FDA《食物影响的生物利用度及饮食条件下的生物等效性研究》指导原则介绍

发布日期20140404栏目化药药物评价>>综合评价标题FDA以药动学为终点评价指标的仿制药生物等效性研究指导原则（草案）介绍作者李丽张玉琥部门化药药学二部正文内容2013年12月美国食品药品监督管理局(FDA)颁布了《以药动学为终点评价指标的仿制药生物等效性研究指导原则》（草案）。

该指导原则修订并替代了两个既往指导原则（即《口服制剂生物利用度/生物等效性(BA/BE)研究的总体考虑》（2003）和《食物对生物利用度的影响以及餐后生物等效性研究技术指导原则》)中有关仿制药BE研究的内容。

相比2003版《口服制剂生物利用度/生物等效性（BA/BE)研究的总体考虑》，本指导原则主要在以下方面进行了更新:1．适用于BE研究，未涉及BA研究的有关内容。

2．适用于仿制药（ANDA)申请及其补充申请。

3．系统整合了餐后BE研究的相关内容。

4．具体技术要求的完善：1)系统归纳了三种BE试验设计方案及其适用范围。

2)明确了受试者的选择要求。

3）强调进行稳态研究的试验设计主要出于安全性考虑,因而入选正在接受药物治疗的患者进行多次给药药动学达稳态的BE临床试验。

4）对于半衰期较长的（24小时以上)药物，如果药物分布和清除个体内变异较大，明确说明不能截取部分AUC来评价药物暴露量。

5）如果因为在给药后短时间内（5-15分钟)未采集早期的样本,导致首个样本即为Cmax,则一般不应将该受试者的数据纳入统计分析.6）特殊问题点考虑到了酒精对非常释制剂可能的影响，以及内源性化合物BE研究的相关问题。

7）试验设计的一般原则中整合了餐后BE的研究技术要求（包括适用范围,研究方案设计，以及撒布性给药方式和特殊饮料送服药物的情况）以及其标准餐的要求。

总体上看，该指导原则对仿制药BE研究的思路更清晰，要求更具体，更具有可操作性.但仍有些问题未明确解决方案，如窄治疗窗药物的BE研究，不进入循环系统的局部给药的药物的BE研究等。

生物利用度和生物等效性试验生物样品的处理和保存要求2004年5月 美国FDA发布2009年6月 药审中心组织翻译萌蒂制药有限公司翻译北核协会审核药审中心最终核准目录I. 引言 (1)II. 背景 (1)III. 抽样方法 (2)IV. 对多个研究和多次运送的保存 (3)V. 保留样品数量 (4)VI. 各种研究设置下的职责 (4)A 在CRO、大学、医院或医生诊所进行的研究 (4)B SMO参与的研究 (5)C 由SMO中参与的盲态药效学或临床终点研究 (7)D 研究申办者和/或药品生产商进行的企业内部研究 (8)E 体外BE研究 (9)VII. 吸入剂产品的例外情况 (10)词汇表 (11)生物利用度和生物等效性试验生物样品的处理和保存要求 I. 引言本指导原则旨在向研究申办者和/或药品生产商、合同研究组织（CRO）、中心管理组织（SMO）、临床研究者和独立的第三方机构提供以下方面的建议：按照21 CFR 320.38和320.63的要求，对相关生物利用度（BA）和生物等效性（BE）研究保留样品进行处理的方法。

本指导原则将强调以下内容：（1）将用于BA和BE研究的试验物质与参比标准品运送至研究机构的方法；（2）研究机构随机选择试验样品进行测试和选择原料作为保留样品材料的方法；（3）对保留样品进行保存的方法。

另外，本指导原则还对§§ 320.38和320.63中的要点进行了说明和强调。

FDA的指导原则文件（包括本指导意见）不属于法律强制性责任，而只是说明本机构，目前对本专题的看法，只能认为是一种建议，除非已经在特殊药政法规或法令要求中进行了说明。

审评机构指导原则中所使用的词汇“应该，should”的意思是建议的或推荐的、并非强制要求的。

II. 背景在19世纪80年代出现非专利药丑闻后，FDA于1990年11月08日联邦文件档中发布了一份关于保存BA和BE试验样品的暂行规定1。

行业指导原则NDAs或INDs的体内生物利用度和生物等效性研究—一般性考虑指导原则草案本指导原则仅供征求意见关于本草案的建议和意见请在《联邦公报》刊登关于指导原则草案有效性的通知后60天内提交。

以电子形式提交至下述网站，以书面形式提交至下述地址：Division of Dockets Management （HFA-305），Food and Drug Administration，5630 Fishers Lane，rm.1061，Rockville，MD 20852.所有建议均应标明《联邦公报》刊登的有效性通知中列出的文件编号。

有关于本文草案的问题，请联系CDER，临床药理学办公室，联系电话：301-796-5008，或OCP@.美国卫生和公众服务部食品药品监督管理局药品评价与研究中心（CDER）2014年3月生物药剂学行业指导原则NDAs或INDs的体内生物利用度和生物等效性研究— 一般性考虑从以下部门可得到额外的副本：药品信息资源处沟通办公室，WO51，2201室药品评价与研究中心食品药品监督管理局10903 New Hampshire Avenue, Sliver Spring, MD 20993Tel: 301-796-3400; Fax: 301-847-8714;druginfo@/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm美国卫生和公众服务部食品药品监督管理局药品评价与研究中心（CDER）2014年3月生物药剂学目录目录I.前言 (4)II.背景 (5)A．总论 (6)B．生物利用度 (6)C. 生物等效性 (7)III.确证BA和BE的方法 (9)A.药代动力学研究 (9)B.支持BA/BE的其他方法 (13)IV．不同剂型制剂的BA和BE确证 (15)A．溶液和其他溶解剂型 (15)B．速释制剂 (15)C. 释放特性改进的制剂 (16)D. 批量 (19)V．体外研究方法的其他信息 (19)A. 为支持免除体内BA或BE数据进行体外研究的要求 (19)B. 为支持确证体内BA或BE进行的体外研究 (20)VI. 特殊问题 (23)A.含酒精饮料对MR制剂的影响 (23)B．对映体VS 外消旋体 (23)C. 活性成分是复合物的药物制剂 (23)D. 长半衰期的药物 (24)E. 局部起作用的口服药物 (24)F. 复方制剂和合并用药 (24)G. 内源性物质 (25)H. 高变异药物 (26)附录A：一般研究设计和数据处理 (27)行业指导原则1NDAs 或INDs 的体内生物利用度和生物等效性研究— 一般性考虑I. 前言本指导原则的目的是向计划在研究性新药申请（IND ）、新药申请（NDA ）、NDA 补充申请（称为NDA BA 和BE 指导原则草案）2中包括制剂的生物利用度（BA ）和生物等效性（BE ）研究内容的申办者和/或申请者提供建议。

美国，加拿大和欧洲各国对药物生物等效性研究的要求简介摘要本文的主旨是解读汇总美国，欧盟及加拿大各国对药品生物等效性研究的注册要求。

在药企进行生物等效性研究之前对要进入该国市场的相关指导原则进行研究。

这篇文章总结了生物等效性研究中的关键要点如试验设计，禁食或者非禁食研究，志愿者招募，试验剂量，采血点，分析方法验证参数，血浆分析，药代动力学参数，生物等效标准，GCP要求等，这些都是制药企业在进行生物等效性研究申报需要考虑的。

另外，还需要考虑供试品及参比制剂等问题。

供试品通常是由委托方生产，参比制剂则是由政府机构指定。

采血点也根据各国的指导原则不同而不同但是均遵循ICH GCP指导原则。

生物等效性标准包括Cmax, AUCt,AUC0–的90%CI 在80-125%。

简介由于生物利用度与生物等效性在专利药及仿制药申请中的应用，在过去得30年中获得了相当大的重视。

期间，法规机构也开始对仿制药的开发和批准制定相应的知道原则及法规。

因此，再申报中这些科学概念的评价方法有巨大的调整和更新。

BA和BE成为全球范围内专利药和仿制药批准的基础，并且也为专利药开发减少了研发成本。

令人鼓舞的是，在国内和国际上，法规机构和科学界均在做不断的努力，去理解和开发更有效率的及科学的方法去评价不同剂型包括一些艰难复杂的特殊剂型的BE方法。

由于仿制药在医疗健康中的重要性，因此必须确实地评价仿制药的质量及体内特性。

另外由于仿制药将来会替换专利药在市场中的位置，所以应该证实仿制药的安全性和有效性与创新药安全性和有效性的可比性。

所以应运用体内等效或者生物等效研究来评价这种“可互换性”。

美国对生物等效性要求口服药物生物等效性研究注册要求详见21 CFR 320。

1.1 实验设计一个随机，平衡，单次，2种处理(非禁食VS禁食)，2个周期，2个交叉设计的实验来研究食物对速释或者缓控释药物的生物利用度的影响。

供试品和参比制剂在进食的情况下服用后，经过一个适当的清洗期将两种处理隔开。

EMA 和FDA 生物等效性试验指导原则要点制剂生物等效的基本原则是上世纪90 年代初确定的，即受试制剂和参比制剂主要药动学参数（AUC 和Cmax）几何均值比的90% 置信区间应落在80%~125% 之间。

