biosimilarity are critical. Under the auspices of the American Association of Pharmaceutical Scientists (AAPS) Ligand-Binding Assay Bioanalytical Focus Group (LBABFG), a Biosimilars Action Program Committee (APC) was formed in 2011. The goals of this Biosimilars APC were to provide a forum for in-depth discussions on issues surrounding the development and validation of PK and immunogenicity assays in support of biosimilar drug development and to make recommendations thereof. The Biosimilars APC’s recommendations for the development and validation of ligand-binding assays (LBAs) to support the PK assessments for biosimilar drug development are presented here. Analytical recommendations for the development and validation of LBAs to support immunogenicity assessments will be the subject of a separate white paper.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9669-5) contains supplementary material, which is available to authorized users.KEY WORDS: bioanalytical method validation, biological product, biosimilar, ligand-binding assay, pharmacokinetic     

Biosimilar: what it is not

A biosimilar is a high quality biological medicine shown to be in essence the same as an original product. The European Medicines Agency (EMA) paved the way in the regulatory arena by creating a safeguarding framework for the development of biosimilars. Biosimilar is thus a regulatory term that alludes to the evidence-based studies required to demonstrate such very high similarity. They are therefore not innovative products but the pathway laid down by the EMA for their approval represented a new paradigm. This has brought some confusion and has cast doubts among healthcare professionals about the scientific evidence behind their authorization. Many papers have been published to clarify the concept, and to reassure those professionals, but misconceptions frequently still arise. Unfortunately, this prevents biosimilars from deploying their full therapeutic added value. This paper is intended to approach those misconceptions from a new angle, by explaining what a biosimilar is not…and why. A biosimilar is neither a generic, nor an original product. It is not a biobetter or a ‘stand-alone’. Therefore, it should not be managed as such therapeutically, commercially or from a healthcare policy viewpoint. The EMA''s criteria were acknowledged by other agencies, but a significant regulatory gap with a vast majority of regulatory bodies still remains. This leaves room for the so-called non-original biologics (NOB), i.e. non-biosimilar biologics, to be launched in many regions. Raising awareness of what a biosimilar is and what it is not, will generate trust in biosimilars among healthcare professionals and will ultimately benefit patients     

Medicamentos biosimilares. Controversias científicas y legales

Patent expiry dates for early biotechnological drugs is giving rise to the availability of biosimilar drugs. According to the EMEA, these are defined as drugs with a biotechnological origin that have proven comparable to their reference product once the latter's patent expired. Modifications in the manufacturing process of biotechnological medications or treatment changes from one biotechnological molecule to another have not been debated until these biosimilar drugs have become available. It is then that, among other issues, the potential risks of their substitution for reference molecules became controversial. EMEA guidelines for biosimilar drug approval grant that these will be as effective and safe as any other newly available biotechnological medicinal product, or as any other drug undergoing changes in its manufacturing processes once marketed. Their availability will promote competition and reduce the high financial impact healthcare systems endure following the introduction of new therapies based on biotechnological drugs.     

Role of Modeling and Simulation in the Development of Novel and Biosimilar Therapeutic Proteins

Modeling and simulation (M&S) is an important enabler of knowledge integration in novel biological product development programs. Given the volume of data generated from clinical trials and the complexity of pharmacokinetic (PK) and pharmacodynamic (PD) properties for reference products, extending the use of M&S to biosimilar development is logical. Assessing PK and PD similarity is normally a critical part of demonstrating biosimilarity to a reference product. Thoughtful considerations are necessary in study design to minimize the PK and PD variability, thereby increasing the sensitivity for detecting potential differences between products. In addition, the sensitivity of PD biomarkers depends partly on their relevance to the mechanism(s) of action and the dynamic range of PD response(s), including the impact of certain structural differences on PD in the relevant population. As such, opportunities exist for leveraging the available M&S knowledgebase to maximize the efficiency in the design and interpretation of PK and PD similarity studies. This article describes M&S applications which have contributed to and can continue to enhance biosimilar development programs.     

各国生物类似药命名原则的比对研究及完善我国生物类似药命名原则的建议

对生物类似药名称进行规范管理不仅有利于医生处方和患者用药的准确性,更重要的是利于药品上市后不良反应的可追溯。对美国、欧洲、日本、韩国等国家或地区以及WHO生物类似药命名方式、命名技术要求进行比对研究,尽管各国生物类似药的命名方式有所不同,但"可区分"是各国共同遵循的原则。在对比研究的基础上,结合我国命名、处方管理相关要求、问卷调研和专家研讨,提出完善我国生物类似药命名原则的建议。     

A Tolerance Interval Approach to Assessing the Biosimilarity of Follow-On Biologics

With many important biologic products due to lose patent protection in the next few years, the development of follow-on biologics has received much attention from both sponsors and regulatory authorities. Biologics are often produced in living systems. The living systems used to produce biologics are highly complex and could be sensitive to very minor changes in the manufacturing process. According to the guideline published by the European Medicines Agency, biosimilar products are similar, not identical, to the innovator products they seek to copy. Therefore, in developing a biosimilar, it is important to assess the similarity between it and the innovator product. In this article, we consider a two-arm, parallel design with a reference biological product and a biosimilar. Then, we construct a biosimilarity index for assessing the degree of similarity based on the tolerance limits. The acceptance criterion is proposed to judge whether the biosimilar is similar to the reference product. We also address the determination of the number of subjects to ensure that the occurring probability of biosimilarity criterion is maintained at a desired level, say 80% or 90%. Supplementary materials for this article are available online.