FDA对咀嚼片生物等效性要求的分析

研究国内外药品监管机构对咀嚼片仿制药品种的关键质量属性及生物等效性试验的要求及相关指导原则,为企业开展相关品种的一致性评价工作提供借鉴和帮助。从试验设计、检测物质选择、受试者选择、给药条件、豁免条件、体外溶出试验等多个方面对FDA发布的《单项品种的生物等效性指导原则》中相关内容进行详细分析,以指导我国咀嚼片仿制药质量与疗效的一致性评价。     

WHO关于口服仿制药生物等效豁免相关政策的介绍

目的介绍WHO关于口服仿制药生物等效豁免的相关政策。方法总结了WHO关于生物药剂分类系统分类标准的修订、口服仿制药生物等效豁免的相关条件,并介绍了WHO关于基本药品目录中药物生物等效豁免可能性的评估情况。结果与结论结果与结论：在FDA相关指导原则的基础上,综合考虑药物的溶解性、渗透性、体外溶出特性这三个影响药物吸收的主要因素,WHO出台了关于口服仿制药生物等效豁免的相关政策。希望能对我们的相关工作有所启发。     

逆向工程法在仿制药开发中的应用及关注点

在我国仿制药一致性评价政策的推动下,随着ICH M9等指导原则的实施,对参比制剂处方的正确解析直接决定了是否可豁免仿制药的生物等效试验,且关系到仿制药与参比制剂生物等效试验的成败。该文全方位阐述了如何将逆向工程法用于参比制剂解析,包括处方、生产工艺及包装等方面,并结合审评经验进行案例分析,旨在引导业界探索更多的逆向工程技术用于开发高质量的仿制药,以期加速仿制药上市。     

仿制药盐酸胍法辛缓释片的制备及体外评价

目的 制备仿制药物盐酸胍法辛缓释片并探究仿制缓释制剂处方开发思路。方法 根据CFDA颁布的仿制药研究和评价相关指导原则为导向,结合原研药品处方的分析,对仿制药的体外药物释放、稳定性和工艺进行单因素研究。结果 用筛选得到的最佳处方完成盐酸胍法辛缓释片商业化批量的生产,可实现仿制药与原研药品在多种介质下释药曲线相似,同时满足小规格品种的BE豁免需求。结论 自研药物盐酸胍法辛缓释片处方设计合理,制剂制备工艺可行。     

中美日仿制药一致性评价政策比较研究

目的:对中美日三国仿制药一致性评价政策进行比较研究,为我国仿制药质量和疗效一致性评价政策的完善提供参考。方法:以"仿制药""一致性评价""Generic drug""Quality evaluation""DESI"等为主题词检索1950年1月1日-2016年6月30日在中国知网、Web of Science、Elsevier、Springer数据库以及美国FDA等网站中发表或报道的相关文献或信息,对中美日三国仿制药一致性评价政策出台的历史背景、评价方法、政策实施效果等进行比较分析。结果:中美日三国仿制药一致性评价政策出台的历史背景、评价方法、参与主体及政策影响力均不同。美国针对历史上药品法规不完善进行的药品有效性再评价,采用专家团队进行审查,依据FDA、企业、科学文献三方证据以及专家所长进行评价;日本仿制药再评价主要采用体外溶出试验的方法;我国仿制药一致性评价的重点在于仿制药市场准入评价,主要采用体内生物等效性评价方法,参比制剂的标准从原基本类似药品逐步上升为原研药。结论:与美日等以创新药为主的国家相比,我国仿制药评价中参比制剂可获得性较低,政策环境更为复杂。我国应进一步完善法律法规,给予仿制药企业合理的缓冲期,并充分考虑评价方法的多样性、特殊情况的豁免情形以及我国医药工业的现状,注重技术监管与制度监管的平衡。     

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。     

国内外特殊注射剂生物等效性指导原则的介绍分析

制剂生物等效性试验是评价仿制药内在质量的关键之一。美国食品药品监督管理局和欧洲药品管理局颁布的"单项品种生物等效性指导原则"中,对特殊注射剂如何进行生物等效性试验进行了推荐和相应要求,本文对其要点包括试验设计、检测指标、受试者选择、生物豁免原则、体外方法等进行总结分析,以对我国正在开展的仿制药质量与疗效一致性评价工作起到借鉴和指导意义。     