美国、日本、欧盟、加拿大和南非等国相继制定了各自的指导原则。

中国药典2000 年版首次制订了《药物制剂人体生物利用度和生物等效性试验指导原则》，国家药品监督管理局药品审评中心也在2005 年3 月推出了《化学制剂人体生物利用度和生物等效性研究技术指导原则》。

欧盟于1992 年6 月颁布了首个生物利用度（BA）和生物等效性（BE）研究指导原则，2001 年7 月颁布了《对生物利用度和生物等效性研究的说明》。

2010 年1 月EMA 颁布了《生物利用度和生物等效性研究指导原则》，对既往指导原则做了修订。

该指导原则仅适用于仿制化学药品的普通制剂，不包括调释制剂、透皮制剂、经口吸入制剂以及无法用药物浓度证明生物等效性，需要药效动力学或临床终点试验证明等效的药物制剂。

FDA 于2003 年颁布了《口服制剂生物利用度/ 生物等效性（BA/BE）研究的总体考虑》，另外，针对具体药物，FDA 均给出了具体的指导意见。

2007 年FDA 又颁布了《食物对生物利用度的影响以及餐后生物等效性研究技术指导原则》，作为对上一个指导原则的补充。

2013 年12 月FDA 颁布了《以药动学为终点评价指标的仿制药生物等效性研究指导原则》（草案），该指导原则修订并拟替代前两个指导原则中有关仿制药BE 研究的内容。

