Botanical Drug
Development Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to https://www.doczj.com/doc/62793859.html,. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document contact (CDER) Sau L. Lee at sau.lee@https://www.doczj.com/doc/62793859.html, 301-796-2905, or Rajiv Agarwal at rajiv.agarwal@https://www.doczj.com/doc/62793859.html, 301-796-1322.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2015
Pharmaceutical Quality/CMC
Revision 1
植物药研发
行业指南
指南草案
本指南发布仅用于征询意见目的。
涉及本指南文件的意见和建议应在联邦公告通告公布本指南草案的60日内提交涉及本指南文件的意见和建议。电子版意见、建议请提交至https://www.doczj.com/doc/62793859.html,。书面意见、建议提交至the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.。
所有意见、建议应标明联邦公告公布通告中所列出的卷宗号。
与本指南相关的问题，请致电301-796-2905或发送电子邮件sau.lee@https://www.doczj.com/doc/62793859.html,垂询药品审评与研究中心Sau L. Lee，或致电301-796-1322或发送电子邮件rajiv.agarwal@https://www.doczj.com/doc/62793859.html,垂询Rajiv Agarwal。
美国卫生与人类服务部
食品药品管理局
药品审评与研究中心（CDER）
制药质量/化学、制造、控制（CMC）
修订版1
Botanical Drug Development Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@https://www.doczj.com/doc/62793859.html,
https://www.doczj.com/doc/62793859.html,/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2015
Pharmaceutical Quality/CMC
Revision 1
植物药研发
行业指南
另外的副本可从以下部门得到：
马里兰州银泉市新罕布什尔大道10001号Hillandale 楼4层药品信息处，对外信息办公室，
邮政编码：20993
电话：855-543-3784或301-796-3400; 传真：301-431-6353
电子邮件：druginfo@https://www.doczj.com/doc/62793859.html,
https://www.doczj.com/doc/62793859.html,/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
美国卫生与人类服务部
食品药品管理局
药物评估和研究中心（CDER）
2015年8月
制药质量/化学、制造、控制（CMC）
修订版1
目录
I. INTRODUCTION (1)
I. 简介 (1)
II. BACKGROUND (2)
II. 背景 (2)
III. GENERAL REGULATORY APPROACHES (3)
III．一般监管方法 (3)
A. Marketing of Botanical Drugs under OTC Drug Monographs (4)
A. 按照非处方药专论的植物药上市销售 (4)
A. Marketing of Botanical Drugs under NDAs (5)
A. 按照新药申请申请的植物药上市销售 (5)
IV. BOTANICAL DRUG DEVELOPMENT UNDER INDS (7)
IV. 按照研究用新药申请（INDs）的植物药研发 (7)
V. INDS FOR PHASE 1 AND PHASE 2 CLINICAL STUDIES (8)
V. 针对1期和2期临床研究的研究用新药申请（INDS） (8)
A. Description of Product and Documentation of Prior Human Experience (10)
A. 产品说明和既往人体体验文件记录 (10)
1. Description of Botanical Raw Materials Used and Known Active Constituents or
Chemical Constituents (§ 312.23(a)(3)(i)) (10)
1. 使用的植物原药材和已知活性成分或化学成分说明 (10)
2. Prior Human Experience (§§ 312.23(a)(3)(ii),(a)(9)) (11)
2.既往人体体验(§§ 312.23(a)(3)(ii),(a)(9) ) (11)
B. Chemistry, Manufacturing, and Controls (12)
B.化学、制造和控制 (12)
1. Botanical Raw Materials (§ 312.23(a)(7)(i)) (12)
1. 植物原药材(§ 312.23(a)(7)(i)) (12)
2. Botanical Drug Substance (§ 312.23(a)(7)(iv)(a)) (14)
2. 植物原料药(§ 312.23(a)(7)(iv)(a)) (14)
3. Botanical Drug Product (§ 312.23(a)(7)(iv)(b)) (17)
3.植物药药品(§ 312.23(a)(7)(iv)(b)) (17)
4. Placebo (§ 312.23(a)(7)(iv)(c)) (19)
4.安慰剂(§ 312.23(a)(7)(iv)(c)) (19)
5. Environmental Assessment or Claim of Categorical Exclusion (§ 312.23(a)(7)(iv)(e)) . 19
5. 环境评价或条件排除声明(§ 312.23(a)(7)(iv)(e)) (19)
C. Nonclinical Pharmacology/Toxicology (19)
C.非临床药理学/毒理学 (19)
D. Clinical Pharmacology (22)
D．临床药理学 (22)
E. Clinical Considerations (23)
E. 临床注意事项 (23)
VI. INDS FOR PHASE 3 CLINICAL STUDIES (24)
VI.用于3期临床研究的研究用新药申请（INDS） (24)
A. General Regulatory Considerations in Late‐Phase Development (24)
A. 晚期研发中的总体监管考虑 (24)
B. Description of Product and Documentation of Prior Human Experience (26)
