第 III 章 生物等效性的建立 ( III. ESTABLISHING BIOEQUIVALENCE )
餐后生物等效性研究 ( III. A. 10 Fed Bioequivalence Studies )：该部分澄清了针对速释药品的餐后生物等效性研究，除了橙皮书收录的参照药品标签说明的剂量与用法部分说明药品应空腹服用 ( 餐前1小时或餐后2小时 ) 的情况外，所有情况下均需开展餐后生物等效性研究。如果标签说明建议与食物一起服用药品，除了预期会发生严重的空腹服用不良事件的情况外，均要求开展空腹研究。
在特定饮料中的生物等效性研究 ( III. A. 12 Bioequivalence Studies of Products Administered in Specific Beverages )：该部分声明，如果橙皮书收录的参照药品标签说明规定，药品必须与特定饮料服用，那么必须开展与标签说明中提及的饮料之中的一种混合服用的生物等效性研究。如果列有其它饮料，申请人应提供使用这些额外的饮料不会导致生物等效性差异的证据。
第 IV 章 不同剂型生物等效性的建立 ( IV. ESTABLISHING BIOEQUIVALENCE FOR DIFFERENT DOSAGE FORMS )
母体药物与代谢物 ( V. A. 1 Parent Drug Versus Metabolites )：该部分属于第一个主题—待测基团，澄清了在所有情况下依赖母体药物来测定生物等效性，除了母体药物不能精确测量或含量水平过低不能充分鉴定的情况外。该部分还提供了何时测定代谢物的指南。只要母体药物能够充分测定，就可作为生物等效性测定基础，如果代谢物可以测定，可提供“治疗效果相当的支持性证据”。
对映体与外消旋体 ( V. A. 2 Enantiomers Versus Racemates ) 和以复杂化合物作为活性成分的药品 ( V. A. 3 Drug Products with Complex Mixtures as the Active Ingredients )：这两部分指南没有变化。
长半衰期药品 ( V. B. Long Half-Life Drugs )：该部分除了规定长半衰期为>24h外，无变化。
第一点药峰浓度 ( V. C. First Point Cmax )：该部分原则上没有变化。
酒精饮料对缓控释药品的作用 ( V. D. Alcoholic Beverage Effects On Modified Release Drug Products )：这是新增加的部分，建议申请人使用不同酒精混合物中的体外测试研发这些产品。某些情况下，可能需要体内生物等效性研究。具体的产品指南，参见各个产品生物等效性建议。
内源性化合物 ( V. E. Endogenous Compounds )：这是另一个新增部分，指导如何设计和开展针对内源性化合物的生物等效性研究。
预期用于局部作用的口服药品 ( V. F. Orally Administered Drugs Intended For Local Action )和体外溶出度检测( V. G. In Vitro Dissolution Testing )：与之前的指南相比，这两部分没有根本性改变。
The promised update to the guidance on Bioequivalence and Bioavailability Studies (the so-called “General Considerations” guidance) has published. This draft guidance addresses only bioequivalence studies for ANDAs and so does not address bioavailablity studies or bioequivalence studies for any other purpose such as INDs or NDAs.
The draft guidance is titled “Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA” and can be found in the CDER Guidances section under the “Biopharmaceutics” heading. The introduction states that guidance for bioavailability studies and for other bioequivalence studies will be published “soon”. Note that because this only addresses updates for ANDAs, the General Considerations guidance and the Food-Effect Bioavailability and Fed Bioequivalence Studies guidance remain in the guidance list.
The new guidance addresses aspects of the General Considerations guidance and the Fed Studies guidance as they apply to bioequivalence studies for ANDAs. In general the update is good and clarifies a number of issues that had not been previously defined but had existed in the realm of “usual and customary practice” which is always an uncomfortable space when dealing with OGD.
These notes concentrate on areas where new, changed, or expanded guidance is provided. There are many sections where previous guidance is reiterated in this guidance.
The guidance begins with an Introduction and briefly discussed 12 listed topics that are general in nature to bioequivalence studies. There is an attachment which addresses General Design and Data Handling. There are no significant changes in this attachment.
Fed Bioequivalence Studies – This section clarifies that for immediate-release products fed studies are required in all cases except when the dosage and administration section of the RLDlabeling states that the product should be taken on an empty stomach (that is 1 hour before or 2 hours after a meal). When the label recommends taking the product with food, fasting studies are required except when serious adverse events are expected with fasting administration.