该指导原则也适用于缓控释制剂的BE 试验。

相对于EMA 的指导原则，FDA 的指导原则更加细致、具体和严格。

本文通过对EMA 和FDA 指导原则的要点进行比较，介绍国外对口服制剂生物等效性研究的新规定和观点，以及对我国相应领域的启示。

1 生物等效性试验设计EMA 和FDA 指导原则中，标准的设计都是2?2 的双周期交叉试验设计。

Food-Effect Bioavailability and Fed Bioequivalence StudiesU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)December 2002BPFood-Effect Bioavailability and Fed Bioequivalence StudiesAdditional copies are available from:Office of Training and CommunicationsDivision of Drug Information, HFD-2405600 Fishers LaneRockville, MD 20857(Tel) 301-827-4573(Internet) /cder/guidance/index.htmU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)December 2002BPTable of ContentsI.INTRODUCTION (1)II.BACKGROUND (1)A.Potential Mechanisms of Food Effects on BA (1)B.Food Effects on Drug Products (2)III.RECOMMENDATIONS FOR FOOD-EFFECT BA AND FED BE STUDIES (3)A.Immediate-Release Drug Products (3)B.Modified-Release Drug Products (4)IV.STUDY CONSIDERATIONS (4)A.General Design (4)B.Subject Selection (5)C.Dosage Strength (5)D.Test Meal (5)E.Administration (6)F.Sample Collection (6)V.DATA ANALYSIS AND LABELING (6)VI.OTHER CONSIDERATIONS (8)A.Sprinkles (8)B.Special Vehicles (8)Guidance For Industry 1Food-Effect Bioavailability and Fed Bioequivalence StudiesI.INTRODUCTIONThis guidance provides recommendations to sponsors and/or applicants planning to conduct food-effect bioavailability (BA) and fed bioequivalence (BE) studies for orally administered drug products as part of investigational new drug applications (INDs), new drug applications (NDAs), abbreviated new drug applications (ANDAs), and supplements to these applications. This guidance applies to both immediate-release and modified-release drug products. Theguidance addresses how to meet the BA and BE requirements in 21 CFR 320, 314.50 (d) (3), and 314.94 (a) (7) as they apply to oral dosage forms. This guidance provides recommendations for food-effect BA and fed BE study designs, data analysis, and product labeling. It also provides information on when food-effect BA and fed BE studies should be performed. 2II.BACKGROUNDFood effect BA studies are usually conducted for new drugs and drug products during the IND period to assess the effects of food on the rate and extent of absorption of a drug when the drug product is administered shortly after a meal (fed conditions), as compared to administration under fasting conditions. Fed BE studies, on the other hand, are conducted for ANDAs to demonstrate their bioequivalence to the reference listed drug (RLD) under fed conditions.A.Potential Mechanisms of Food Effects on BA 1 This guidance has been prepared by the Food Effect Working Group of the Biopharmaceutics Coordinating Committee in the Office of Pharmaceutical Science, Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA).2 See also the guidance for industry on Bioavailablity and Bioequivalence Studies for Orally Administered Drug Products C General Considerations.Food can change the BA of a drug and can influence the BE between test and reference products. Food effects on BA can have clinically significant consequences. Food can alter BA by various means, including•Delay gastric emptying•Stimulate bile flow•Change gastrointestinal (GI) pH•Increase splanchnic blood flow•Change luminal metabolism of a drug substance•Physically or chemically interact with a dosage form or a drug substanceFood effects on BA are generally greatest when the drug product is administered shortly after a meal is ingested. The nutrient and caloric contents of the meal, the meal volume, and the meal temperature can cause physiological changes in the GI tract in a way that affects drug product transit time, luminal dissolution, drug permeability, and systemic availability. In general, meals that are high in total calories and fat content are more likely to affect the GI physiology and thereby result in a larger effect on the BA of a drug substance or drug product. We recommend use of high-calorie and high-fat meals during food-effect BA and fed BE studies.B.Food Effects on Drug ProductsAdministration of a drug product with food may change the BA by affecting either the drug substance or the drug product. In practice, it is difficult to determine the exact mechanism by which food changes the BA of a drug product without performing specific mechanistic studies. Important food effects on BA are least likely to occur with many rapidly dissolving, immediate-release drug products containing highly soluble and highly permeable drug substances (BCS Class I) because absorption of the drug substances in Class I is usually pH- and site-independent and thus insensitive to differences in dissolution. 3 However, for some drugs in this class, food can influence BA when there is a high first-pass effect, extensive adsorption, complexation, or instability of the drug substance in the GI tract. In some cases, excipients or interactions between excipients and the food-induced changes in gut physiology can contribute to these food effects and influence the demonstration of BE. For rapidly dissolving formulations of BCS Class I drug substances, food can affect C max and the time at which this occurs (T max) by delaying gastric emptying and prolonging intestinal transit time. However, we expect the food effect on these measures to be similar for test and reference products in fed BE studies.For other immediate-release drug products (BCS Class II, III, and IV) and for all modified-release drug products, food effects are most likely to result from a more complex combination of factors that influence the in vivo dissolution of the drug product and/or the absorption of the drug substance. In these cases, the relative direction and magnitude of food effects on formulation BA and the effects on the demonstration of BE are difficult, if not impossible, to predict without conducting a fed BE study.3 See the guidance for industry on Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System.III.RECOMMENDATIONS FOR FOOD-EFFECT BA AND FED BE STUDIESThis section of the guidance provides recommendations on when food-effect BA studies should be conducted as part of INDs and NDAs and when fed BE studies should be conducted as part of ANDAs. For postapproval changes in an approved immediate- or modified-release drug product that requires in vivo redocumentation of BE under fasting conditions, fed BE studies are generally unnecessary.A.Immediate-Release Drug Products1.INDs/NDAsWe recommend that a food-effect BA study be conducted for all new chemical entities(NCEs) during the IND period.Food-effect BA studies should be conducted early in the drug development process toguide and select formulations for further development. Food-effect BA informationshould be available to design clinical safety and efficacy studies and to provideinformation for the CLINICAL PHARMACOLOGY and/or DOSAGE ANDADMINISTRATION sections of product labels. If a sponsor makes changes incomponents, composition, and/or method of manufacture in the clinical trial formulation prior to approval, BE should be demonstrated between the to-be-marketed formulationand the clinical trial formulation.Sponsors may wish to use relevant principles described in the guidance for industry onSUPAC-IR: Immediate Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (SUPAC-IR guidance) to determine if in vivo BEstudies are recommended. These BE studies, if indicated, should generally be conducted under fasting conditions.2.ANDAsIn addition to a BE study under fasting conditions, we recommend a BE study under fed conditions for all orally administered immediate-release drug products, with thefollowing exceptions:•When both test product and RLD are rapidly dissolving, have similar dissolution profiles, and contain a drug substance with high solubility and high permeability(BCS Class I) (see footnote 3), or•When the DOSAGE AND ADMINISTRATION section of the RLD label states that the product should be taken only on an empty stomach, or•When the RLD label does not make any statements about the effect of food on absorption or administration.B.Modified-Release Drug ProductsWe recommend that food-effect BA and fed BE studies be performed for all modified-release dosage forms.1.INDs/NDAsWe recommend a study comparing the BA under fasting and fed conditions for all orally administered modified-release drug products.When changes occur in components, composition, and/or method of manufacturebetween the to-be-marketed formulation and the primary clinical trial material, thesponsor may wish to use relevant principles described in the guidance for industry onSUPAC-MR: Modified Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry, Manufacturing, and Controls: In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation (SUPAC-MR guidance) to determine ifdocumentation of in vivo BE is recommended. These BE studies, if indicated, shouldgenerally be conducted under fasting conditions.2.ANDAsIn addition to a BE study under fasting conditions, a BE study under fed conditionsshould be conducted for all orally administered modified-release drug products.IV.STUDY CONSIDERATIONSThis section provides general considerations for designing food effect BA and fed BE studies. A sponsor may propose alternative study designs and data analyses.The scientific rationale and justification for these study designs and analyses should be provided in the study protocol. Sponsors may choose to conduct additional studies for a better understanding of the drug product and to provide optimal labeling statements for dosage and administration (e.g. different meals and different times of drug intake in relation to meals). In studying modified-release dosage forms, consideration should be given to the possibility that co-administration with food can result in dose dumping, in which the complete dose may be more rapidly released from the dosage form than intended, creating a potential safety risk for the study subjects.A.General DesignWe recommend a randomized, balanced, single-dose, two-treatment (fed vs. fasting), two-period, two-sequence crossover design for studying the effects of food on the BA of either an immediate-release or a modified-release drug product. The formulation to be tested should be administered on an empty stomach (fasting condition) in one period and following a test meal(fed condition) in the other period. We recommend a similar, two-treatment, two-period, two-sequence crossover design for a fed BE study except that the treatments should consist of both test and reference formulations administered following a test meal (fed condition). An adequate washout period should separate the two treatments in food-effect BA and fed BE studies.B.Subject SelectionBoth food-effect BA and fed BE studies can be carried out in healthy volunteers drawn from the general population. Studies in the patient population are also appropriate if safety concerns preclude the enrollment of healthy subjects. A sufficient number of subjects should complete the study to achieve adequate power for a statistical assessment of food effects on BA to claim an absence of food effects, or to claim BE in a fed BE study (see DATA ANALYSIS AND LABELING section). A minimum of 12 subjects should complete the food-effect BA and fed BE studies.C.Dosage StrengthIn general, the highest strength of a drug product intended to be marketed should be tested in food-effect BA and fed BE studies. In some cases, clinical safety concerns can prevent the use of the highest strength and warrant the use of lower strengths of the dosage form. For ANDAs, the same lot and strength used in the fasting BE study should be tested in the fed BE study. For products with multiple strengths in ANDAs, if a fed BE study has been performed on the highest strength, BE determination of one or more lower strengths can be waived based on dissolution profile comparisons (for details see the guidance on Bioavailablity and Bioequivalence Studies for Orally Administered Drug Products - General Considerations.D.Test MealWe recommend that food-effect BA and fed BE studies be conducted using meal conditions that are expected to provide the greatest effects on GI physiology so that systemic drug availability is maximally affected. A high-fat (approximately 50 percent of total caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) meal is recommended as a test meal for food-effect BA and fed BE studies. This test meal should derive approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively.4 The caloric breakdown of the test meal should be provided in the study report. If the caloric breakdown of the meal is significantly different from the one described above, the sponsor should provide a scientific rationale for this difference. In NDAs, it is recognized that a sponsor can choose to conduct food-effect BA studies using meals with different combinations of fats, carbohydrates, and proteins for exploratory or label purposes. However, one of the meals for the food-effect BA studies should be the high-fat, high-calorie test meal described above.4 An example test meal would be two eggs fried in butter, two strips of bacon, two slices of toast with butter, four ounces of hash brown potatoes and eight ounces of whole milk. Substitutions in this test meal can be made as long as the meal provides a similar amount of calories from protein, carbohydrate, and fat and has comparable meal volume and viscosity.E.AdministrationFasted Treatments: Following an overnight fast of at least 10 hours, subjects should be administered the drug product with 240 mL (8 fluid ounces) of water. No food should be allowed for at least 4 hours post-dose. Water can be allowed as desired except for one hour before and after drug administration. Subjects should receive standardized meals scheduled at the same time in each period of the study.Fed Treatments: Following an overnight fast of at least 10 hours, subjects should start the recommended meal 30 minutes prior to administration of the drug product. Study subjects should eat this meal in 30 minutes or less; however, the drug product should be administered 30 minutes after start of the meal. The drug product should be administered with 240 mL (8 fluid ounces) of water.No food should be allowed for at least 4 hours post-dose. Water can be allowed as desired except for one hour before and after drug administration. Subjects should receive standardized meals scheduled at the same time in each period of the study.F.Sample CollectionFor both fasted and fed treatment periods, timed samples in biological fluid, usually plasma, should be collected from the subjects to permit characterization of the complete shape of the plasma concentration-time profile for the parent drug. It may be advisable to measure other moieties in the plasma, such as active metabolites, and sponsors should refer to the guidance on Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations for recommendations on these issues. Consideration should be given to the possibility that co-administration of a dosage form with food can alter the time course of plasma drug concentrations so that fasted and fed treatments can have different sample collection times. V.DATA ANALYSIS AND LABELINGFood-effect BA studies may be exploratory and descriptive, or a sponsor may want to use a food-effect BA study to make a label claim.5 The following exposure measures and pharmacokinetic parameters should be obtained from the resulting concentration-time curves for the test and reference products in food-effect BA and fed BE studies:•Total exposure, or area under the concentration-time curve (AUC0-inf, AUC0-t)•Peak exposure (C max)•Time to peak exposure (T max)•Lag-time (t lag) for modified-release products, if present•Terminal elimination half-life•Other relevant pharmacokinetic parametersIndividual subject measurements, as well as summary statistics (e.g., group averages, standard deviations, coefficients of variation) should be reported. An equivalence approach is5 Regulations on labeling requirements for a drug product submitted in an NDA can be found in 21 CFR part 201.recommended for food-effect BA (to make a claim of no food effects) and fed BE studies, analyzing data using an average criterion. Log-transformation of exposure measurements (AUC and C max ) prior to analysis is recommended. The 90 percent CI for the ratio of population geometric means between test and reference products should be provided for AUC0-inf, AUC0-t, and C max (see guidance for industry on Statistical Approaches to Establishing Bioequivalence). For IND or NDA food-effect BA studies, the fasted treatment serves as the reference. For ANDA fed BE studies, the RLD administered under fed condition serves as the reference treatment.The effect of food on the absorption and BA of a drug product should be described in the CLINICAL PHARMACOLOGY section of the labeling. In addition, the DOSAGE AND ADMINISTRATION section of the labeling should provide instructions for drug administration in relation to food based on clinical relevance (i.e., whether or not the changes in systemic exposure caused by co-administration with food results in safety or efficacy concerns, or when there is no important change in systemic exposure but there is a possibility that the drug substance causes GI irritation when taken without food).For an NDA, an absence of food effect on BA is not established if the 90 percent CI for the ratio of population geometric means between fed and fasted treatments, based on log-transformed data, is not contained in the equivalence limits of 80-125 percent for either AUC0-inf (AUC0-t when appropriate)or C max. When the 90 percent CI fails to meet the limits of 80-125 percent, the sponsor should provide specific recommendations on the clinical significance of the food effect based on what is known from the total clinical database about dose-response (exposure-response) and/or pharmacokinetic-pharmacodynamic relationships of the drug under study. The clinical relevance of any difference in T max and t lag should also be indicated by the sponsor. The results of the food-effect BA study should be reported factually in the CLINICAL PHARMACOLOGY section of the labeling and should form the basis for making label recommendations (e.g., take only on an empty stomach) in the DOSAGE AND ADMINISTRATION section of the labeling. The following are examples of language for the package insert:A food-effect study involving administration of [the drug product] to healthy volunteersunder fasting conditions and with a high-fat meal indicated that the C max and AUC wereincreased 57% and 45%, respectively, under fed conditions. This increase in exposurecan be clinically significant, and therefore [the drug] should be taken only on an emptystomach (1 hour before or 2 hours after a meal)A food-effect study involving administration of [the drug product] to healthy volunteersunder fasting conditions and with a high-fat meal indicated that the C max was decreased15% while the AUC remained unchanged. This decrease in exposure is not clinicallysignificant, and therefore [the drug] could be taken without regards to meals.An absence of food effect on BA is indicated when the 90 percent CI for the ratio of population geometric means between fed and fasted treatments, based on log-transformed data, is contained in the equivalence limits of 80-125 percent for AUC0-inf (AUC0-t when appropriate)and C max. In this case, a sponsor can make a specific claim in the CLINICAL PHARMACOLOGY or DOSAGE AND ADMINISTRATION section of the label that no food effect on BA is expectedprovided that the T max differences between the fasted and fed treatments are not clinically relevant. The following is an example of language for the package insert:The C max and AUC data from a food-effect study involving administration of [the drugproduct] to healthy volunteers under fasting conditions and with a high-fat meal indicatedthat exposure to the drug is not affected by food. Therefore, [the drug product] may betaken without regard to meals.For an ANDA, BE of a test product to the RLD product under fed conditions is concluded when the 90 percent CI for the ratio of population geometric means between the test and RLD product, based on log-transformed data, is contained in the BE limits of 80-125 percent for AUC and C max. Although no criterion applies to T max, the T max values for the test and reference products are expected to be comparable based on clinical relevance. The conclusion of BE under fed conditions indicates that with regard to food, the language in the package insert of the test product can be the same as the reference product.VI.OTHER CONSIDERATIONSA.SprinklesIn NDAs, the labeling of certain drug products (e.g., controlled-release capsules containing beads) can recommend that the product be sprinkled on soft foods, such as applesauce, and swallowed without chewing. For the labeling to indicate that the drug product can be sprinkled on soft foods, additional in vivo relative BA studies should be performed by sprinkling the product on the soft foods to be listed in the labeling (test treatment) and comparing it to the product administered in the intact form (reference treatment), then administering both on an empty stomach.In ANDAs, BE of the test to the RLD is demonstrated in a single dose crossover study. Both treatments should be sprinkled on one of the soft foods mentioned in the labeling, usually applesauce. The BE data should be analyzed using average BE and the 90 percent CI criteria should be used to declare BE. If there are questions about other foods, the design, or the analysis of such BE studies, the sponsors and/or applicants should contact the Office of Generic Drugs.B.Special VehiclesFor NDAs, the labeling for certain oral solution products (e.g., cyclosporine oral solution, modified) recommends that the solution be mixed with a beverage prior to administration. The BA of these products can change when mixed with different beverages due to the formation of complex mixtures and other physical-chemical and/or physiological factors. NDA sponsors should contact the Office of Clinical Pharmacology and Biopharmaceutics to determine what data should be submitted to support labeling.In ANDAs, BE of the test to the RLD is demonstrated in a single-dose crossover study. Both treatments should be mixed with one of the beverages mentioned in the labeling. Sponsorsshould provide evidence that BE differences would not be expected from the use of other listed vehicles. The BE data should be analyzed using average BE, and the 90 percent CI criteria should be used to declare BE. If there are questions about other vehicles, or the design or analysis of such BE studies, the sponsors and/or applicants should contact the Office of Generic Drugs.。