B. 产品说明和既往人体体验文件记录 (26)
C. Chemistry, Manufacturing, and Controls (26)
C.化学、制造和控制 (26)
1. Botanical Raw Material (26)
1. 植物原药材 (26)
2. Botanical Drug Substance and Drug Product (27)
2．植物药原料药与药品 (27)
D. Nonclinical Safety Assessment (28)
D．非临床安全性评价 (28)
1. General Pharmacology/Toxicology (28)
1. 全身药理学/毒理学 (28)
2. Nonclinical Pharmacokinetic/Toxicokinetic Studies (29)
2.非临床药代动力学/毒代动力学研究 (29)
3. Reproductive Toxicology (30)
3. 生殖毒性 (30)
4. Genotoxicity Studies (30)
4. 遗传毒性研究 (30)
5. Carcinogenicity Studies (30)
5.致癌性研究 (30)
6. Other Toxicity Studies (31)
6.其它毒性研究 (31)
7. Regulatory Considerations (31)
7. 监管考虑要点 (31)
E. Clinical Pharmacology (32)
E.临床药理学 (32)
F. Clinical Considerations (32)
F.临床考虑要点 (32)
1. Study Design for Multiple Batch Analyses (33)
1. 多批次分析的研究设计 (33)
2. Dose‐Response Effect (34)
2.剂量‐响应效应 (34)
3.Clinical Studies of Botanical Drugs for Serious Conditions (35)
3.用于严重疾病的植物药品的临床研究 (35)
4. Other Study Design Issues (35)
4. 其它研究设计问题 (35)
G. Applicability of Combination Drug Regulations (36)
G.复方药品法规的适用性 (36)
VII. NDAS FOR BOTANICAL DRUG PRODUCTS (37)
VII．植物药品新药申请 (37)
A. Description of Product and Documentation of Prior Human Experience (38)
A. 产品说明及既往人体体验证明 (38)
B. Quality Control (38)
B.质量控制 (38)
1. Botanical Raw Material (38)
1. 植物原药材 (38)
2. Botanical Drug Substance and Drug Product (39)
2.植物原料药和药品 (39)
C. Nonclinical Safety Assessment (45)
C．非临床安全性评价 (45)
D. Clinical Pharmacology (45)
D. 临床药理学 (45)
E. Clinical Evidence of Efficacy and Safety (46)
E.疗效与安全性的临床证据 (46)
F. Evidence to Ensure Therapeutic Consistency (46)
F. 确保疗效等效性的证据 (46)
1. Raw Material Control (47)
1. 原药材控制 (47)
2. Quality Control by Chemical Tests and Manufacturing Control (48)
2．通过化学检验和制造控制方法的质量控制 (48)
3. Biological Assay(s) and Clinical Data (48)
3. 生物检定与临床数据 (48)
G. Postmarketing Considerations (49)
G. 上市后考虑要点 (49)
Botanical Drug Development1
Guidance for Industry 1
行业指南1
植物药研发1
This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.
本指南草案在最终定稿时将体现食品药品管理局（FDA）关于这一主题的最新见解。本
指南不为任何人或对任何人创造或赋予任何权利，不起束缚FDA或公众的作用。如果替
代方法能够满足适用法律、法规的要求，您可以使用替代方法。如果您希望讨论一种替
代性方法，请与标题页列出的负责执行本指南的FDA工作人员联系。
I.INTRODUCTION
I.简介
This guidance describes the Center for Drug Evaluation and Research’s (CDER’s) current thinking on appropriate development plans for botanical drugs to be submitted in new drug applications (NDAs) and specific recommendations on submitting investigational new drug applications (INDs) in support of future NDA submissions for botanical drugs. In addition, this guidance provides general information on the over-the-counter (OTC) drug monograph system for botanical drugs. Although this guidance does not intend to provide recommendations specific to botanical drugs to be marketed under biologics license applications (BLAs), many scientific principles described in this guidance may also apply to these products.
本指南阐述药品评价与研究中心（CDER）对以新药申请（NDA）形式提交的植物药适用的研发计划的最新想法，以及对提交用于支持未来植物药新药申请的研究用新药申请（INDs）的具体建议。此外，本指南也对植物药非处方药（OTC）专论系统提供通用信息。尽管本指南并不旨在提供依照生物制品许可申请（BLAs）上市的植物药的具体建议，但本指南所阐述的多个科学原则也可适用于这些产品。
1This guidance has been prepared by a working group composed of staff from the Office of Pharmaceutical Quality, Office of New Drugs, Office of Translational Sciences, and Office of Medical Policy in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.
