FDA,WHO和EMA关于基于生物药剂学分类系统的生物等效性豁免指导原则的比较

本文比较了FDA,WHO和EMA各自发布的关于基于生物药剂学分类系统(biopharmaceuticsclassification system,BCS)的生物等效性豁免的指导原则。结果表明它们的基本理念都源于Amidon等提出的BCS理论,因此豁免的基本原则和考虑因素保持一致,但一些重要概念和豁免标准存在较大差异,WHO和EMA拓宽了FDA关于生物豁免应用的范围。文中总结了运用基于BCS的生物等效性豁免时需考虑的主要因素并进行了讨论,希望有助于深入理解这一科学理念并尽快在中国实施。     

FDA对撒拌及经鼻胃管等特殊给药方式的固体口服仿制药生物等效性试验要求的分析

摘 要研究美国食品药品管理局（FDA）对撒拌及经鼻胃管等特殊给药方式的固体口服仿制药如何开展生物等效性试验的要求及相关指导原则,针对该类仿制药物关键质量属性、生物等效性试验的设计、体外鼻胃管对比试验等多个方面对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,为企业研发该类仿制药产品及开展相关品种的一致性评价工作及提供借鉴和帮助。     

美国FDA《特定药物的生物等效性指导原则》 高变异性药物生物等效性指导原则调研

目的：研究美国食品药品管理局（FDA）《特定药物的生物等效性指导原则》对高变异性药物生物等效性研究相关规定,为我国仿制药质量和疗效一致性评价工作提供借鉴和帮助。方法：从剂型、给药方式、试验设计、受试者选择、给药条件、检测物质选择、豁免条件、体外溶出试验等多个方面对美国FDA公布的高变异性药物《特定药物的生物等效性指导原则》进行详细分析,并特别指出涉及我国仿制药质量与疗效一致性评价首批品种的高变异性药物。结果：美国FDA公布的涉及高变异性药物《特定药物的生物等效性指导原则》对具体化学仿制药的生物等效性评价从多个方面进行较为详细的规范,是对美国FDA相关生物等效性总则的补充和解读,对仿制药的发展有重要的推动作用。结论：在我国国家食品药品监督管理总局（CFDA）尚未颁布针对具体高变异性药物相关生物等效性指导原则的背景下,美国FDA《特定药物的生物等效性指导原则》中对高变异性药物相关规范对我国正在进行的仿制药质量和疗效一致性评价具有一定指导和借鉴意义。     

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。     

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。     

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。     

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。     

浅谈世界卫生组织的药品生物等效性豁免

介绍世界卫生组织(WHO)有关药品生物等效性实验豁免(以下简称生物豁免)的政策指南,使国内制药行业对其有所了解。就WHO的生物豁免政策而言,更多的药品可以避免进行体内生物等效性研究,这对于以仿制药为主的药品研发更具节约时间和开发成本的效益,也为国内的有关生物等效性豁免提供借鉴。     

鼻用喷雾剂/气雾剂生物等效性评价及其统计学应用考量

目的 系统阐述局部作用的鼻用喷雾剂和鼻用气雾剂生物等效性（bioequivalence,BE）评估背景,以及美国、欧盟和中国监管机构对该类复杂药械组合BE评估的基本要求。方法 详细解释美国食品药品监督管理局（Food and Drug Administration,FDA）采用的创新性证据加权理念,和该类制剂BE评估的统计学原理、方法和考量。通过FDA颁布的布地奈德吸入混悬液指导原则和丙酸氟替卡松鼻用喷雾剂指导原则草案中的计算方法,通过R语言编程计算双侧和单侧群体生物等效性（population bioequivalence,PBE）计算统计学参数,并提供计算程序的伪代码。介绍了欧盟和中国对于鼻用喷雾剂和鼻用气雾剂相关的指导原则和评审理念。结果与结论 局部作用的鼻用喷雾剂/鼻用气雾剂为近年来新药及仿制药开发的热点,本文为该类制剂的研发、质量控制以及仿制制剂BE评价提供有益的思路与参考。     