Technique Guideline for Human Bioavailability and BioequivalenceStudies on Chemical Drug ProductsContents(Ⅰ) Establishment and Validation for Biological Sample Analysis Methods (2)1. Common Analysis Methods (2)2. Method Validation (2)2.1 Specificity (2)2.2 Calibration Curve and Quantitative Scale (3)2.3 Lower Limit of Quantitation (LLOQ) (3)2.4 Precision and Accuracy (4)2.5 Sample Stability (4)2.6 Percent recovery of Extraction (4)2.7 Method Validation with microbiology and immunology (4)3. Methodology Quality Control (5)(Ⅱ) Design and Conduct of Studies (5)1. Cross-over Design (5)2. Selection of Subjects (6)2.1 Inclusion Criteria of Subjects: (6)2.2 Cases of Subjects (7)2.3 Division into Groups of the Subjects (7)3. Test and Reference Product, T and R (8)4. Sampling (8)(Ⅲ) Result Evaluation (9)(Ⅳ) Submission of the Contents of Clinical Study Reports (9)Technique Guideline for Human Bioavailability and BioequivalenceStudies on Chemical Drug ProductsSpecific Requirements for BA and BE Studies(Ⅰ) Establishment and Validation for Biological Sample Analysis MethodsBiological samples generally come from the whole blood, serum, plasma, urine or other tissues. These samples have the characteristics such as little quantity for sampling, low drug concentration, much interference from endogenous substances, and great discrepancies between individuals. Therefore, according to the structure, biological medium and prospective concentration scale of the analytes, it is necessary to establish the proper quantitative assay methods for biological samples and to validate such methods.1. Common Analysis MethodsCommonly used analysis methods at present are as follows: (1) Chromatography: Gas Chromatography(GS), High Performance Liquid Chromatography (HPLC), Chromatography－mass Spectrometry (LC-MS, LC-MS-MS, GC-MS, GC-MS-MS), and so on. All the methods above can be used in detecting most of drugs; (2) Immunology methods: radiate immune analysis, enzyme immune analysis, fluorescent immune analysis and so on, all these can detect protein and polypeptide; (3) Microbiological methods: used in detecting antibiotic drug.Feasible and sensitive methods should be selected for biologic sample analysis as far as possible.2. Method ValidationEstablishment of reliable and reproducible quantitative assay methods is one of the keys to bioequivalence study. In order to ensure the method reliable, it is necessary to validate the method entirely and the following aspects should be generally inspected:2.1 SpecificityIt is the ability that the analysis method has to detect the analytes exactly and exclusively, when interference ingredient exists in the sample. Evidences should be provided that the analytes are the primary forms or specific active metabolites of the test drugs. Endogenous instances, the relevant metabolites and degradation products in biologic samples should not interfere with the detection of samples. If there are several analytes, each should be ensured not to be interfered, and the optimal detecting conditions of the analysis method should be maintained. As for chromatography, at least 6 samples from different subjects, which include chromatogram of blank biological samples, chromatogram of blank biologic samples added control substance (concentration labeled) and chromatogram of biologic samples after the administration should beexamined to reflect the specificity of the analytical procedure. As for mass spectra (LC-MS andLC-MS-MS) based on soft ionization, the medium effect such as ion suppression should be considered during analytic process.2.2 Calibration Curve and Quantitative ScaleCalibration curve reflects the relationship between the analyte concentration and the equipment response value and it is usually evaluated by the regression equation obtained from regression analysis (such as the weighted least squares method). The linear equation and correlation coefficient of the calibration curve should be provided to illustrate the degree of their linear correlation. The concentration scale of calibration curves is the quantitative scale. The examined results of concentration in the quantitative scale should reach the required precision and accuracy in the experiment.Dispensing calibration samples should use the same biological medium as that for analyte, and the respective calibration curve should be prepared for different biological samples. The number of calibration concentration points for establishing calibration curve lies on the possible concentration scale of the analyte and on the properties of relationship of analyte/response value. At least 6 concentration points should be used to establish calibration curve, more concentration points are needed as for non-linear correlation. The quantitative scale should cover the whole concentration scale of biological samples and should not use extrapolation out of the quantitative scale to calculate concentrations of the analyte. Calibration curve establishment should be accompanied with blank biologic samples. But this point is only for evaluating interference and not used for calculating. When the warp* between the measured value and the labeled value of each concentration point on the calibration curve is within the acceptable scale, the curve is determined to be eligible. The acceptable scale is usually prescribed that the warp of minimum concentration point is within ±20% while others within ±15%. Only the eligible calibration curve can be carried out for the quantitative calculation of clinical samples. When linear scale is somewhat broad, the weighted method is recommended to calculate the calibration curve in order to obtain a more exact value for low concentration points. ( *: warp=[(measured value － labeled value)/labeled value]×100%)2.3 Lower Limit of Quantitation (LLOQ)Lower limit of quntitation is the lowest concentration point on the calibration curve, indicating the lowest drug concentration in the tested sample, which meets the requirements of accuracy and precision. LLOQ should be able to detect drug concentrations of samples in 3~5 eliminationhalf-life or detect the drug concentration which is 1/10~/20 of the C max. The accuracy of the detection should be within 80~120% of the real concentration and its RSD should be less than 20%. The conclusions should be validated by the results from at least 5 standard samples.2.4 Precision and AccuracyPrecision is, under the specific analysis conditions, the dispersive degree of a series of the detection data from the samples with the same concentration and in the same medium. Usually, the RSD from inter- or intra- batches of the quality control samples is applied to examine the precision of the method. Generally speaking, the RSD should be less than 15% and that around LLOQ should be less than 20%. Accuracy is the contiguous degree between the tested and the real concentrations of the biological samples (namely, the warp between the tested and the real concentrations of the quality-controlled samples). The accuracy can be obtained by repeatedly detecting the analysis samples of known concentration which should be within 85~115% and which around LLOQ should be within 80~120%.Generally, 3 quality-control samples with high, middle and low concentrations are selected for validating the precision and accuracy of the method. The low concentration is chosen within three times of LLOQ, the high one is close to the upper limit of the calibration curve, and the middle concentration is within the low and the high ones. When the precision of the intra-batches is detected, each concentration should be prepared and detected at least 5 samples. In order to obtain the precision of inter-batches, at least 3 qualified analytical batches, 45 samples should be consecutively prepared and detected in different days.2.5 Sample StabilityAccording to specific instances, as for biological samples containing drugs, their stabilities should be examined under different conditions such as the room temperature, freezing, thaw and at different preservation time, in order to ensure the suitable store conditions and preservation times. Another thing that should be paid attention to is that the stabilities of the stock solution and the analyte in the solution after being treated with, should also be examined to ensure the accuracy and reproducibility of the test results.2.6 Percent recovery of ExtractionThe recovery of extraction is the ratio between the responsive value of the analytes recovered from the biological samples and that of the standard, which has the same meaning as the ratio of the analytes extracted from the biologic samples to be analyzed. The recovery of extraction of the 3 concentrations at high, middle and low should be examined and their results should be precise and reproduceable.2.7 Method Validation with microbiology and immunologyThe analysis method validation above mainly aims at chromatography, with many parameters and principles also applicable for microbiological and immunological analysis. However, some special aspects should be considered in the method validation. The calibration curve of the microbiological and immunological analysis is non-linear essentially, so more concentration pointsshould be used to construct the calibration curve than the chemical analysis. The accuracy of the results is the key factor and if repetitive detection can improve the accuracy, the same procedures should be taken in the method validation and the unknown sample detection.3. Methodology Quality ControlThe unknown samples are detected only after the method validation for analysis of biological samples has been completed. The quality control should be carried out during the concentration detection of the biological samples in order to ensure the reliability of the method in the practical application. It is recommended to assess the method by preparing quality-control samples of different concentrations by isolated individuals.Each unknown sample is usually detected for only one time and redetected if necessary. In the bioequivalence experiments, biological samples from the same individual had better to be detected in the same batch. The new calibration curve should be established when detecting biological samples of each analysis batch and high, middle and low concentrations of the quality-control samples should be detected at the same time. Each concentration should at least have two samples and should be equally distributed in the detection sequence of the unknown samples. When there are a large number of unknown samples in one analysis batch, the number of the quality-control samples at different concentrations should be increased to make the quality-control samples exceed 5% of the unknown sample population. The warp of detection result from the quality-control samples should usually be less than 15%, while the warp of the low concentration point should be less than 20% and at most 1/3 results of the quality-control samples at different concentrations are allowed to exceed the limit. If the detection results of the quality-control samples do not accord with the above requirements, the detection results of the samples in this analysis batch should be blanked out.The samples with concentrations higher than the upper quantitation limit should be detected once more using corresponding diluted blank medium. As for those samples with concentrations lower than the lower quantitation limit, during pharmacokinetics analysis, those sampled before reaching C max should be calculated as zero while those after C max should be calculated as ND (Not detectable), so as to decrease the effect of the zero value on the AUG calculation.