口服仿制药生物等效豁免体系构建探讨

自2000年至今,美国食品药品监督管理局(FDA)、世界卫生组织(WHO)、欧洲医药产品管理局(EMEA)陆续基于生物药剂分类系统对普通口服固体制剂出台了生物等效豁免政策.在此基础上,结合国内的现实情况,本文提出了在国内针对口服仿制药构建生物等效豁免体系的一些看法.该体系主要包括4个方面的内容:技术考虑要素、相关基础数据库的构建、审评资源的配置以及上市后的风险管理.     

FDA关于普通口服固体制剂生物等效豁免的相关政策介绍

目的介绍FDA关于普通口服固体制剂生物等效豁免的相关政策。方法FDA针对普通口服固体制剂的生物等效豁免先后出台了4个指导原则,对其主要内容进行介绍,并说明起草背景。结果与结论自生物药剂分类系统（BCS）提出以来,对于普通口服固体制剂采用体外溶出对比研究来替代体内生物等效性研究（即生物等效豁免）已成为可能。     

仿制药人体生物等效性试验的若干问题

对于仿制药的人体生物等效性试验虽然已有相关指导原则对其加以指导和规范,但随着国内仿制药研究和评价实践的不断拓展和深入,仍然有一些问题需要进一步探讨和明确,例如立体异构体问题、代谢物问题、高变异药物、长半衰期药物等。本文旨在对这些问题进行初步汇总和探讨。     

化学仿制药口服溶液剂的药学研究关注点

化学仿制药口服溶液剂是可能豁免人体生物等效性研究的口服给药剂型,其药学研究关注点与口服固体制剂、注射剂等剂型均有一定差异,但目前国内尚未出台相关药学研究技术指导原则。简要介绍了化学仿制药口服溶液剂药学研究中需要关注的问题,包括处方工艺、质量研究、稳定性研究等方面,重点关注了微生物控制方面的内容,结合审评实践提出了研究建议;同时在国内外相关法规要求的基础上,探讨了豁免人体生物等效性研究的相关要求。旨在为后续化学仿制药口服溶液剂的药学研究提供更多参考。     

FDA仿制药申请生物等效性数据资料提交指导原则介绍

美国FDA于2009年4月16日颁布了<仿制药申请生物等效性数据资料提交指导原则>,规范了仿制药申请提交生物等效性资料和相关研究数据的要求,这对我国的现实国情比较有借鉴意义,可资业内同仁参考.     

口服抗肿瘤仿制药生物等效性研究的考虑要点

以我国生物等效性研究相关指导原则为主要依据,参考国际监管机构相关要求,旨在从科学、伦理及审评的角度,以细胞毒、小分子靶向类口服抗肿瘤药为例,对口服抗肿瘤仿制药生物等效性研究考虑要点进行综述.     

WHO和欧盟生物仿制药注册审评制度及对我国的启示

为完善我国生物仿制药注册审评制度,通过查阅相关文献,分析了WHO和欧盟生物仿制药注册审评制度现状.分析结果表明,与WHO和欧盟相比,我国生物仿制药注册审评制度尚需改善,建议应从基本原则、参照生物药选择、药学研究资料要求等方面进行完善.     

仿制药质量与疗效一致性评价的生物豁免原则及各国及国际组织的生物等效性豁免品种

目的 为我国仿制药质量与疗效一致性评价的生物等效性试验,提供可豁免药物品种的参考。方法 以《人体生物等效性试验豁免指导原则（征求意见稿）》为基础,以我国一致性评价的首批药物为前提,简要介绍和归纳美国食品药品管理局（FDA）、世界卫生组织（WHO）、欧洲药品局（EMA）的生物等效性试验豁免的标准和可申请豁免的药物品种。结果 对比FDA,289个一致性评价药物品种中可申请豁免的有59个,不可申请豁免的有19个;对比WHO,可豁免的药物有10个,EMA中有1个。结论 目前,我国生物等效性试验豁免的具体药物名单尚未公布,企业应该对比参考国内外的相关标准和具体药物,以加快一致性评价工作的进展。     

