Additional copies are available from:
额外副本可从以下地址获取：
Office of Training and Communications
办公室培训和通讯
Division of Communications Management
通讯管理部
Drug Information Branch, HFD-210
药物信息科，HFD-210
5600 Fishers Lane
Rockville, MD 20857 罗克维尔，马里兰州 20857
(Tel) 301-827-4573 （电话）301-827-4573
(Internet) http://www.fda.gov/cder/guidance/index.htm
（互联网）http://www.fda.gov/cder/guidance/index.htm

This Guidance provides recommendations to pharmaceutical sponsors on methods to document in vivo bioequivalence of topical dermatologic corticosteroids, hereinafter referred to as topical corticosteroids. The Guidance becomes effective 2 June 1995. Any investigations initiated after that date should generally conform to the recommendations of the Guidance. The Guidance utilizes a pharmacodynamic approach, based on an update of the Stoughton-McKenzie vasoconstrictor bioassay, to assess bioequivalence of topical corticosteroids. The method utilizes a duration of exposure (dose duration) approach to control the dose of topical corticosteroid that is delivered. The proposed methodology includes a pilot dose duration-response study to determine the appropriate dose duration for use in the pivotal study, followed by the pivotal in vivo bioequivalence study incorporating replicate design and documentation of acceptable individual subject dose duration-response. As with all bioanalytical methods, this pharmacodynamic bioassay will require careful validation on the part of pharmaceutical sponsors.
本指南为制药赞助商提供有关记录局部皮肤科皮质类固醇体内生物等效性的方法建议，以下简称为局部皮质类固醇。本指南自 1995 年 6 月 2 日起生效。此后启动的任何调查通常应遵循指南的建议。本指南采用药效学方法，基于对 Stoughton-McKenzie 血管收缩剂生物测定法的更新，以评估局部皮质类固醇的生物等效性。该方法采用暴露持续时间（剂量持续时间）方法来控制递送局部皮质类固醇的剂量。拟议的方法包括一项试点剂量持续时间-反应研究，以确定用于关键研究的适当剂量持续时间，随后进行包括重复设计和记录可接受的单个受试者剂量持续时间-反应的关键体内生物等效性研究。与所有生物分析方法一样，这种药效学生物测定将要求制药赞助商进行仔细的验证。

Potent topical corticosteroid products may suppress the hypothalamic-pituitary-adrenal (HPA) axis. In the past, when in vivo bioequivalence of such products was documented using the single time point Stoughton-McKenzie study design, the Office of Generic Drugs (OGD) required an HPA axis suppression test when test and reference formulations were significantly different. Products documented to be bioequivalent using this Guidance will not be required to submit HPA axis suppression test data.
强效局部皮质类固醇产品可能会抑制下丘脑-垂体-肾上腺（HPA）轴。在过去，当使用单时间点 Stoughton-McKenzie 研究设计证明此类产品的体内生物等效性时，仿制药办公室（OGD）要求在测试和参比制剂显著不同时进行 HPA 轴抑制测试。根据本指南证明生物等效性的产品将无需提交 HPA 轴抑制测试数据。

The 1 July 1992 Interim Guidance, Topical Corticosteroids: In Vivo Bioequivalence and In Vitro Release Methods ${}^1$${}^1$^(1){ }^{1} included dermatopharmacokinetic (skin stripping) studies and in vitro release studies. The agency currently has insufficient data to recommend skin stripping methods to document bioequivalence of topical corticosteroids. However, this methodology for documentation of bioequivalence may be used if appropriate validation data are provided. At the present time, OGD will not require in vitro release data to support approval of ANDA’s for topical corticosteroids. Following future recommendations of the Scale-Up and Post-Approval Changes for Semisolids (SUPAC-SS) Working Group, OGD may recommend the submission of in vitro release
1992 年 7 月 1 日的《临时指南》，局部皮质类固醇：体内生物等效性和体外释放方法，包括皮肤药代动力学（皮肤剥离）研究和体外释放研究。该机构目前缺乏足够的数据来推荐使用皮肤剥离方法来证明局部皮质类固醇的生物等效性。然而，如果提供适当的验证数据，此方法可用于证明生物等效性的文件。目前，OGD 不会要求提供体外释放数据来支持局部皮质类固醇 ANDA 的批准。根据未来半固体（SUPAC-SS）工作组关于扩大规模和批准后变更的建议，OGD 可能会建议提交体外释放

data to support waiver of in vivo bioequivalence of the lower strength(s) of topical corticosteroid products, scale-up of production batches, and approval of formulation, process, and site changes in the absence of in vivo data. Future use of these data as a quality control tool is also envisioned.
支持降低强度外用皮质类固醇产品体内生物等效性豁免、生产批次放大以及无体内数据的情况下批准配方、工艺和场地变更的数据。还设想将这些数据作为质量控制工具的未来使用。