Bioequivalence Studies of Products Administered in Specific Beverages – This section states that if the labeling of the RLD specifies that the product must be administered in a specific beverage(s), then BE studies for these products should be administered mixed with one of the beverages mentioned in the labeling. If additional beverages are listed then sponsors should provide evidence that using these additional beverages would not result in BE differences.
Under the heading “Different Dosage Forms” the guidance deals with Oral Solutions, IR Tablets and Capsules, Suspensions, Delayed-release and Extended-release Products, and Chewable Tablets. In this section regarding biowaivers, the guidance presents an expanded discussion of dose proportionality, pseudo-dose proportionality, and other situations (that is neither dose proportional nor pseudo-dose proportional). Although this is expanded and presented in some depth, it still leaves open the “other situations” definition. This issue of what compositions are eligible for biowaivers has caused much anxiety among sponsors and although the new guidance goes some way towards a definitive answer, there are still gray areas.This section also states that where post approval changes that require bioequivalence studies are made, that these studies should be post change product against RLD and not against pre change product.
The next section is titled “Special Topics”. The first special topic is moieties to be measured.
Parent Drug Versus Metabolites – This section clarifies the reliance on parent drug to determine bioequivalence in all circumstances except where the parent drug cannot be accurately measured or the levels are too low to allow adequate characterization. It also provides guidance on when to measure metabolites. Wherever parent drug can be adequately characterized, it is serves as the basis of bioequivalence determination, metabolites, if measured, providing “supportive evidence of a comparable therapeutic outcome”.
Guidance on Enantiomers Versus Racemates and Drug Products with Complex Mixtures as the Active Ingredients is unchanged.
Long Half-Life Drugs – Unchanged except that a long half-life is given as >24 hours.
The section on First Point Cmax is essentially unchanged but for a little elaboration on the concern in these cases.
Alcoholic Beverage Effects On Modified Release Drug Products – This is a new section suggesting that sponsors develop these products using in vitro testing in various alcohol mixtures. In some instances an in vivo BE study may be required. For specific product guidance see the Individual Product Bioequivalence Recommendations.
Endogenous Compounds – This is another new section which gives guidance on how design and conduct BE studies for endogenous compounds.
Sections on Orally Administered Drugs Intended For Local Action and In Vitro Dissolution Testing are essentially unchanged from previous guidance.
Overall this is a helpful guidance which cleans up many previously gray areas and should make the conduct of bioequivalence studies to support ANDAs easier for sponsors. 北京大学药物信息与工程研究中心 Garth Boehm 博士 2013-12-11
Lachman CONSULTANTS的博客文章
New Revised Bioequivalence Guidance Clarifies Requirements
Written by Bob Pollock • December 09, 2013
FDA issued a newly revised Draft Guidance entitled Bioequivalence Studies with Pharmacokinetic Endpoints for Drug Submitted Under an ANDA (here). The new Guidance document is specific to abbreviated new drug applications (ANDAs) and combines part of two previous guidance documents on general bioequivalence (BE) and BE for fed studies for ANDAs. The document does not address bioavailability (BA) or BE for investigational new drug applications (INDs) or for studies required to support BE for new drug applications (NDAs).
This document deals with both BE and in vitro requirements for approval and post-approval changes to ANDAs and addresses many topics, including, but not limited to:
when fed studies are necessary
specific BE requirements for immediate-release products, suspensions, solutions and modified-release and extended release dosage forms
sprinkle study requirements
when BE waivers are appropriate
Special topics covered include:
Moieties to be measured in the various studies
Fed studies
Alcohol studies
The issue of racemates and also how to handle evaluation of drugs containing endogenous compounds
Drugs with a Long half-life
First point Cmax and importance of Tmax
Partial AUCs
Orally administered drugs intended for local action
Narrow therapeutic range drugs
Parallel and replicate design studies
The Guidance also clarifies with certainty when and what products must be tested in vivo or in vitro when considering original ANDA approval or when making a post-approval change,which is an issue that has never really been spelled out before with as much clarity as in this document. There are also specific instruction on how to handle the BE testing of chewable tablets. There is also a section that deals with complex mixtures as the active ingredients that sheds some light on Office of Generic Drugs (OGD) expectations.
This ANDA-specific Guidance provides in one place information that has been scattered in various documents and some new direction for ANDA applicants in a manner that is straightforward and leaves no doubt as to OGD's intention.