(Ⅱ) Design and Conduct of Studies1. Cross-over DesignCurrently, the crossover design is the most wildly applied method in the BE study. As for the drug absorption and clearance, there is a transparent variation among individuals. Therefore, the coefficient of variability among individuals is far greater than that of the individual himself. That is why the bioequivalence study is generally required to be designed on the principle of self crossover control. Subjects are randomly divided into several groups and treated in sequence, of whichsubjects in one group take the test products first and then the reference product, while subjects in the other take the reference products first and then the test products. A long enough interval is essential between the two sequences, which is called Wash-out period. In this way, every subject has been treated twice or more times sequentially, which is equal to self-control. Therefore, the influence of drug products on drug absorption can be discriminated from the others, and the effect of various test periods and individual difference on the results can be eliminated.Two-sequence crossover design, three-sequence crossover design are adopted respectively according to the amount of the test product. If two varieties of drug products are to be compared, the two-treatment, two-period or two-sequence crossover design will be a preferable choice. When three varieties of products (two test products and one reference product) are included, thethree-formulation, three-period and double 3×3 Latin square design will be the suitable choice. And a long enough wash-out period is required among respective periods.Wash-out period is set on purpose to eliminate the mutual disturbance of the two varieties of drug products and avoid the treatment in the prior period from affecting that of the next period. And the wash-out period is generally longer than or equal to 7 elimination half lives.While the half-lives of some drugs or their active metabolites are too long, it is not suitable to apply the crossover design. Under this circumstance, parallel design is adopted, but the sample size should be enlarged.However, as for some highly variable drugs, except for increase of the subjects, repetitive cross-over design can be applied, to test possibly existing difference in individual when receive the same preparation twice.2. Selection of Subjects2.1 Inclusion Criteria of Subjects:The difference among individuals of the subjects should be minimized so that the difference of the drug products can be detected. The inclusion criteria and exclusion criteria should be noted in the trial scheme.Male healthy subjects are recruited generally. And as to the drugs of special purpose, proper subjects are recruited according to specific conditions. If female healthy subjects are recruited, the possibility of gestation should be avoided. If the drugs to be tested have some known adverse effects, which may do harm to the subjects, patients can also be included as the subjects.Age: 18~ 40 years old generally. The difference in age of the subjects in one batch should not be more than 10 years.Body weight: not less than 50kg as to normal subjects. Body Mass Index (BMI), which is equal to body weight (kg)/ body height 2 (m2), is generally required to be in the range of standard body weight. For the subjects in one batch, the taken dosage is the same, the range of the bodyweight, therefore, should not have great disparity.The subjects should receive the overall physical examination and be proved healthy. There is not medical history of heart, kidney, digestive tract, nervous system, mental anomaly, metabolism dysfunction, and so on. The physical examination has revealed normal blood pressure, heart rate, electrocardiogram, and respiratory rate. Laboratory data have revealed normal hepatic function, renal function and blood function. Those examinations are essential to prevent the metabolism of drugs in vivo from being interfered by the diseases. According to the classification and safety of drugs, special items examinations are required before, during and after the test, such as the blood glucose examination, which is required in the drug trial of hypoglyceimic agents.In order to avoid the interference by other drugs, no administration of other drugs is allowed from two weeks before and till the end of the test. Moreover, the cigarette, wine,beverage with caffeine, or some fruit juice that may affect the metabolism of the drug, is forbidden during the trial period also. The subjects had better have no appetite of cigarette and wine. Possible effects of the cigarette-addicted history should not be neglected in the discussion of results.Due to the metabolism variance resulted by known genetic polymorphism of drugs, the safety factor which may be effected by the slow metabolism speed of drugs should be considered.2.2 Cases of SubjectsThe cases of the subjects should meet the statistic requirement. And according to the current statistical methods, 18~24 cases are enough for most drugs to meet the requirement of sample size. But as to some drugs of high variability, more cases may be required correspondingly.The cases of a clinic trial are determined by three fundamental factors: （1）Significance level: namely, the value of α, for which value 0.05 or 5% is often adopted;（2）Power of a test: namely, the value of 1-β. β is the index that represents the probability of the type error, which is also theⅡprobability of misjudging the actually efficacy drugs as inefficient drugs, and value not less than 80% is commonly stated; （3）Coefficient of variance（CV%）and Difference（θ）: In the equivalence test of two drugs, the greater CV% and θ of the test indexes are, the more cases are required. The CV% and θ are unknown before the trial and can only be estimated by the above parameters of the owned reference products or running the preliminary test. Moreover, when a BA test has been finished, the value of N can be calculated according to the parameters such as θ, CV% and 1-β and then compared with the cases adopted in the finished BA test to determine whether the cases are reasonable or not.2.3 Division into Groups of the SubjectsThe subjects should be randomly divided into different comparable groups. The cases of the two groups should guarantee the best comparability.3. Test and Reference Product, T and RThe quality of the reference products directly affect the results reliability of BE trial. Generally, the domestic innovator products of the same dosage form which has been approval to be on sale are commonly selected. If it failed in acquiring the innovator products, the key product on the market can also be chosen as the reference product and the related quality certifications (such as the test results of the assay and dissolution) and the reasons for option should be provided. When it comes to the drug study of specific purpose, other on-sale dosage forms which are of the same kind and similar with pharmaceutics properties are selected as the reference products and those reference products should be already on sale and qualified in quality. The difference in assay between the test product and reference product should not exceed 5%.The test product should be the scale-up product or manufacture scale product, which is consistent with the quality standards for clinical application. And the indexes such as the in vitro dissolution, stability, content or valence assay, consistency reports between batches should be provided to the test unit for reference. As for some drugs, the data of polymorphs and optical isomers should be offered additionally. The test and reference product should be noted with the advanced development unit, batch number, specification, storage conditions and expiry date.For future reference, the test and reference product should be kept long enough after the trialtill the product is approved to be on sale.4. SamplingThere is a significant sense in designing the sampling point to guarantee both the reliability of the trial results and the rationality of calculating the pharmacokinetics parameters. Commonly, there should be preliminary tests or the pharmacokinetics literatures at home and abroad served as the evidences of designing the reasonable sampling points. When the blood-drug concentration assay is performed, the absorption phase, balance phase and clearance phase should be considered overall. There must be enough sampling points in every phase of the C-T curve and around the T max. The concentration curve, therefore, can fully reflect the entire procedure of the drugs distribution in vivo. And the blank blood samples are taken before the administration. Then at least 2~3 points are sampled in the absorption phase, at least 3points are sampled near the C max and 3-5 points in the clearance phase. Try to avoid that the first point gets the C max, and running the preliminary test may avoid this. When the continuously-sampling results show that the drugs’ primary forms or the active metabolites are at the point of 3～5 half- lives or the blood drug concentration is 1/10～1/20 ofC max, the values of AUC0-t/AUC0-∞are generally bigger than 80% .For the terminal clearance item doesn’t affect the evaluation of the products’ absorption process much, as to the long half-life drugs, the sampling periods should be continued long enough, so that the whole absorption process can be compared and analyzed. In the multiple administration study, the BA of some drugs is known to beaffected by the circadian rhythm, samples of which should be taken 24 hours continuously if possible.When the BA of the test drugs can’t be determined by detecting the blood-drug concentration, if the primary forms and the active metabolites of the test drugs are mainly be excreted in urine (more than 70% of the dosage), the BA assay may be performed by detecting the urine drug concentration, which is the test of the accumulated excretion quantity of drugs in urine to reflect the intake of drugs. The test products and trial scheme should accord with the demands of BA assay. The urine samples should be collected at intervals, and the collection frequency and intervals of which should meet the demands of evaluating the excretion degree of the primary forms and the active metabolites of the test products in urine. However this method cannot reflect the absorption speed of the drugs and gets many error factors, it is not recommended generally.Some drugs metabolize so rapidly in vivo that it is impossible to detect the primary forms in biological samples. Under these circumstances, the method determining the concentration of corresponding active metabolites in biological samples is adopted to perform the BA and BE studies.(Ⅲ) Result EvaluationAt present, the weighting function of AUC on drug absorption degree is comparatively affirmed, while C max and T max sometimes are not sensitive and seemly enough for weighting the absorption speed due to their dependence on the arrangement of sampling time, and they are therefore not suitable for drug products with multi-peak phenomena and for experiments with large individual variation. During the evaluation, if there are some special instances of inequivalence, a specific analysis should be performed for specific problems.As for AUC，the 90% confidence interval is generally required within the scope of 80%~125%. As for the drugs with narrow treatment spectrum, the above scope should likely be appropriately reduced. While in a few instances, having been validated to be reasonable, the scope can also be increased. So does C max. And as for T max, statistical evaluation is required only when its release speed is closely correlated to clinical therapeutic effects and safety, the equivalence scope of which can be ascertained according to the clinical requirements.When bioavailability ratio of test products is higher than that of reference products, which is called suprabioavailability, the following two instances can be considered: 1). Whether the reference product itself is a product with low bioavailability, which results in the improvement of the test drug's bioavailability; 2). The quality of the reference product meets the requirement, and the test drug really has higher bioavailability.(Ⅳ) Submission of the Contents of Clinical Study ReportsIn order to satisfy the demand of evaluation, a clinical report of bioequivalence study shouldinclude the following contents: (1)Experiment subjective;(2) Establishment of analysis methods for bioavailability samples and data of inspection, as well as provision of the essential chromatograms;(3) Detailed experiment design and operation methods , including data of all the subjects，sample cases，reference products，given dosage，usage and arrangement of sampling time;(4) All data about original measurement of unknown sample concentrations，pharmacokinetics parameters and drug-time curve of each subjects;(5) Data handling procedure and statistical analysis methods as well as detailed procedure and results of statistics;(6) Observation results of clinical adverse reactions after taking medicine，midway exit and out of record of subjects and the reasons;(7) Result analysis and necessary discussion on bioavailability or bioequivalence; (8) References. A brief abstract is required before the main body; at the end of the main body, names of the experiment unit, chief persons of the study and experiment personnel should be signed to take the responsibility for the results of the study.。