速释口服固体制剂人体生物等效性试验豁免药学研究的要求

随着科学认知的不断深入,为缩短药品的批准上市时间,不同药品监管机构相继出台了人体生物等效性豁免的相关法规及技术文件,旨在通过体外研究来替代体内试验。总结和比较国内外相关指导原则对速释口服固体剂型的仿制药药学研究的要求,重点关注存在的差异之处,探讨背后的科学原因,并在最终经国际人用药品注册技术协调委员会协调一致的过程中得到思考和启示,以期增加仿制药被豁免体内试验的成功率、进而降低仿制药的开发成本,但同时亦能保证其质量和疗效与参比制剂一致,真正实现其临床可替代性。     

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。     

仿制药品的生物豁免

目前在我国上市销售的药品中，大多数为仿制药品，国外除了大公司原创药物较多外，仿制药品也占了相当的比例。仿制药品在促进市场竞争，降低药品价格，造福人民健康方面做出了重大贡献。根据我国现行的《药品注册管理办法》，仿制药品的申报需要向药事管理部门提供生物等效性研究资料。生物等效性是指两种制剂在相同试验条件下，服用相同剂量，其活性成分在吸收程度和速度上无显著性差异。目前国际通用方法一般采用生物利用度比较研究，即对不同时间点生物样本（如血浆、血清、尿液）中的药物含量进行测定，获得相应的AUC（曲线下面积）、Cmax（达峰浓度）、Tmax（达峰时间）等指标，根据临床经验预先制订的等效标准和限度评价拟上市药品和被仿制药品是否为等效制剂。     

WHO药物管理机构和基本药物选择简介

目的：为了更好地宣传和推广国家基本药物。方法：本文介绍世界卫生组织（WHO）的药物管理机构和基本药物选择。结果：通过介绍使广大医药工作者能更好地理解和贯彻执行国家基本药物,并促进我国国家基本药物制度和推广和实施。结论：国家基本药物的推广和执行,有利于我国的药品生产和临床合理用药。     

仿制药一致性评价中的博弈及政策建议

目的 探讨政府促进国内制药企业(简称药企)参与仿制药一致性评价的最优决策.方法 利用博弈论方法分析国内药企与政府在仿制药一致性评价问题的博弈均衡.结果 可能会产生两种均衡,一种是地方各级政府相关部门均严格执行一致性评价政策,药企则选择积极参与一致性评价;另一种是地方各级政府相关部门执行政策不统一,如适当"延期",且在省...     

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Ondansetron

Literature data pertaining to the physicochemical, pharmaceutical, and pharmacokinetic properties of ondansetron hydrochloride dihydrate are reviewed to arrive at a decision on whether a marketing authorization of an immediate release (IR) solid oral dosage form can be approved based on a Biopharmaceutics Classification System (BCS)-based biowaiver. Ondansetron, a 5HT₃ receptor antagonist, is used at doses ranging from 4 mg to 24 mg in the management of nausea and vomiting associated with chemotherapy, radiotherapy, and postoperative treatment. It is a weak base and thus exhibits pH-dependent solubility. However, it is able to meet the criteria of “high solubility” as well as “high permeability” and can therefore be classified as a BCS class I drug. Furthermore, ondansetron hydrochloride 8 mg IR tablets (Zofran^® 8 mg) and multiples thereof (16 mg = Zofran^® 8 mg × 2 tablets and 24 mg = Zofran^® 8 mg × 3 tablets) meet the criteria of “rapidly dissolving” in dissolution testing. Ondansetron hydrochloride has a wide therapeutic window and is well-tolerated after oral administration. Based on its favorable physicochemical properties, pharmacokinetic data and the minimal risks associated with an incorrect bioequivalence decision, the BCS-based biowaiver procedure can be recommended for ondansetron hydrochloride dihydrate IR tablets.     