The Guidance has been prepared by staff of the Division of Bioequivalence (HFD-650), with the participation of staff of the Division of Topical Drug Products (HFD-540) and the Division of Biometrics (HFD-710). It is a general guidance intended to apply to topical corticosteroids of all potency groups. Because dose duration-response characteristics may vary with the particular drug of interest, as well as with study conditions, the Guidance encourages the performance of a pilot study to define appropriate parameters for the pivotal study. Staff members of HFD-650 are available to work with pharmaceutical sponsors in the design of specific studies to meet the recommendations of the Guidance.
本指南由生物等效性部（HFD-650）的员工编制，并得到了局部药物产品部（HFD-540）和生物统计学部（HFD-710）员工的参与。这是一份旨在适用于所有效力组的局部皮质类固醇的一般指南。由于剂量持续时间-反应特征可能因感兴趣的具体药物以及研究条件而异，因此指南鼓励进行一项试点研究，以确定关键研究的适当参数。HFD-650 的员工可以与制药赞助商合作，设计特定研究以满足指南的建议。

The determination of bioequivalence of two solid oral dosage forms generally rests on a comparison of drug and/or metabolite concentrations in an accessible biologic fluid, such as blood or urine, after administration of a single or multiple doses of each drug product to healthy volunteers. In the absence of this methodology, the Food and Drug Administration may, through provisions of the Food, Drug and Cosmetic Act and implementing regulations ( 21 CFR $\mathrm{\S }320$$\mathrm{\S }320$§320\S 320 ), rely on other in vivo and in vitro methods to assess bioequivalence. In descending order of preference within the Office of Generic Drugs, these methods include: 1) pharmacodynamic effect studies; 2) clinical trials, 3) in vivo animal studies; and 4) in vitro studies. Although the methods in the latter two categories are acceptable from a statutory/regulatory standpoint, the Division of Bioequivalence in OGD historically has relied only on in vivo pharmacodynamic or clinical studies to assess bioequivalence of drug products that do not produce measurable concentrations of drug or metabolite in an accessible biological fluid. Clinical trials generally require large numbers of subjects and often lack sensitivity. In contrast, pharmacodynamic effect studies offer the possibility of developing acceptable bioequivalence data in a relatively small number of subjects.
两种固体口服剂型生物等效性的确定通常基于对健康志愿者给予单个或多个剂量后，药物和/或代谢物在可获取的生物液体（如血液或尿液）中的浓度的比较。在没有这种方法的情况下，食品药品监督管理局可以通过《食品、药品和化妆品法》及其实施条例（21 CFR $\mathrm{\S }320$$\mathrm{\S }320$§320\S 320 ）的规定，依靠其他体内和体外方法来评估生物等效性。在仿制药办公室，根据优先顺序，这些方法包括：1）药效学效应研究；2）临床试验；3）体内动物研究；4）体外研究。尽管后两类方法在法律/监管方面是可接受的，但仿制药办公室的生物等效性分部历史上仅依靠体内药效学或临床研究来评估那些在可获取的生物液体中不产生可测量浓度的药物或代谢物的药物产品的生物等效性。临床试验通常需要大量受试者，并且往往缺乏敏感性。 相比之下，药效学效应研究有可能在相对较少的受试者中开发出可接受的生物等效性数据。

For many years, the Division of Bioequivalence has relied on pharmacodynamic effect methodology to approve generic topical corticosteroid drug products. The approach is based on the property of corticosteroids to produce blanching or vasoconstriction in the microvasculature of the skin. This property presumably relates to the amount of drug entering the skin ${}^2$${}^2$^(2){ }^{2} and thus becomes a possible basis for the comparison of drug delivery from two potentially equivalent topical corticosteroid formulations. Development of the methodology is attributed to Dr. R.B. Stoughton and Dr. A.W. McKenzie, who initially developed it as a means to assess potency of different topical corticosteroids. ${}^3$${}^3$^(3){ }^{3} Subsequently it was applied by pharmaceutical manufacturers and accepted by the Food and Drug Administration as a means of assessing bioavailability and bioequivalence. In these and other applications, it is referred to variously as the Stoughton-McKenzie test, the vasoconstrictor assay, or the skin blanching assay. Although there are many forms of the vasoconstrictor assay, the general method is
多年来，生物等效性部门一直依赖药效学效应方法来批准仿制外用皮质类固醇药物产品。这种方法基于皮质类固醇在皮肤微血管中产生脱色或血管收缩的特性。这种特性可能与其进入皮肤的药物量有关，因此可能成为比较两种可能等效的外用皮质类固醇制剂药物递送的可能基础。该方法的开发归功于 R.B. Stoughton 博士和 A.W. McKenzie 博士，他们最初将其开发为评估不同外用皮质类固醇活性的手段。随后，该技术被制药公司应用，并被食品药品监督管理局接受，作为评估生物利用度和生物等效性的方法。在这些和其他应用中，它被分别称为 Stoughton-McKenzie 测试、血管收缩剂试验或皮肤脱色试验。尽管血管收缩剂试验有许多形式，但一般方法是