I期药物临床试验病房营养配餐和膳食设计1正常人营养食谱是什么？是平衡膳食的一种表现形式，根据受试者的身体需要，和食物中各种营养物的含量，拟定的食谱。

2受试者为什么要进行营养配餐。

根据试验方案，设计一天或几天的食谱，使受试者摄入的蛋白质,脂肪，碳水化合物维生素等几大营养素数量充足和比例合理。

3营养食谱编制的基本原则（六条基本原则）（1）保证营养充足和平衡，促使临床试验更好顺利的完成。

（2）食物多样和比例适当（食物多样，粗细搭配，适量选用动物性食物，充足的蔬菜和油类。

（3）照顾饮食习惯和适口性（4）考虑食物定量（5）合理分配三餐，保持能量均衡（早，中，晚）三餐（6）与医院食堂合作，保证饮食卫生，安全。

4如何进行营养配餐及膳食设计？要做到营养配餐科学合理需要以一系列营养理论为指导依据《中国居民膳食指南》《中国居民平衡膳食宝塔》《中国居民每日膳食参考摄入量》通过《食物成分表》计算或设计出受试者的一餐或一天所需要的各类食物数量，再按照食补养生理论进行原料选择与搭配，最后通过合理的加工，制作出符合受试者及药物临床试验的标准餐。

5平衡膳食的构成（1）人体营养素的需要量与膳食供应量之间的平衡（2）膳食中三种宏量营养素需要保持一定的比例平衡（3）膳食中优质蛋白质与普通蛋白质保持一定的比例（4）饱和，单不饱和和多不饱和脂肪酸之间的平衡（5）钙与磷，钾与钠，铁与锌的平衡6营养素的分类营养素：食物中含有对人体具有生理功能的各种物质，维持人体正常健康分为：碳水化合物蛋白质脂类维生素矿物质水（一）碳水化合物：（1）碳水化合物是由单糖，双糖，寡糖，多糖组成（2）来源：谷类，根茎食物：大米，薯类，麦类（3）碳水化合物供给热量：每g被消化的碳水化合物可提供16，7KJ（4kcal）的热量。

（4）每人每天碳水化合物的摄取量占热量的55%-65%。

（二）蛋白质：（1）自然界的蛋白质约含22种不同的氨基酸。

（2）蛋白质为三大产能营养素之一，来源：动物食品，大豆及其制品。

FDA《口服制剂的生物利用度和生物等效性研究一般性考虑》介绍《口服制剂的生物利用度和生物等效性研究：一般性考虑》是由美国食品和药物管理局（FDA）颁布的一项指南，旨在指导药物研发人员和监管机构评估口服制剂的生物利用度和生物等效性。