1本指南由来自于FDA药品审评与研究中心（CDER）制药质量办公室、新药办公室、转化科学办公室和医学政策办公室雇员所组成的工作组制定。
This guidance specifically discusses several areas in which, due to the unique nature of botanical drugs, the Agency finds it appropriate to apply regulatory policies that differ from those applied to nonbotanical drugs, such as synthetic, semi-synthetic, or otherwise highly purified or chemically modified drugs, including antibiotics derived from microorganisms. Because this guidance focuses on considerations unique to botanical drugs, policies and recommendations applicable to both botanical and nonbotanical drugs are generally not covered in this document; readers should refer to other FDA guidance documents for appropriate information.
本指南具体讨论了几个领域，由于植物药的独有的特点，FDA确定这一独有的特点适用于应用有别于适用于非植物药产品的监管政策，例如合成、半合成或其它情况下高度提纯或化学修饰药品，包括源于多种微生物的抗生素。由于本指南侧重于对植物药特有的考虑，因此本文件一般未覆盖对植物药和非植物均适用的政策与建议；适用信息，请参考FDA的其它指南文件。
This guidance revises the Guidance for Industry on Botanical Drug Products issued in June 2004. After it has been finalized, this guidance will replace the June 2004 guidance. The general approach to botanical drug development has remained unchanged since that time; however, based on improved understanding of botanical drugs and experience acquired in the reviews of NDAs and INDs for these drugs, specific recommendations have been modified and new sections have been added to better address late-phase development and NDA submission for botanical drugs.
本指南对2004年6月发布的《行业指南：植物药品》做出修订。在最终修订之后，本指南将取代2004年6月发布的指南。自2004年6月以来，植物药研发的一般方法未发生变化；然而，根据对植物药认识的提高，以及针对这些药品的NDAs和INDs审评中所获取的经验，修订了具体建议，增加了新节，以更好地解决植物药晚期研发和NDA提交。
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
FDA的指南文件，包括本指南在内，不具有规定依法强制执行责任。相反，除非引述具体的监管或法规要求，指南描述的是本机构目前对该主题的看法，应该仅仅被视为建议。在本机构指南中所使用的“应该”一词，指建议或推荐某事，并非必须的。
II.BACKGROUND
II.背景
For the purposes of this document, the term botanicals means products that include plant materials, algae, macroscopic fungi, and combinations thereof. It does not include:
本指南范围内，植物药产品这一术语涵盖植物材料、藻类、大型真菌及其组合产品。不包括：
Products that contain animals or animal parts (e.g., insects and annelids) and/or minerals, except when these are a minor component in a traditional botanical preparation.
含有动物或动物部分（例如昆虫和环节动物）和/或矿物，但传统植物药制剂中的次要组分除外。
Materials derived from botanical species that are genetically modified with the intention of producing a single molecular entity (e.g., by recombinant DNA technology or cloning).
源于经过转基因（例如通过重组D 技术或克隆）以期产生单分子实体的植物物种的材料。
ation of yeast, bacteria, plant cells, or other microscopic Products produced by ferment
organisms, including plants used as substrates, if the objective of the fermentation process is to produce a single molecular entity (e.g., antibiotics, amino acids, and vitamins).
通过酵母、细菌、植物细胞活其它微生物发酵生成的产品，如果发酵工艺的目的是生成单分子实体（例如抗生素类、氨基酸类和维生素类），那么也包括用作基质的植物。
Highly purified substances, either derived from a naturally occurring source (e.g., paclitaxel) or chemically modified (e.g., estrogens synthesized from yam extracts).
高度提纯原料药，源于天然来源（例如紫杉醇）或经化学修饰（例如合成自薯蓣提取物的雌激素类）。
If the botanical material is derived from traditional cultivation or breeding techniques (e.g., not genetic engineering), or if fermentation is part of the manufacturing process to produce a product that is a natural mixture consisting of multiple active constituents, 2then appropriate provisions in this guidance will apply.
如果植物材料源于传统种植或繁育技术（例如，非转基因），或者如果发酵是生成由多种活性成分2组成的天然混合物产品的制造工艺的组成部分，本指南适用条款将适用。
When a drug product contains a botanical drug substance in combination with either a (1) synthetic or highly purified drug or (2) biotechnology-derived or other naturally derived drug, this guidance can generally be applied to the botanical portion of the product.