美国FDA鼻用制剂相关个药指导原则汇总分析

目的 通过梳理美国食品药品监督管理局（Food and Drug Administration,FDA）发布的鼻用制剂相关个药指导原则,总结FDA对鼻用制剂仿制药的研究要求,为国内鼻用制剂仿制药开发和评价提供参考。方法 在FDA官网发布的个药指导原则中筛选出鼻用制剂相关指导原则,进行汇总分析。结果 目前FDA现行43个鼻用制剂相关个药指导原则,推荐的生物等效性方法包括体外生物等效性研究、药动学研究、比较临床终点研究方法等,因不同品种而有所区别。部分个药指导原则已收录先进的体外检测技术如形态定向拉曼光谱用于代替体内临床试验。本文对不同种类生物等效性试验的试验设计、主要研究终点和等效性标准方面进行了代表性描述。结论 本文对FDA发布的鼻用制剂相关个药指导原则进行了汇总分析,为国内鼻用制剂仿制药开发和评价提供参考。     

益血生胶囊联合多糖铁复合物治疗妊娠期缺铁性贫血的临床研究

在仿制药研究过程中通过体外评价方法替代体内生物等效性研究可以减少临床资源消耗,加快药品上市进度,这是基于生物药剂学分类系统（BCS）的生物等效性豁免的主要原因。随着我国仿制药的快速发展,企业基于BCS的生物豁免申请需求越来越迫切,当药物制剂为具有全身作用的普通口服制剂,且药物活性成分符合溶解性和渗透性（BCS I和III类）标准,受试制剂剂型和规格与参比制剂相同,可适用基于BCS的生物等效性豁免。对国内外的基于BCS分类的生物豁免研究进展和法规进行综述,并对具体操作及申报要求提出一些思考。     

我国化学仿制药参比制剂落选品种的特征分析

参比制剂是指用于仿制药开发的对照药品,是仿制药研发过程中的关键因素之一,也是有效进行仿制药开发以及开展一致性评价工作的重要条件.化学仿制药参比制剂遴选相关政策及其目录的发布与执行,有效推动了我国化学仿制药一致性评价工作的进程,也为药品安全性、有效性的科学监管奠定了坚实基础.通过对2020年1月-2021年10月中国化学...     

Applications of In Vitro–In Vivo Correlations in Generic Drug Development: Case Studies

In vitro–in vivo correlation (IVIVC) is a predictive mathematical model describing the relationship between an in vitro property and a relevant in vivo response. The main objective of an IVIVC is to serve as a surrogate for human bioequivalence (BE) studies, which may reduce the number of BE studies performed during the initial approval process as well as with certain scale-up and postapproval changes. The US Food and Drug Administration (FDA) published a regulatory guidance related to development, evaluation, and applications of IVIVC for extended-release (ER) oral dosage forms in September 1997. Despite the publication of this guidance, the deficiencies related to IVIVC are still identified by the Division of Bioequivalence in the process of Abbreviated New Drug Application (ANDA) review. Thus, the main objective of this article is to present the most commonly occurring deficiencies associated with IVIVCs via selected case studies from the ANDAs for oral ER drug products only. We searched internal FDA databases from January 1996 to December 2014 to identify the ANDAs for proposed generic oral ER drug products containing IVIVC. Only 14 ANDA submissions had IVIVC data, and most were not acceptable. Only one ANDA submission included adequate information related to IVIVC data enabling the completion of BE review within first review cycle. It is hoped that awareness of the deficiencies presented in our article would help the generic drug applicants to submit complete and appropriate information related to IVIVC data, ultimately, resulting in a more timely approval of ANDAs.KEY WORDS: bioequivalence, extended-release drug products, generics, IVIVC, SUPAC     

An evaluation of consumers’ knowledge, perceptions and attitudes regarding generic medicines in Auckland