本文将对该指南进行详细介绍。

首先，生物利用度是衡量口服制剂在体内吸收程度的指标。

它是通过比较口服给药和静脉给药后药物在体内浓度的变化来评估的。

生物利用度高意味着药物能够更有效地被吸收，从而提高治疗效果。

而生物等效性则是判断不同制剂之间的可互换性的指标。

该指南首先阐述了生物利用度和生物等效性的概念和重要性。

接着，它详细解释了口服制剂的生物利用度评价的原则和方法。

除了传统的生物利用度评估方法，如血药浓度-时间曲线和药物代谢动力学分析，指南还介绍了现代生物技术在生物利用度评估中的应用。

同时，指南还提供了评价食物对生物利用度的影响的指导原则。

然后，指南介绍了生物等效性评价的原则和方法，包括在健康志愿者中进行的生物等效性研究设计和统计分析等方面的要点。

此外，指南还解释了当使用生物等效性研究设计可能存在困难或不切实际时的替代方法。

在指南的最后，它提供了一些特殊情况下的考虑事项和建议，例如对口服溶解速度较慢的药物、控释剂型制剂和具有良好肠黏附性的药物的评价方法。

此外，指南还指出了在特殊人群（如儿童和老年人）中进行生物等效性评价时需要考虑的因素。

《口服制剂的生物利用度和生物等效性研究：一般性考虑》的发布为药物研发人员和监管机构提供了一套科学合理的评价标准和方法，以确保口服制剂的质量和可互换性。

这对于提高药物的疗效和安全性具有重要意义，并有助于加快新药的上市速度。

但需要注意的是，该指南并非硬性要求，而是一份指导性文件，在具体情况下可能需要根据实际情况进行调整和灵活应用。

总之，FDA《口服制剂的生物利用度和生物等效性研究：一般性考虑》为口服制剂的生物利用度和生物等效性评价提供了科学指导，促进了药物的质量和可互换性评估工作。

食物对生物利用度的影响以及餐后生物等效性研究技术指导原则2002年12月 美国FDA发布2009年6月 药审中心组织翻译西安杨森制药有限公司翻译北核协会审核药审中心最终核准目录I. 前言 (1)II. 背景 (1)A. 食物对生物利用度影响的潜在机制 (1)B. 食物对药品的影响 (2)III. 食物对生物利用度的影响以及餐后生物等效性研究的建议 (2)A. 普通药物制剂 (2)B. 缓释药物制剂 (3)IV. 研究思考 (3)A. 总体设计 (4)B. 受试者的选择 (4)C. 剂量 (4)D. 试验餐 (4)E. 服药方式 (5)F. 样本采集 (5)V. 数据分析和标签 (5)VI. 其他 (7)A. 药物涂抹在食物上（Sprinkles） (7)B. 特殊溶剂 (8)食物对生物利用度的影响以及餐后生物等效性研究技术指导原则I. 前言本指南为主办方和/或申请者计划开展口服药品的食物对生物利用度（BA）影响和餐后生物等效性研究（BE）提供了建议，并将该研究作为新药临床申请（INDs）、新药上市申请（NDAs）、仿制药申请（ANDAs）以及这些申请的补充资料的一部分。

该指南适用于普通制剂和缓释制剂。

在21CFR320、314.50（d）（3）和314.94（a）（7）规定了在申请口服制剂时生物利用度和生物等效性的要求，本指南提供了如何满足这些要求的具体方案。

此外，本指南为食物对生物利用度影响和餐后生物等效性研究的设计、数据分析和产品标识提出了有关建议。

同时明确了何时需要开展食物对生物利用度影响和餐后生物等效性研究。

II. 背景食物对生物利用度影响的研究通常用于新药，并在药品IND阶段开展，旨在比较餐后（饱腹状态）与空腹状态下服用药物制剂后食物对药物吸收速率和吸收程度的影响。

另一方面，餐后物等效性（BE）研究则是在ANDAs阶段开展，目的是证实在进食状态下与对照药（RLD）具有生物等效性。

A. 食物对生物利用度的影响的潜在机制食物能改变一种药物的生物利用度并影响受试药和对照品的生物等效性。

质量标准——药物制剂人体生物利用度和生物等效性试验指导原则2007-10-26 15:26【大中小】【我要纠错】生物利用度是指剂型中的药物被吸进入血液的速率和程度。

生物等效性是指一种药物的不同制剂在相同的试验条件下，给以相同的剂量，反映其吸收速率和程度的主要动力学参数没有明显的统计学差异。

口服或其他非脉管内给药的制剂，其活性成分的吸收受多种因素的影响，包括制剂工艺、药物粒径、晶型或多晶型，处方中的赋形剂、黏合剂、崩解剂、润滑剂、包衣材料、溶剂、助悬剂等。

生物利用度是保证药品内在质量的重要指标，而生物等效性则是保证含同一药物的不同制剂质量一致性的主要依据。

生物利用度与生物等效性概念虽不完全相同，但试验方法基本一致。

为了控制药品质量，保证药品的有效性和安全性，特制订本指导原则。

何种药物制剂需要进行生物等效性或生物利用度试验，可根据有关部门颁布的法规要求进行。

进行药物制剂人体生物利用度和生物等效性试验的临床实验室和分析实验室，应提供机构名称以及医学、科学或分析负责人的姓名、职称和简历。

一、生物样品分析方法的基本要求生物样品中药物及其代谢产物定量分析方法的专属性和灵敏度，是生物利用度和生物等效性试验成功的关键。

首选色谱法，如HPLC、GC以及GC-MS、LC-MS、LC-MS-MS联用技术，一般应采用内标法定量。

必要时也可采用生物学方法或生物化学方法。

由于生物样品取样量少、药物浓度低、内源性物质（如无机盐、脂质、蛋白质、代谢物）及个体差异等多种因素影响生物样品测定，所以必须根据待测物的结构、生物介质和预期的浓度范围，建立适宜的生物样品分析方法，并对方法进行验证。

1．专属性必须证明所测定的物质是原形药物或特定的活性代谢物，内源性物质和相应的代谢物不得干扰样品的测定。

对于色谱法至少要提供空白生物样品色谱图、空白生物样品外加对照物质色谱图（注明浓度）及用药后的生物样品色谱图。

对于复方制剂应特别加强专属性研究，以排除可能的干扰。

生物等效性试验原理和原则1.背景美国对药品质量监管的三项制度安排，使得它在制定和颁布行业法规方面领先于世界。

首先，美国国会授予美国药典（US P）和国家处方集（NF）修订委员会制定药品及其制剂的规格、质量和纯度标准的权利。

尽管USP和NF是私人机构，对美国食品药品监督管理局（FDA）没有管理权。

其次，FDA也由美国国会授权，为开发和制造安全有效的药物制定法规。

最后，主要由美国食品及药物管理局制定，药品生产商实施的药品生产质量管理规范，确保了药品的质量。

FDA还颁布了药品的生物利用度（BA）和生物等效性（BE）的规范。

所有新药申请（NDAs）和新药补充申请必须通过体外的测试阐明药品在体内的生物利用度，以确保各个批次的质量，通常用溶出度测试的方法。

表5.1展示了各种监管法规对不同注册类型的要求。

根据联邦食品、药品和化妆品（FD&C）法案第505（b）节的规定，提交NDA或新动物药品申请（NADA）必须记录BA(21CFR 320.21(a))。

如果药品获得批准，NDA药品可能随后成为参比制剂（RLD）。

根据505（j）章节的规定，申请人提交简化新药申请（ANDA）或简化动物新药申请（ANADA）时必须达到药学等效，再达到生物等效，才能被视为和RLD药品治疗等效。

BE是利用相对生物利用度的方法，比较仿制药和参比制剂的体内行为。

（药学等效是指药品含有相同的活性成分、相同的BE在21 CFR 320.1中被定义为“在相似的试验条件下给以相同摩尔剂量的药物后，受试制剂的活性成分、活性分子的吸收速度和程度与参比制剂相比，无显著性差异。

”FDA通常考虑用血浆中的药物浓度作为药物作用位点的浓度的替代指标。

21 CFR 320.24给出了实现BE的途径。

证明生物等效需要综合多项研究证据，如PK、PD、临床试验、体外实验，以及其他能证明等效的研究资料。

2.获得上市许可的等效性文件药学等效的不同厂家的医药产品必须证明治疗等效，才可以相互替换。

发布日期20070716栏目化药药物评价>>临床安全性和有效性评价标题FDA《食物影响的生物利用度及饮食条件下的生物等效性研究》指导原则介绍作者亚男明部门正文容审评三部亚男、明美国卫生与人类服务部食品药品监督管理局药品评审和研究中心（CDER）2002年4月BPI 前言本指南为新药临床试验（INDs）、新药上市申请（NDAs）、仿制药申请和补充申请（ANDAs）的申办和/或申请者提供了食物对生物利用度和饮食条件下生物等效性研究的建议。

本指南适用于速释制剂和缓控释制剂。

本指南指出当用于口服制剂时，如何和21CFR320，314.50(d)(3)和314.94(a)(7)对BA、BE要求一致。

本指南对试验设计、数据分析、药物标签、试验如何实施方面提出了建议和参考。

II 背景食物影响生物利用度的研究通常在IND阶段的新药和药物上进行，目的是比较饮食和禁食情况下，食物对新药的吸收速度和程度的影响。

另一方面，针对ANDAs，饮食条件下生物等效性研究是比较在饮食情况下与对照品（RLD）的生物等效性。

A：食物影响生物利用度可能的机制食物可能改变药物的生物利用度，可能影响参比制剂和试验制剂的生物等效性。

食物对生物等效性的影响可能带来临床上严重后果。

食物可能通过如下方式改变生物利用度：－延迟胃排空；－刺激胆汁流量；－改变胃肠道（GI）pH值；－增加脏的血流量；－改变药物的代；－与制剂或药物发生物理和化学反应刚刚摄取食物后服药，食物对药物生物利用度影响往往是最大的。