在药品含有植物药原料药与（1）合成或高度提纯药物或（2）生物技术或其它天然来源药物的情况下，本指南通常适用于药品的植物药部分。
III.GENERAL REGULATORY APPROACHES
III．一般监管方法
A botanical product may be a food (including a dietary supplement), drug (including a biological drug), medical device, or cosmetic under the Federal Food, Drug, and Cosmetic Act (FD&C Act). Whether an article is a food, drug, medical device, or cosmetic depends on its intended use,3which is established
2Active constituents are the chemical constituent(s) in a botanical drug substance that contribute significantly to a botanical drug’s intended pharmacological activity or therapeutic effect.
2活性成分指对植物药拟定药理活性或疗效贡献显著的植物药原料药中的化学成分。
3See 21 USC 321(f)(1), (g)(1)(B) and (C), (h)(2) and (3), (i), (ff).
by, among other things, its labeling, advertising, and the circumstances surrounding its distribution.4依据《联邦食品、药品与化妆品法案》（FD&C Act）植物产品可以为食物（包括膳食添加剂）、药物（包括生物药）、医疗器械或化妆品。产品是否为食品、药品、医疗器械或化妆品取决于产品的拟定用途，3 除了其它方面以外，产品预定用途由产品标签及围绕产品流通的广告、环境所决定。4
If a botanical product is intended for use in diagnosing, curing, mitigating, or treating disease, it is a drug under section 201(g)(1)(B) of the FD&C Act and is subject to regulation as such. If a botanical product is intended to prevent disease, it is also a drug under section 201(g)(1)(B). There are a number of exceptions to the drug classification, including an exception for when a food product bears a health claim that is authorized in accordance with section 403(r)(1)(B) of 85 the FD&C Act (21 USC
343(r)(1)(B)); such a product is not a drug solely because its labeling contains such a claim. The recommendations in this guidance are for botanical drugs only.
如果一种植物产品拟定用于诊断、治愈、减轻或治疗疾病，依据《联邦食品、药品与化妆品法案》第201(g)(1)(B)节，该产品为药品，因此受制于监管。如果一种植物产品拟定用于预防疾病，依据《联邦食品、药品与化妆品法案》第201(g)(1)(B)节，也被视为药品。药品归类中存在多项例外，这些例外中，包括食品具有依据《联邦食品、药品与化妆品法案》(21 USC
343(r)(1)(B))第403(r)(1)(B)节获得批准的健康声明。本指南的推荐仅针对植物药。
A.Marketing of Botanical Drugs under OTC Drug Monographs
A.按照非处方药专论的植物药上市销售
Any drug that does not fall within the definition of a prescription drug in section 503(b)(1) of the
FD&C Act is a nonprescription or OTC drug. A botanical drug that has been marketed for a material time and to a material extent for a specific OTC indication may be eligible for consideration in the OTC drug monograph system.5Currently, several botanical drug substances (e.g., psyllium and senna) are included in the OTC drug review, and witch hazel is currently 95 marketed under an OTC drug monograph. To be included in an OTC drug monograph, a 96 botanical drug must generally be recognized as safe and effective based on the standards for safety and effectiveness set forth in 21 CFR 330.10(a)(4).
未落在《联邦食品、药品与化妆品法案》第503(b)(1) 节定义范围内的药品为非处方药品或OTC药品。已在实际时间和实际范围内上市销售、用于具体的非处方适应症的植物药有资格纳入非处方药品专论体系考虑。5目前，一些植物药（例如车前草和番泻叶）纳入非处方药药品审评，金缕梅目前也依照处方药专论上市销售。为纳入非处方药专论，一种植物药必须按照21 CFR 330.10(a)(4)规定的安全性和有效性标准，通常被认为是安全和有效的。
421 CFR 201.128.
3参见21 USC 321(f)(1), (g)(1)(B) and (C), (h)(2) and (3), (i), (ff)。
4参见21 CFR 201.128。
5See 21 CFR Part 330.
5参见21 CFR Part 330。
A request to amend an OTC drug monograph to include a botanical drug substance may be submitted by a citizen petition in accordance with 21 CFR 10.30 and 330.10(a)(12) or a Time and Extent Application (TEA) in accordance with 21 CFR 330.14. 6To be included in an OTC drug monograph, a botanical drug substance must be recognized in an official United States Pharmacopeia and National Formulary (USP-NF) drug monograph that sets forth its standards of identity, strength, quality, and purity.7Therefore, a request for a botanical drug substance to be included in an OTC drug monograph should include a reference to the applicable USP-NF drug monograph. In the absence of such a USP-NF drug monograph, the request should include a proposed standard for inclusion in an article to be recognized in an official USP-NF drug monograph, as described in 21 CFR 330.10(a)(2). Considering the complexity of botanical drugs, there are challenges to this approach. Interested parties (e.g., a botanical drug manufacturer) should contact the Division of Nonprescription Drug Products in CDER’s Office of New Drugs/Office of Drug Evaluation IV for additional information about the OTC drug monograph approach to marketing a botanical drug.