Objectives The aim of this project was to evaluate the perceptions, knowledge and attitudes regarding generic medicines. Methods A cross-sectional study, with self administered questionnaires, was conducted to survey consumers visiting pharmacies in four regions of Auckland (North Shore, Waitakere, Central Auckland and South Auckland). Through stratified random sampling, approximately 10% of pharmacies from each region were selected, which turn out to be 30 pharmacies. Every alternate customer coming to the pharmacy, who was eligible to participate in the study, was asked by the researchers to complete the questionnaire. Results A total of 441 questionnaires were included in the analysis. Different response rates were obtained in different regions of Auckland. Of all respondents, 51.6% had previous knowledge of generic medicines. Pharmacists were the main source of information regarding generic medicines followed by doctors and media. A higher level of education had a direct relationship with having correct knowledge of generics (P = .002). Attitude of participants toward the use of generic medicines was determined by their knowledge of generics, whether it was recommended by a pharmacist and their type of illness. Participants were more prepared to change to a generic for a minor illness (79%) than for a major illness (58.7%). Those who had better knowledge were more likely than those with poor knowledge to say they would to use a generic in major illness (P = .001) as well as minor illness (P < .0001). Previous positive experiences with generics also determined consumers’ willingness to use generics. Conclusion Many consumers have misconceptions regarding generic medicines. Having knowledge about generics and the advice by doctors and pharmacists are key indicators to improve the quality use of generic medicines.     

Comparative study of anti-inflammatory activity of some branded generic and generic non-steroidal anti-inflammatory drugs

Generic drugs play a very important role in health care. A study was undertaken to ascertain the equality or inequality between generics and branded generics. NSAIDs are the most commonly used drugs. So these drugs were chosen for the study. Selected branded generic and generic products of ibuprofen, nimesulide, and diclofenac sodium were tested by oral administration of their suspensions to different groups of rats. Freshly prepared drug suspensions equivalent to doses of 40, 10, and 5?mg/kg of ibuprofen, nimesulide, and diclofenac sodium, respectively, were administered orally to the rats and anti-inflammatory activity was measured by the carrageenan-induced rat paw edema model employing Zeitlin’s apparatus to measure the paw thickness. Statistical analysis by t-test, of the activity at the point of maximum difference indicated that with respect to anti-inflammatory activity generic ibuprofen and generic diclofenac sodium are better than branded generic ibuprofen and branded generic diclofenac sodium, respectively, and generic nimesulide is similar to branded generic nimesulide. All the products studied meet the Pharmacopoeial requirements. Hence it may be concluded that branded generic and generic NSAIDs, tested in this study, are of the same efficacy and inter-changeability among branded generics, and switching between branded generics and generics would not result in any difference in efficacy.     

Generic medicines: perceptions of consumers in Melbourne,Australia

Objective The objective of this study was to explore consumers' perceptions and opinions of generic medicines and to identify barriers to their use of generic medicines. Method A qualitative approach was used. A purposive sample of consumers, aged 22–80 years, living in the Melbourne, Australia, metropolitan area were interviewed using a semi‐structured interview guide. Key findings Sixteen consumers were interviewed. Thematic content analysis of the interviews identified four major themes: knowledge about generic medicines, acceptance of generics, non‐acceptance of generics, and education needs pertaining to generic medicine use. In terms of knowledge, some consumers were not familiar with the term ‘generic medicines’, but were more familiar with the term ‘cheaper brand of medicine’. The major reason for acceptance of generic medicines among the consumers interviewed was cost. Positive encouragement from the healthcare providers was seen to influence generic medicine uptake by consumers. The major barriers to acceptance included influence from medical practitioners, side‐effects from generic brands, and confusion that may arise from using different brands. To encourage future uptake of generics by consumers, some of the respondents recommended that education strategies be implemented by healthcare practitioners and governmental agencies to educate people on the safety and efficacy of generic medicines. Conclusions This study indicated that consumers interviewed generally had positive attitudes towards the use of generic medicines. The findings also suggest that direct patient education by the healthcare providers on issues relating to safety and efficacy of generic medicines could further enhance their uptake.     

Assessment of the possibility of using comparative <Emphasis Type="Italic">in vitro</Emphasis> dissolution kinetics (biowaiver) instead of <Emphasis Type="Italic">in vivo</Emphasis> bioequivalence evaluation for establishing the interchanbeability of generic drugs

One way of establishing the interchangeability of generic drugs is based on an in vitro study of the dissolution kinetics (biowaiver). The most common approaches for assessing the ability to use the biowaiver procedure instead of the traditional bioequivalence evaluation for generics are reviewed.     