盐酸西替利嗪片人体生物等效性试验

目的 评价健康受试者空腹和餐后条件下单剂量服用盐酸西替利嗪片受试制剂和参比制剂是否具有生物等效性。方法 采用随机、开放、单剂量、自身交叉设计,液质联用（LC-MS/MS）法测定健康受试者空腹或餐后给药后血浆中西替利嗪的药物浓度,使用Phoenix Winnonlin 8.0软件计算药动学参数,使用SAS 9.4软件进行生物等效性评价。结果 空腹BE试验：24名健康受试者分别单次空腹服用受试制剂和参比制剂10 mg后,Cmax、AUC0-t、AUC0-∞几何均数的比值分别为100.18%、96.37%、96.00%,其90%置信区间分别为95.72% ~ 14.84%、92.37% ~ 100.55%、91.77% ~ 100.42%,均落在等效区间80.00% ~ 125.00%之间;餐后BE试验：22名健康受试者分别单次餐后服用受试制剂和参比制剂10 mg后,Cmax、AUC0-t、AUC0-∞几何均数的比值分别为103.98%、102.19%、101.58%,其90%置信区间分别为98.31% ~ 109.97%、98.33% ~ 106.20%、98.07% ~ 105.20%,均落在等效区间80.00% ~ 125.00%之间。结论 两种制剂对于空腹和餐后条件下的健康成年受试者具有生物等效性。     

BCS Biowaivers: Similarities and Differences Among EMA,FDA, and WHO Requirements

The Biopharmaceutics Classification System (BCS), based on aqueous solubility and intestinal permeability, has enjoyed wide use since 1995 as a mechanism for waiving in vivo bioavailability and bioequivalence studies. In 2000, the US-FDA was the first regulatory agency to publish guidance for industry describing how to meet criteria for requesting a waiver of in vivo bioavailability and bioequivalence studies for highly soluble, highly permeable (BCS Class I) drugs. Subsequently, the World Health Organization (WHO) and European Medicines Agency (EMA) published guidelines recommending how to obtain BCS biowaivers for BCS Class III drugs (high solubility, low permeability), in addition to Class I drugs. In 2015, the US-FDA became better harmonized with the EMA and WHO following publication of two guidances for industry outlining criteria for obtaining BCS biowaivers for both Class I and Class III drugs. A detailed review and comparison of the BCS Class I and Class III criteria currently recommended by the US-FDA, EMA, and WHO revealed good convergence of the three agencies with respect to BCS biowaiver criteria. The comparison also suggested that, by applying the most conservative of the three jurisdictional approaches, it should be possible for a sponsor to design the same set of BCS biowaiver studies in preparing a submission for worldwide filing to satisfy US, European, and emerging market regulators. It is hoped that the availability of BCS Class I and Class III biowaivers in multiple jurisdictions will encourage more sponsors to request waivers of in vivo bioavailability/bioequivalence testing using the BCS approach.     

Comparison of WHO and US FDA biowaiver dissolution test conditions using bioequivalent doxycycline hyclate drug products

Objectives The dissolution characteristics of immediate‐release doxycycline hyclate products with certified in‐vivo bioequivalence to the innovator product were tested with a view to possible application of biowaiver‐based approval. Methods Five products were tested using US Pharmacopeia Apparatus 2: Antodox 100 mg hard gelatin capsules, Doxycyclin AL 100 T tablets, Doxycyclin‐ratiopharm 100 soft gelatin capsules, Doxycyclin STADA 100 mg tablets and Doxy‐Wolff 100 mg tablets. Three compendial buffers were used as dissolution media: simulated gastric fluid without pepsin, pH 1.2, acetate buffer, pH 4.5, and simulated intestinal fluid without pancreatin, pH 6.8. Results were obtained at two paddle speeds recommended for biowaiver applications: 75 rpm (World Health Organization; WHO) and 50 rpm (US Food and Drug Administration; US FDA). Key findings The results for the tablets and hard gelatin capsules indicate that a paddle speed of 75 rpm is more representative than 50 rpm, since 75 rpm generates dissolution profiles corresponding more closely to the in‐vivo profiles than those at 50 rpm. For evaluating soft gelatin capsule formulations with lipid fill, both US FDA and WHO methods were found to be over‐discriminating. Conclusions Bioequivalence of immediate‐release doxycycline hyclate tablets and hard gelatin capsules, but not soft gelatin capsules, can be evaluated in vitro using the biowaiver dissolution test conditions specified by the WHO.     