要求修订非处方药品专论纳入一种植物药的请求，可依照21 CFR 10.30和330.10(a)(12)以公民请愿的形式，或依照21 CFR 330.14，以时间和范围申请（Time and Extent Application，TEA）的形式提交。6为纳入非处方药品专论，植物药必须得到规定鉴别、规格、质量和纯度的官方美国药典和国家处方集（USP-NF）药品专论认可。7因此，植物药纳入非处方药专论的请求应包括援引适用的美国药典-国家处方集（USP-NF）药品专论的内容。依据21 CFR
330.10(a)(2)规定，在没有这样的美国药典-国家处方集（USP-NF）药品专论情况下，请求应包括书面形式的拟定纳入标准，以获得官方的美国药典-国家处方集（USP-NF）药品专论认可。考虑到植物药的复杂性，这一方法存在挑战。有意者（例如植物药制造商）应与药品审评与研究中心新药办公室药品评价IV部非处方药品处联系，以获得上市销售植物药的非处方药品专论方法相关信息。
A. Marketing of Botanical Drugs under NDAs
A. 按照新药申请申请的植物药上市销售
Any person who wishes to market a new drug in the United States must submit an NDA and obtain Agency approval prior to marketing the new drug product for the proposed use (see sections 201(p) and 505 of the FD&C Act). FDA may approve a drug product containing such a drug substance for OTC sale pursuant to an application submitted under section 505 of the FD&C Act. Accordingly, an applicant could seek marketing approval for a botanical drug under section 505 of the FD&C Act for
621 CFR 330.14 sets forth criteria and procedures by which OTC drugs initially marketed in the United States after the OTC drug review began and OTC drugs without any U.S. marketing experience can be considered in the OTC drug monograph system. Basic information to be provided in the TEA includes a detailed description of the botanical drug substance, as set forth in 21 CFR 330.14(c)(1)(ii).
7See 21 CFR 330.10(a)(2) and 330.14(i).
6 21 CFR 330.14对非处方药品审评开始之后非处方药品最初在美国上市销售，以及缺乏在美国上市销售体验的非处方药品被考虑纳入非处方药品专论体系的标准和程序做出规定。依照21 CFR 330.14(c)(1)(ii)规定，时间与范围申请（TEA）中提供的基本信息包括植物药的详细说明。
7参见21 CFR 330.10(a)(2)和330.14(i)。
either prescription or OTC use.8
希望在美国销售新药者必须提交新药申请（NDA）并在上市销售新药用于拟定用途前获得FDA批准。FDA可根据依据《联邦药品、食品与化妆品法案》第505节提交申请批准含有这种原料药的药品。因此，申请人可依据《联邦药品、食品与化妆品法案》第505节寻求用于处方药或非处方药用途的植物药上市批准。8
Because of the heterogeneous nature of a botanical drug and possible uncertainty about its active constituents, one of the critical issues for botanical drugs is ensuring that the therapeutic effect for marketing drug product batches is consistent. In general, therapeutic consistency can be supported by a “totality of the evidence” approach, including the following considerations:
由于植物药由不同成分组成的特性及活性成分可能存在不确定性，因此，植物药的关键议题之一，是确保上市销售药品批次的治疗效果一致。一般来讲，疗效一致性可通过”证据汇总“方法支持，包括下列注意事项：
·Botanical raw material control (e.g., agricultural practice and collection).
·植物原药材控制（例如规范化种植与采收）。
·Quality control by chemical test(s) (e.g., analytical tests such as spectroscopic and/or chromatographic methods that capture the active or chemical constituents of a botanical drug substance) and manufacturing control (e.g., process validation).
·采用化学检测的质量控制（例如，诸如获取植物药活性或化学成分的色谱和/或光谱法的分析检验方法）和生产控制（例如工艺验证）。
·Biological assay (e.g., a biological assay that reflects the drug’s known or intended mechanism of action) and clinical data (for details regarding use of clinical data in ensuring therapeutic consistency, see Section VI(F)(1) of this guidance under Study Design of Multiple Batch Analyses and Section
VI(F)(2) of this guidance under Dose-Response Effect).
·生物检定（例如反映药品已知或拟定作用机制的生物检定）和临床数据（临床数据在确保疗效一致方面的运用，详见本指南剂量-响应效应部分多批次分析研究设计和第VI(F)(2)节）。
Section VII of this guidance describes recommendations for submitting NDAs, including instructions for submitting information to support therapeutic consistency for botanical drug products, and discusses post-marketing issues for botanical drug products.
本指南第VII节阐述了针对提交新药申请（NDAs）的建议，包括用于支持植物药品疗效一致性的资料提交说明，并讨论了针对植物药品的上市后议题。
8See section 503(b)(1) of the FD&C Act.