食物的营养成分、热量、食物的体积和食物的温度能改变胃肠道的生理环境，由此影响药物在胃肠道的滞留时间、溶解度、渗透性和机体可利用度。

通常情况下，高脂、高热量食物更容易影响胃肠道的生理功能，结果导致药物或制剂的生物利用度发生较大的改变。

我们建议在食物影响生物利用度及饮食条件下生物等效性研究中采用高热量和高脂肪食物。

B：食物对药物制剂的影响制剂和食物同服，可以通过影响药物本身或制剂来改变制剂的生物利用度。

FDA指导原则fda指导原则（中文）目录非专利药物晶型研究技术指南Pdf口服固体制剂溶出度试验技术指南Pdf口服缓释制剂体外和体内相关性研究技术指南Pdf改变制剂处方和变更药物给药途径的非临床安全性评价技术指导原则.pdf终端灭菌产品实施参数放行的相关申报资料要求.pdf制剂注册申请对所附原料药生产工艺资料的要求.pdf药用辅料的非临床安全性评价技术指导原则.pdf原料药、药用辅料和包装材料申请材料的内容和格式要求Pdf无菌制剂生产质量管理规范Pdf无菌工艺验证数据申请要求Pdf工艺验证的一般原则和方法Pdf药物临床安全性评价审评报告撰写指导原则.pdf药品审评质量管理规范.pdf生物利用度和生物等效性试验用生物样品的处理和保存要求Pdf群体药代动力学研究技术指南Pdf食物对生物利用度的影响以及餐后生物等效性研究技术指导原则.pdf临床试验中人种和种族数据收集的技术指导原则.pdf因临床研究者失职叫停临床试验的相关规定.pdf药物上市前风险评估的技术指导原则.pdf药物警戒管理规范和药物流行病学评估技术指南Pdf药物肝毒性评估技术指南Pdf药物代谢产物安全性试验技术指导原则.pdf现有治疗定义和新治疗评估的技术指南Pdf人体第一剂最大安全初始剂量的估计Pdf 新药临床试验样品制备的技术指南Pdf新药ⅱ期和ⅲ期临床试验药学申报资料的内容及格式要求.pdf新药ⅰ期临床试验申报资料的内容及格式要求.pdf临床研究进程中沟通交流会的药学资料准备要求.pdf临床试验中应用计算机系统的技术指导原则.pdf建立临床试验数据监测委员会和工作技术指南Pdf紧急临床研究豁免知情同意的相关规定Pdf风险最小化执行方案的制定和完善的技术指导原则.pdfⅱa期临床试验结束后沟通交流会的有关要求.pdfⅰ期临床试验用样品的生产质量管理规范.pdf获得药品临床研究有效性证据的技术指导原则.pdf上市药物和生物制品添加新抗肿瘤适应症的技术指南Pdf上市抗肿瘤药物新临床试验豁免申请的相关要求Pdf糖尿病药物研究和预防指南。

新药研发过程中食物影响研究技术指导原则2021年12月目录一、概述 (1)二、总体考虑 (2)（一）开展食物影响研究的时间 (2)（二）食物影响研究的一般考虑 (2)三、研究设计 (3)（一）试验设计 (3)（二）样本量 (4)（三）膳食类型 (4)（四）受试者 (5)（五）剂量选择 (6)（六）给药方法 (7)1. 空腹状态 (7)2. 进餐状态 (7)3. 限定进餐间隔的特定状态 (7)（七）生物样本采集 (7)（八）检测物质 (8)四、数据分析与结果报告 (8)五、其他考虑 (10)（一）可与松软食物同服的药物 (10)（二）说明书标明的特定溶剂 (10)（三）特殊人群 (10)1. 老年用药 (10)2. 儿童用药 (10)（四）说明书起草建议 (11)六、参考文献 (11)七、附录 (12)新药研发过程中食物影响研究技术指导原则一、概述食物影响（Food effect, FE）研究是新药临床药理学研究的重要组成部分。

药物-食物相互作用可能对药物的安全性和有效性产生显著影响。

药物与食物同服可能影响药物的吸收和系统暴露，引起药物的安全性和有效性发生改变。

因此，评估食物对药物生物利用度的影响，对于保障临床用药的安全性和有效性、确定与食物相关的最佳用药方案来说非常重要。

由于饮食状况会随着食物数量和种类的不同而变化，且难以长期严格地控制，因此鼓励研发不受食物影响的药物制剂。

当无法研发此类制剂时，可通过开展良好和规范的FE研究，探究药物是否能与食物同服、以及何时/如何与食物同服。

通过FE研究可获得以下信息：（1）食物是否影响药物的系统暴露，其影响程度如何；（2）食物是否改变药物系统暴露的变异程度；（3）某些情况下，膳食中营养成分构成或热量的不同（如高脂餐/低脂餐），是否会导致食物对药物影响的程度发生变化。

本指导原则适用于口服给药的药物制剂，旨在为FE研究的研究设计、研究实施、数据分析以及药品说明书撰写提供建议和参考。

FDA《口服制剂的生物利用度和生物等效性研究:一般性考虑》介绍审评四部审评七室陈俊春审校I. 前言本指导原则的目的是向计划在研究性新药申请（IND）、新药申请（NDA）、简化新药申请（ANDA）及其补充申请中包括口服制剂的生物利用度（BA）和生物等效性（BE）研究内容的申办者和/或申请者提供建议。

本指导原则包含的建议是关于在申请口服制剂时如何满足第320部分（21 CFR 320）所规定的对BA和BE的要求。

该指导原则也适合于可用全身暴露测量指标来确证BA和BE的非口服给药制剂（如：经皮给药系统和某些直肠给药或鼻腔给药的制剂）。

我们相信本指导原则将有助于申请者合理规划为申报NDA而在IND期间进行的BA和BE研究，以及为申报ANDA而进行的BE研究和为在NDA和ANDA批准后的某些变更而进行BE研究。

本指导原则对2000年10月份的指导原则进行了修订。

我们在下述几个方面做了修订：(1) 研究设计和溶出方法的进展；(2) BA测量指标的比较；(3) 有比例关系的定义；(4) 免做生物等效性研究的条件。

本指导原则还有一些修改是为了澄清一些问题。

我们相信这些修订给进行口服制剂BA和BE研究的申办者提供了明确的指导意见。

FDA的指导原则文件，包括本指导原则，都不是法律的强制要求。

相反，这些指导原则代表了管理当局对某个问题当前的想法，应当看作只是建议，除非引用了具体的法规要求。

FDA指导原则中所用的单词“应该”的意思是提议或建议，而不是必须要求。

II. 背景A. 总论测定一个产品的BA和/或确定其BE的研究是支持IND、NDA、ANDA及其补充申请的重要内容。

作为口服制剂IND和NDA的一部分，BA研究的重点是测定一种药物从口服制剂中释放并进入作用部位的过程。

BA数据是对药物吸收比例以及其随后分布和消除情况的估计。

BA一般可以通过测定一定时间内药物和/或其代谢产物在血液循环中的浓度，得到其全身暴露情况，由此确证BA。

2014年FDA新药生物利用度和生物等效性试验指导原则更新要点 美国FDA在2013 年12 月发布的《以药动学为终点评价指标的仿制药生物等效性研究指导原则》（草案），以及2014年 3 月发布的《新药（IND/NDA）进行生物利用度和生物等效性研究的指导原则》（草案），（下文简称《新药BA/BE 指导原则》）。

标志着对新药BA/BE 研究和以药代动力学方法进行仿制药BE 研究分别颁布了各自相应的指导原则。

《新药BA/BE 指导原则》更新并替代了2003版BA/BE 指导原则中有关新药申请及其补充申请中涉及的BA/BE 研究的内容，但不包含仿制药BE研究和生物制品上市申请（biologicslicense applications，BLA）的相关内容。

《新药BA/BE 指导原则》也不包含考察进食对BA/BE 的影响的相关内容，这部分内容须参照FDA2002 年12 月颁布的《饮食对生物利用度的影响以及餐后生物等效性》指导原则（下文简称food-BA fed-BE 指导原则）。

需要进行说明的是，虽然美国的相关法规中没有对新药进行BA/BE 研究的明确要求，但有时新药进行BA/BE 研究可以支持其安全性和有效性评价，所以新药BA /BE 研究结果的解释需要更多地考虑其临床有效性和安全性。

为了便于读者理解，《新药BA/BE指导原则》将 2 个或多个制剂的相对生物利用度研究称为新药的生物等效性研究。

与2003 版BA/BE 指导原则相比，《新药BA/BE 指导原则》在多个方面进行了更新和扩充。

主要更新要点依次为： ①扩展了对缓释制剂（extendedrelease，ER）部分的要求。

②增加了对合并用药/复方制剂的要求。

③增加了含酒精饮料对非常释制剂（modified release，MR）影响的考察要求。

④增加了对内源性物质的有关要求。

⑤增加了对高变异药物的要求。

⑥明确了需要进行多次给药（multipledose，MD）稳态BA 研究的情况。