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Sitagliptin Phosphate Monohydrate

Sitagliptin is an antihyperglycemic drug used in adults for the treatment of diabetes Type 2. Literature data and in-house experiments were applied in this monograph to assess whether methods based on the Biopharmaceutics Classification System (BCS) could be used to assess the bioequivalence of solid immediate-release (IR) oral dosage forms containing sitagliptin phosphate monohydrate, as an alternative to a pharmacokinetic study in human volunteers. The solubility and permeability characteristics of sitagliptin were reviewed according to the BCS, along with dissolution, therapeutic index, therapeutic applications, pharmacokinetics, pharmacodynamic characteristics, reports of bioequivalence (BE) / bioavailability problems, data on interactions between the drug and excipients and other data germane to the subject.All data reviewed in this monograph unambiguously support classification of sitagliptin as a BCS Class 1 drug. In light of its broad therapeutic index and lack of severe adverse effects, the clinical risks associated with moderately supraoptimal doses were deemed inconsequential, as were the risks associated with moderately suboptimal doses. Taking all evidence into consideration, it was concluded that the BCS-based biowaiver can be implemented for solid IR oral drug products containing sitagliptin phosphate monohydrate, provided (a) the test product is formulated solely with excipients commonly present in solid IR oral drug products approved in ICH or associated countries and used in amounts commonly applied in this type of product, (b) data in support of the BCS-based biowaiver are obtained using the methods recommended by the WHO, FDA, EMA or ICH and (c) the test product and the comparator product (which is the innovator product in this case) meet all in vitro dissolution specifications provided in the WHO, FDA, EMA or ICH guidance.     

Classification of torasemide based on the Biopharmaceutics Classification System and evaluation of the FDA biowaiver provision for generic products of CLASS I drugs

The biopharmaceutical properties of an in-house developed new crystal modification of torasemide (Torasemide N) were investigated in comparison with the most well known crystal modification form of torasemide (Torasemide I) in order to classify the drug according to the Biopharmaceutics Classification System (BCS), and to evaluate the data in line with current US Food and Drug Administration (FDA) guidance (with biowaiver provision for Class I drugs) to determine if the biowaiver provision could be improved. The solubility profiles of Torasemide I and Torasemide N were determined, and tablets prepared from both forms of the drug were studied for in-vitro release characteristics in media recommended by the current FDA guidance for biowaiver of generic products, and in other media considered more appropriate for the purpose than the ones recommended by the FDA. Two separate bioequivalence studies in healthy humans (following oral administration) were performed with two test products (both prepared from Torasemide I) against a single reference product (prepared from Torasemide N). The absorption profiles of the drug from the tablets were determined by deconvolution for comparison with the in-vitro release profiles to determine the appropriateness of some dissolution media for predicting in-vivo performance and to determine the comparative rate and extent of absorption. The drug was absorbed from the tested products quickly and almost completely (about 95% within 3.5 h of administration). However, one test product failed to meet the bioequivalence criteria and had a significant initial lower absorption rate profile compared with the reference product (P< or =0.05), whereas the other product was bioequivalent and had a similar absorption profile to the reference product. A dissolution medium at pH 5.0, in which torasemide has minimum solubility, was found to be more discriminatory than the media recommended by the FDA. Torasemide has been classified as a Class I drug according to the BCS up to a maximum dose of 40 mg and the data suggest that the current FDA guidance could be improved by giving more emphasis to selection of appropriate dissolution media than is given in its current form for approving biowaiver to generic products of Class I drugs.     

Modern approaches to quality evaluation of generic drugs for their registration (a review)

At present the quality of generic drugs for registration in the Russian Federation is checked by studying their bioequivalence. According to FDA and WHO guidelines, some generic drugs can be registered on the basis of only in vitro data (dissolution test) without testing for the bioequivalence in vivo. A biowaiver procedure that is based on a biopharmaceutical classification system is developed for such a simplified registration scheme.     