8参见《联邦药品、食品与化妆品法案》第503(b)(1)节。
IV.BOTANICAL DRUG DEVELOPMENT UNDER INDS
IV. 按照研究用新药申请（INDs）的植物药研发
To develop information to support either an NDA or an OTC monograph for a botanical drug, interested parties may need to develop data by, among other things, conducting clinical investigations.
为了编写支持针对植物药的新药申请（NDA）和非处方药专论资料，除其它事项之外，有意者可能需要开展临床研究以开发数据。
Section 505(i) of the FD&C Act and 21 CFR Part 312 require clinical investigations in which a drug is administered to human subjects to be conducted under an IND (unless exempt under § 312.2(b)). To determine whether a proposed study would be exempt from the IND requirements, a sponsor9(or sponsor-investigator of an individual investigator-initiated study) should consult the Guidance for Clinical Investigators, Sponsors, and Institutional Review Boards on Investigational New Drug Applications (INDs)—Determining Whether Human Research Studies Can Be Conducted Without an IND.10If a sponsor is uncertain, we recommend that the sponsor contact the appropriate Office of New Drugs (OND) review division for advice about whether the IND regulations apply.
《联邦药品、食品与化妆品法案》第505(i)节与21 CFR第312部要求依照研究用新药申请（IND）开展人类受试者服用药品的临床研究（除非依据§ 312.2(b)给予豁免）。为决定拟定的研究能否豁免研究用临床新药申请（IND）要求，发起方（或单个研究方发起的研究的发起方-研究方）应参考《临床研究方、发起方9和伦理委员会指南：研究用新药申请（INDs）― 决定是否可以在不开展研究用新药申请（INDs）的情况下开展人体研究》。10如果发起方尚不确定，我们建议发起方垂询合适的新药办公室（OND）审评部门，征询研究用新药申请（IND）法规是否适用的建议。
Pre-IND, end-of-phase 1, end-of-phase 2 and 2A, pre-phase 3, and pre-NDA consultations11are strongly encouraged for the sponsor of a botanical drug to assess the adequacy of existing information for an IND submission or an NDA, obtain advice regarding the need for additional studies, ensure that clinical protocols are properly designed, and allow discussion of the initial or overall development plan. The sponsor should submit all available information to the appropriate OND review division in accordance with the content and format requirements outlined below.
向植物药发起方强烈建议临床前、1期末、2期末和2A、3期前和新药申请前咨询，11 以评价针对研究用新药申请（IND）提交或新药申请的现有资料的充分性，获得需要开展其它研究
9In this guidance, “sponsor” refers to anyone who submits an IND and “applicant” refers to anyone who submits an NDA.
10CDER updates guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance web page at
https://www.doczj.com/doc/62793859.html,/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
9在本指南中，“发起方”指提交研究用新药申请（IND）的任何人，“申请人”指提交新药申请（NDA）的任何人。
10药品审评与研究中心定期更新指南。为保证您有指南的最新版本，请访问下述网址查询相关的FDA药品指南: https://www.doczj.com/doc/62793859.html,/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm。
11See the Guidance for Industry on Formal Meetings Between the FDA and Sponsors or Applicants and the Guidance for Industry on End-of-Phase 2A Meetings.
11参见《行业指南：FDA与发起方或申请人之间的正式会议》，以及《行业指南：2A期末会议》。
的建议，确保临床方案设计正确，并就初步和总体研发计划展开讨论。发起方应向适当的新药办公室(OND)审评部门提交符合下文所列的内容和格式要求的所有现有资料。
The format and content requirements for IND submissions are provided in § 312.23 and discussed in several FDA guidance documents.12In general, an IND must contain sufficient information to demonstrate that the drug is safe for testing in humans and that the clinical protocol(s) is properly designed for its intended objectives. While these general requirements are applicable to botanical drug INDs, botanical drugs have certain unique characteristics that may affect the information necessary to be provided in an IND. Botanical drugs are generally heterogeneous mixtures. As such, their chemical constituents often are not well defined; in some cases, their active constituents are not identified and their biological activities are not well characterized. However, certain botanical drugs may have been used in humans prior to submission, which may provide some indication of their safety. The unique characteristics of such botanical drugs could have significant impact on their development program (e.g., quality control and clinical study design). Sections V and VI below provide recommendations for IND submissions that consider these unique characteristics.
