各国生物类似药立法发展现状和批准产品的研究进展

通过对美国、欧盟、日本、韩国及我国生物类似药的立法发展及法规进行梳理,了解我国生物类似药法规方面存在的主要差异。通过对美国、欧盟、日本、韩国及我国生物类似药的批准及在研情况进行梳理,摸清国内外生物类似药的上市及研发现状,为我国生物类似药法规体系研究奠定基础。主要综述了各国生物类似药立法发展现状和批准产品的研究进展。     

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。     

韩国生物类似药注册管理法规体系概况

随着生物技术产业的发展,韩国开始把重点放在提升生物医药制造和临床标准上,逐步从生产仿制药转变为开发更多新分子实体、生物制品和生物类似药。2009年韩国发布了《生物类似药评估指南》,2010年推行了动态药品生产管理规范(c GMP),目前韩国大多数工厂都通过了美国FDA和欧盟药品局(EMA)检查,韩国公司与跨国生物医药公司的合作也越加紧密。从注册分类、注册程序和技术指南体系方面对韩国生物类似药注册管理法规体系做出框架性梳理。     

刍议美国生物类似药行动计划

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比制剂具有相似性的治疗性生物制品。结合美国、欧盟、日本和世界卫生组织对生物类似药研发及监管思路,重点介绍了2018年度美国食品药品监督管理局发布的《生物类似药行动计划——简介和概述：创新与竞争间的平衡》,以期对我国生物类似药监管政策的制定提供借鉴。     

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。     

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。     

利妥昔单抗生物类似药——rituximab-abbs

Rituximab-abbs是利妥昔单抗的生物类似药,也是美国食品药品监督管理局批准的首个利妥昔单抗生物类似药,目前该药已相继在韩国、欧洲、美国以及加拿大上市,主要用于治疗成人非霍奇金淋巴瘤等血液系统恶性肿瘤、类风湿性关节炎以及肉芽肿性血管炎和显微镜下多血管炎。尽管生物类似药与原研药在结构及临床特性上均高度相似,但其有效性及安全性问题仍需予以重视。为加深临床工作者对该药的理解,本文针对其药理机制、药动学特性及临床应用等作一综述。     

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。     

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。     

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。     

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.     

The regulatory landscape of biosimilars: Algeria's efforts and progress made from 2006 to 2021

Biologics are tremendously efficacious biological molecules that have enabled the treatment of many life-threatening diseases, which have previously been hard to treat. Biosimilars, also known as “follow-on biologics”, are highly similar versions of another already approved biologic, called the Reference Product. The European Union has been a pioneer in the regulation of biosimilars. WHO guideline on evaluation of biosimilars published in 2009 was an important landmark in biosimilar regulations worldwide, and several countries have adopted its principles in the development of their own regulatory pathway for the approval of biosimilars. Most countries in the Middle East North Africa (MENA) region still lack official and scientific guidelines for biosimilar approval pathways. This article explores the regulatory situation of biosimilar registration pathways in Algeria and describes the progress made and the regulatory landscape changes for biosimilars in Algeria during the past ten years. Our findings indicate that the development of biosimilar regulation in Algeria went through three major phases between 2006 and 2021, during which there has been much progress in drafting guidance documents for biosimilars. Since 2016, Algeria has used the EMA, FDA and WHO guidelines as the basis for approval of several biosimilars and no national guidelines or regulations have been adopted to date. Additionally, there has been no regulation on substitution/interchangeability. The Algerian regulatory authority has gained considerable experience with approval and use of increasingly complex biosimilars over the past 5 years and has the potential to create its own biosimilar-specific regulatory pathway in the near future.     

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.     

Biosimilars lining up to compete with Herceptin – opportunity knocks

Trastuzumab is a monoclonal antibody developed by Genentech as a treatment for breast cancer and gastric cancer when the cancer cells overexpress HER2, a membrane-bound receptor activated by epidermal growth factor. Now marketed by Roche under the trade name Herceptin, trastuzumab has been readily adopted as treatment for some of the most invasive types of breast cancer. The cost for Herceptin is over $50,000 for a full course of treatment. With the development of regulatory pathways for biosimilar products, and the imminent expiry of patents covering Herceptin, several companies have developed biosimilar trastuzumab products. As biosimilar manufacturers look for opportunities to market biosimilar trastuzumab products, Roche has positioned itself to protect its market by developing additional anti-HER2 products complementary to Herceptin. The advent of competition from biosimilars should bring some opportunity for cost savings for patients, as well as incentive for continued advancement in development of better treatments to fight breast cancer.     

各国生物类似药上市后监测要求及非可比生物制品对比研究及建议

通过对美国、欧盟、日本、韩国等国家生物类似药上市后监测的管理要求进行比对研究以及对WHO非可比生物制品管理的研究,提炼生物类似药上市后监测和非可比生物制品的管理要素;结合我国现状、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上市后监测及非可比生物制品管理的建议和建议的考量。     

我国生物类似药相关法规体系研究的总体原则

生物类似药法规体系研究在我国尚属空白。为保证研究方向的质量,确立了我国生物类似药相关法规体系研究的总体原则:以解决国内患者生物制品药物的可及性为核心目标、以遵循生物类似药研发规律为原则、以夯实生物制品民族产业基础为出发点、汲取化药仿制药产业发展的经验教训以及研究建议的可操性。主要对我国生物类似药相关法规体系研究的总体原则进行阐述。     

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.     

伴随诊断试剂的监管浅析

目的：介绍伴随诊断试剂的历史、发展以及各国的监管政策,为我国体外诊断试剂行业相关从业人员提供参考信息。方法：从美国伴随诊断试剂的发展、监管政策的发展、相关指导原则、监管面临的挑战以及各国的监管现状等五个方面,浅析伴随诊断试剂的监管情况。结果与结论：伴随诊断试剂能精准地评估不同患者对个体化药物的治疗受益程度以及潜在副作用与风险,对于保证个体化药物的安全性与有效性至关重要,此外还能够加快新的个体化药物研发流程、缩短临床试验时间以及降低研发成本。因此,越来越多的制药公司与体外诊断试剂公司积极推进"个体化药物-伴随诊断试剂"联合研发,各国监管部门也积极响应行业和市场的需求。根据伴随诊断试剂的特点制定合理的监管政策,有助于伴随诊断试剂的发展及精准医学的普及。     

On safety margin for drug interchangeability

ABSTRACT

As more and more generic (or biosimilar) drug products become available in the market place, it is a concern whether the approved generic (or biosimilar) drug products are safe and efficacious and hence can be used interchangeably. According to current regulation, most regulatory agencies such as the United States Food and Drug Administration (FDA) indicate an approved generic (or biosimilar) drug product can serve as a substitute for the innovative drug product. Bioequivalence (biosimilarity) assessment for regulatory approval among generic copies (or biosimilars) of the innovative drug product are not required. In practice, approved generic (or biosimilar) drugs are commonly used interchangeably without any mechanism of safety monitoring. In this article, current bioequivalence (or biosimilarity) limit is adjusted according to the observed geometric mean ratio and corresponding variability for development of safety margins for monitoring of drug interchangeability by minimizing the relative change in response with and without the switching.