The biowaiver procedure: its application to antituberculosis products in the WHO prequalification programme

In 2005, the World Health Organization (WHO) proposed that provided an active pharmaceutical ingredient could meet certain criteria, bioequivalence could be evaluated with a set of laboratory tests, obviating the need for expensive and time-consuming pharmacokinetic studies in humans. The aim of this work was to determine whether this so-called "biowaiver" procedure can be applied to antituberculosis products. Antituberculosis products from the WHO Prequalification Programme, including three ethambutol, two isoniazid and one pyrazinamide product, were investigated. In vitro dissolution data for these products were generated according to the biowaiver method stipulated in the WHO Guidance, and the bioequivalence decision based on these data was compared with that based on the corresponding in vivo pharmacokinetic data. In no case was a "false positive" bioequivalence decision reached using the biowaiver procedure, that is, all products deemed bioequivalent according to the biowaiver methods also proved to be bioequivalent in the corresponding pharmacokinetic study. These findings open the way to a simplified method of ensuring bioequivalence of antituberculosis drug products, thereby improving access to high quality antituberculosis medicines for a greater number of patients.     

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

目的 探讨益血生胶囊联合多糖铁复合物胶囊治疗妊娠期缺铁性贫血的临床疗效.方法 选取2018年8月—2020年8月在南阳市中心医院进行治疗的158例妊娠期缺铁性贫血患者为研究对象,根据用药差别分为对照组(79例)和治疗组(79例).对照组口服多糖铁复合物胶囊,0.3 g/次,1次/d;治疗组在对照组基础上口服益血生胶囊,...     

The Impact of the EMA Change in Definition of “Dose” on the BCS Dose–Solubility Ratio: A Review of the Biowaiver Monographs

The Biopharmaceutics Classification System (BCS) defines the solubility characteristics of an active pharmaceutical substance based on its dose–solubility ratio: for highly soluble drugs this ratio is less than 250 mL over a defined pH range. Prior to the revision of the European Medicines Agency (EMA, formerly EMEA) guideline in 2010, the “dose” in this ratio was consistently defined by the US FDA, the EMA, and the WHO biowaiver guidelines as the highest dosage strength. However, in the revised EMA guideline, the dose is defined as the highest single dose administered according to the Summary of Product Characteristics. The new EMA criterion for highly soluble may be closer to the actual conditions of use, but it is not in line with the dose that would be used in the in vivo bioequivalence study. This paper evaluates the impact on the BCS classification of the active pharmaceutical ingredients of the published biowaiver monographs and discusses the consequences of the possible change in classification on biowaiver recommendations. Using the current definition of dose by the EMA, the biowaiver recommendations for metoclopramide hydrochloride and verapamil hydrochloride are no longer valid according to EMA criteria. For prednisolone and prednisone, a reevaluation of the biowaiver recommendation, taking into account the usual dosing levels, seems appropriate. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:65–70, 2014     

Justification of metformin hydrochloride biowaiver criteria based on bioequivalence study

The Biopharmaceutics Classification System (BCS) represents the framework for predicting the intestinal drug absorption based on its solubility and intestinal permeability. Recent research has lead to the use of in vitro tests to waive additional in vivo bioequivalence studies for some pharmaceutical products (i.e., biowaiver). The current regulations permit waivers for BCS Class I (highly soluble/highly permeable) drug substances, which represent up to 25% of the drugs. Efforts in both the science and regulatory bodies are being made to extend biowaivers to certain Class II and III products, which would represent more than 50% of all drugs coming to the market. The aim of this study was to investigate the influence of experimental conditions on metformin hydrochloride (CAS 1115-70-4) release from two immediate-release tablet formulations with proven bioequivalence and justify the biowaiver request for dissolution profile similarity in three pH media. The results obtained indicate that differences in drug dissolution observed in vitro were not reflected in vivo. Such data support the existing idea that BCS Class III drugs are eligible biowaiver candidates, even if a very rapid dissolution criterion is not fulfilled.     

浅析以体外结合试验作为评价指标的仿制药生物等效性评价方法

研究美国食品药品监督管理局（FDA）对以体外结合试验作为生物等效性评价指标的仿制药品种,分析其关键质量属性及生物等效性试验的要求及相关指导原则,并结合文献数据和FDA审评情况总结了需要关注的问题,以期为此类产品的开发提供有益的参考,为我国该类仿制药研发和正在开展的仿制药质量和疗效一致性评价提供技术支持。