§ 312.23规定了研究用新药申请（IND）提交的格式和内容要求，并在一些FDA指南文件中讨论。12总体上，研究用新药申请应包括足够的资料证明在人体检测药物是安全的和针对拟定目的临床方案设计正确。尽管这些通行要求适用于植物药的研究用新药申请（INDs），但植物药具有某些独特特点，有可能影响研究用新药申请（IND）所需的资料。植物药通常为不同成分组成的混合物。正因为如此，其化学成分通常没有很好地确定；在一些情况下，其活性成分并不确定，生物活性也未明确。然而，在提交申请前，一些植物药一直用于人体，在安全性方面可能提供一些指示。这些植物药的独特特点对其研发计划（例如质量控制和临床研究设计）有重要作用。虑到这些独特的特点，下述第V、VI节提出一些针对研究用新药申请提交的建议。
V.INDS FOR PHASE 1 AND PHASE 2 CLINICAL STUDIES
V.针对1期和2期临床研究的研究用新药申请（INDS）
Under § 312.22(b), the amount of information that must be submitted in an IND for a particular drug depends on several factors, including the extent of prior human experience and past clinical studies, the drug’s known or suspected risks, and the developmental phase of the drug. For example, a botanical dietary supplement marketed under the Dietary Supplement Health and Education Act of 1994 (DSHEA) that has no known safety issues often would require less chemistry, manufacturing, and controls (CMC) or toxicological data to initiate early-phase studies than would a botanical product that is newly discovered, has not been marketed, or has known safety issues. For most botanical drugs, detailed CMC information (e.g., data on comprehensive characterization of the drug substance) may
12Examples of related guidance documents include the Guidance for Industry on Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products and the Guidance for Industry on INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information.
12相关指南文件实例包括《行业指南：涵盖表征清楚、治疗用生物技术产品的用于药品1期研究的研究用新药申请（INDs）内容与格式》，以及《行业指南：用于2期与3期研究的研究用新药申请（INDS）：化学、生产与控制资料》。
not be warranted for early-phase development (Phase 1 and Phase 2 clinical studies); however, gathering of CMC data should be initiated during these phases because such preliminary information should be submitted prior to initiating Phase 3 studies.
依据§ 312.22(b)，针对具体药物的研究用新药申请（INDS）中必须提交的资料数取决于几个因素，包括既往人体体验范围和过去开展的临床研究，已知和疑似的药物风险，以及药物的研发阶段。例如，对于依据《1994年膳食补充剂卫生与教育法案》（DSHEA）上市的没有已知安全问题的植物膳食补充剂，与新发现、未上市和具有已知安全性问题者相比，启动早期研究要求较少的化学、制造与控制(CMC)或毒理学数据。对于绝大多数植物药，对于早期研发（阶段1、阶段2临床研究），不一定能保证要求有详细的化学、制造与控制资料（例如，原料药的全面特征鉴定数据）；然而，应在这些阶段期间启动化学、制造与控制(CMC)数据收集，原因在于应在启动3期研究之前提交这些初步资料。
Every botanical drug has unique considerations, and the Agency encourages a sponsor to seek input from the appropriate OND review division before formally submitting an IND. We recommend that the clinical development of a botanical drug take a stepwise approach so that raw material control considerations, analytical characterization data, and early-phase study results can assist in the design of late-phase studies. However, botanical drug substances used in various stages of development may differ in some characteristics (e.g., chemical composition), as there could be possible changes in agricultural practice and collection for botanical raw material(s) and/or manufacturing process conditions as a result of process optimization. Therefore, bridging studies may be needed to justify these differences. The sponsor should request input from the appropriate OND review division so the review division can evaluate any changes in the botanical drug substance during development and provide guidance (e.g., on the type of bridging studies that may be needed).
每一个植物药都有独特的考虑，在正式提交研究用新药申请之前，FDA鼓励发起方从适当的新药办公室（OND）审评部门征求意见。我们建议，植物药的临床研发采取步进方法，以便在晚期研究设计中，原药材控制考虑要点、分析表征数据和早期研究结果能够提供帮助。然而，由于在规范化种植和植物原药材采收、和/或由于工艺优化导致制造工艺条件可能出现变化，不同研发阶段所采用的植物药原料药，一些特点可能有异（例如化学组成）。因此，可能需要桥接多项研究，证明这些差异是合理的。发起方应向适当的新药办公室(OND)审评部门征询意见，以便审评部门能在研发阶段评价植物原料药的所有变更并提出指导（例如，可能需要的桥接研究类型）。
To comply with the requirements outlined in 21 CFR 312.23, the sponsor should specifically address the following issues unique to botanical drugs in the IND submission. We recognize that some aspects of the following quality control strategy may not be completed until Phase 3 studies; nonetheless, all available information should be provided:
为符合21 CFR 312.23概述的要求，发起方应在研究用新药（IND）申请提交中具体解决下述议题。我们认识到，直到3期研究时，下述质量控制策略中的一些方面可能尚未完成；尽管如此，应提交所有可用的信息：
A.Description of Product and Documentation of Prior Human Experience
A.产品说明和既往人体体验文件记录
1.Description of Botanical Raw Materials Used and Known Active Constituents or Chemical
Constituents (§ 312.23(a)(3)(i))
1.使用的植物原药材和已知活性成分或化学成分说明
? Provide the following general information for each of the botanical raw materials used as the source of the botanical drug substance in a botanical drug product:
? 对于用作植物药品中的植物原料药的每一种植物原药材，提供下列基本资料：
? Scientific name of the plant species according to international binomial nomenclature convention, including the genus name, the specific epithet, and the name of the botanist who described the species. 根据国际双名法的植物物种学名，包括属名、种名和描述、命名该物种的学者名。
? Synonyms, especially those used in recent publications of scientific studies related to the species. ? 同物异名，尤其是近期与物种有关的科学研究出版物。
? Subspecific rank (subspecies, variety, and form) and cultivars, if applicable.