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Carbamazepine

Literature relevant to assessing whether BCS-based biowaivers can be applied to immediate release (IR) solid oral dosage forms containing carbamazepine as the single active pharmaceutical ingredient are reviewed. Carbamazepine, which is used for the prophylactic therapy of epilepsy, is a non-ionizable drug that cannot be considered “highly soluble” across the range of pH values usually encountered in the upper gastrointestinal tract. Furthermore, evidence in the open literature suggests that carbamazepine is a BCS Class 2 drug. Nevertheless, the oral absolute bioavailability of carbamazepine lies between 70 and 78% and both in vivo and in vitro data support the classification of carbamazepine as a highly permeable drug. Since the therapeutic and toxic plasma level ranges overlap, carbamazepine is considered to have a narrow therapeutic index. For these reasons, a BCS based biowaiver for IR tablets of carbamazepine cannot be recommended. Interestingly, in nine out of ten studies, USP dissolution conditions (900 mL water with 1% SLS, paddle, 75 rpm) appropriately discriminated among bioinequivalent products and this may be a way forward to predicting whether a given formulation will be bioequivalent to the comparator product.     

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Levocetirizine Dihydrochloride

Levocetirizine, a histamine H1-receptor antagonist, is prescribed to treat uncomplicated skin rashes associated with chronic idiopathic urticaria as well as the symptoms of both seasonal and continual allergic rhinitis. In this monograph, the practicality of using Biopharmaceutics Classification System (BCS) based methodologies as a substitute for pharmacokinetic studies in human volunteers to appraise the bioequivalence of immediate-release (IR) oral, solid dosage forms containing levocetirizine dihydrochloride was investigated, using data from the literature and in-house testing.Levocetirizine's solubility and permeability properties, as well as its dissolution from commercial products, its therapeutic uses, therapeutic index, pharmacokinetics and pharmacodynamic traits, were reviewed in accordance with the BCS, along with any reports in the literature about failure to meet bioequivalence (BE) requirements, bioavailability issues, drug-excipient interactions as well as other relevant information. The data presented in this monograph unequivocally point to classification of levocetirizine in BCS Class 1. For products that are somewhat supra-equivalent or somewhat sub-equivalent, clinical risks are expected to be insignificant in light of levocetirizine's wide therapeutic index and unlikelihood of severe adverse effects. After careful consideration of all the information available, it was concluded that the BCS-based biowaiver can be implemented for products which contain levocetirizine dihydrochloride, provided (a) the test product comprises excipients that are typically found in IR oral, solid drug products that have been approved by a country belonging to or associated with ICH and are used in quantities that are typical for such products, (b) data supporting the BCS-based biowaiver are gathered using ICH-recommended methods, and (c) all in vitro dissolution requirements specified in the ICH guidance are met by both the test and comparator products (in this case, the comparator is the innovator product).     

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Efavirenz

Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate-release (IR) solid oral dosage forms containing efavirenz as the only active pharmaceutical ingredient (API) are reviewed. Because of lack of conclusive data about efavirenz's permeability and its failure to comply with the “high solubility” criteria according to the Biopharmaceutics Classification System (BCS), the API can be classified as BCS Class II/IV. In line with the solubility characteristics, the innovator product does not meet the dissolution criteria for a “rapidly dissolving product.” Furthermore, product variations containing commonly used excipients or in the manufacturing process have been reported to impact the rate and extent of efavirenz absorption. Despite its wide therapeutic index, subtherapeutic levels of efavirenz can lead to treatment failure and also facilitate the emergence of efavirenz-resistant mutants. For all these reasons, a biowaiver for IR solid oral dosage forms containing efavirenz as the sole API is not scientifically justified for reformulated or multisource drug products. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:318–329, 2013     

介绍WHO关于《抗逆转录病毒类药物治疗HIV感染妊妇和预防母婴传播的建议书》

母婴垂直传播是儿童HIV感染的主要途径,预防儿童AIDS感染最重要的方法是阻断母婴垂直传播.现有的手段已能明显降低HIV母婴垂直传播,WHO提出将其发生率降至5%以内.本文介绍2009年WHO关于<抗逆转录病毒类药物治疗HIV感染妊妇和预防母婴传播>的建议书.