Survey of International Regulatory Bioequivalence Recommendations for Approval of Generic Topical Dermatological Drug Products

The objective of this article is to discuss the similarities and differences in accepted bioequivalence (BE) approaches for generic topical dermatological drug products between international regulatory authorities and organizations. These drug products are locally applied and not intended for systemic absorption. Therefore, the BE approaches which serve as surrogates to establish safety and efficacy for topical dosage forms tend to differ from the traditional solid oral dosage forms. We focused on 15 different international jurisdictions and organizations that currently participate in the International Generic Drug Regulators Pilot Project. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Association (EMA), Japan, Mexico, New Zealand, Singapore (a member of the Association of Southeast Asian Nations), South Africa, South Korea, Switzerland, the USA and the World Health Organization (WHO). Upon evaluation, we observed that currently only Canada, the EMA, Japan, and the USA have specific guidance documents for topical drug products. Across all jurisdictions and organizations, the three approaches consistently required are (1) BE studies with clinical endpoints for most topical drug products; (2) in vivo pharmacodynamic studies, in particular the vasoconstrictor assay for topical corticosteroids; and (3) waivers from BE study requirements for topical solutions. Japan, South Africa, the USA, and the WHO are also making strides to accept other BE approaches such as in vivo pharmacokinetic studies for BE assessment, in vivo dermatopharmacokinetic studies and/or BE studies with in vitro endpoints.KEY Words: bioequivalence, bioequivalence studies with clinical endpoints, biowaivers, dermatopharmacokinetics, topical dermatological drug products, vasoconstrictor assay     

Current Scientific and Regulatory Approaches for Development of Orally Inhaled and Nasal Drug Products: Overview of the IPAC-RS/University of Florida Orlando Inhalation Conference

This article summarizes discussions at the March 2014 conference organized by the University of Florida (UF) and International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS), entitled “Orlando Inhalation Conference: Approaches in International Regulation.” The special focus of the conference was on global scientific and regulatory issues associated with the testing and demonstration of equivalence for the registration of orally inhaled drug products (OIDPs) in the United States, Europe, Brazil, China, and India. The scope included all types of OIDPs throughout their lifecycle, e.g., innovator/brand-name products, generics, modifications due to lifecycle management, device changes, etc. Details were presented for the U.S. “weight of evidence approach” for registration of generic products (which includes demonstration of in vitro and in vivo equivalence, as well as quantitative and qualitative sameness, and device similarity). The European “stepwise” approach was elucidated, and the thinking of regulatory agencies in the major emerging markets was clarified. The conference also highlighted a number of areas that would benefit from further research and discussion, especially around patient/device interface and human factor studies, statistical methods and criteria for demonstrating equivalence, the relative roles of in vivo and in vitro tests, and appropriate designs and metrics for in vivo studies of inhaled drugs.KEY WORDS: bioequivalence, emerging markets, generics, MDIs and DPIs, regulatory science     

Considerations in establishing bioequivalence of inhaled compounds

Introduction: Generic inhalers are often perceived as inferior to their branded counterparts; however, they are safe and effective if they can meet the regulatory requirements. The approach to assess bioequivalence (BE) in oral dosage form products is not sufficient to address the complexities of inhalational products (e.g., patient-device interface); hence, more considerations are needed and caution should be applied in determining BE of inhaled compounds.

Areas covered: This review outlines the evaluation process for generic inhalers, explores the regulatory approaches in BE assessment, and highlights the considerations and challenges in the current in vitro and in vivo approaches (lung deposition, pharmacokinetic, pharmacodynamic/clinical studies, and patient-device interface) for establishing BE of inhaled compounds.

Expert opinion: The ultimate goals in this field are to establish uniformity in the regulatory approaches to speed the drug submission process in different regions, clear physicians’ misconception of generic inhalers, and have meaningful clinical endpoints such as improvement in patient quality of life when compared to placebo and brand name drugs. As inhalational drugs become more common for other indications such as antibiotics, the technologies developed for inhaled compounds in the treatment of chronic pulmonary diseases may be extrapolated to these other agents.     

Equivalence of ranitidine generic tablets studied using the <Emphasis Type="Italic">in vitro</Emphasis> dissolution test

The pharmaceutical equivalence of Zantac (reference drug) and 10 domestic and foreign generics of ranitidine hydrochloride as 150-mg coated tablets has been studied using the pharmacopoeic (USP 29) dissolution test. Analyses showed insignificant differences in the excipients entering into the compositions of ranitidine generic tablets registered in Russia. It is established that Zantac and generics of two manufacturers are rapidly soluble (according to the WHO classification). Analysis of the similarity coefficients determined for the dissolution profiles measured in media with different pH values showed the biological nonequivalence of some generics and the reference drug. It is demonstrated that the in vitro dissolution test recommended by WHO can be used for determining the bioequivalence of ranitidine generics.