? 如果适用，亚种级别（亚种、变种和变型）及栽培种
? Family name.
? 科名
? Botanical parts used (e.g., aerial parts, roots, rhizomes, flowers, and/or leaves) as the botanical raw material(s).
? 用作植物原药材的植物部位（例如地上部分、根、根茎、花和/或叶）
? Common or usual names of the plant, alga, or macroscopic fungus in English and other languages (e.g., Chinese or Spanish), especially the languages of the region in which the species and the raw materials have medicinal or other significance.
? 植物、藻类或大型真菌常用英文或其它语言常用或通用名（例如，中文或西班牙文），尤其是物种或原药材具有药用或其它重要意义的地区的语言。
? Active constituents identified as individual compounds or chemical classes, if known. If active constituents are not known, chemical constituents that have been identified (e.g., those can be used as a characteristic profile for identification and quality control purposes).
? 已知情况下，鉴定为单个化合物或化学类别的活性成分。如果活性成分未知，已经鉴定的化学成分（例如可以用作鉴定和质量控制用途的特征谱）。
2. Prior Human Experience (§§ 312.23(a)(3)(ii),(a)(9))
2.既往人体体验(§§ 312.23(a)(3)(ii),(a)(9) )
Under § 312.23(a)(9), a sponsor must submit information about prior human experience with the investigational drug, if available. Many botanical drugs have been previously marketed or tested in clinical studies. Where clinical studies have been conducted, the study reports should be submitted in the IND with a critical review of the data quality and the data’s relevance to the proposed use. The botanical drug’s marketing history also should be described. In particular, it should include documentation of the annual sales volume, an estimate of the size of the exposure population, and rates of adverse effects, as well as provide references to compendia and publications (e.g., books of medical practice in Ayurveda, traditional Chinese medicine, Unani, Sidha, and other herbal medicine and pharmacognosy textbooks). For botanical drugs only available in foreign markets, the information’s reliability and relevance to the proposed clinical study should be justified. A sponsor planning to support its IND with a well-designed and well-conducted foreign clinical study or studies not conducted under an IND should refer to § 312.120 259 and related FDA guidance documents.13Any literature that is submitted should be provided in English (and in its original language, if other than English).14
依据§ 312.23(a)(9)，如果可用，发起方必须提交研究用药物的既往人体体验资料。很多植物药之前已经上市销售或已在临床研究中检验。在已经开展临床研究的情况下，应在研究用药物申请中提交研究报告，仔细审查数据质量以及数据与拟定用途的相关性。应说明植物药的上市历史。尤其是，应包括年销售量纪录、暴露人群规模估计、不良作用级别，并提供对药典和出版物的引用（例如，阿育吠陀（Ayuverda）、中药、尤纳尼（Unani）、悉达（Sidha）医学实践书籍。以及其它草药和生药学教科书）。对仅在美国以外市场上市销售的植物药，应说明资料可靠性和与拟开展临床研究的相关性是科学合理的。计划采用在国外开展的设计周到和严格实施的临床研究或是没有按照研究用药物申请开展的研究支持研究用药物申请（IND）的发起方，应参照§ 312.120 259 和相关的FDA指南文件。13提交的所有文献应以英文提交（如果不是英文，以最初发表所采用的语言形式）。14
In addition to a thorough review of the past human experience with the botanical drug, the sponsor should also present information to bridge the past experience with the current proposed investigation. 除了对既往使用相关植物药的人体体验的全面审查之外，发起方还应提交桥接既往体验与目前提出的研究的资料。This information may include a: 该资料应包括a:
? Description of the amount of raw material or traditional preparation that is equivalent to the dose
13Examples of related guidance documents include the Guidance for Industry and FDA Staff on FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND: Frequently Asked Questions and the Guidance for Industry on E5 – Ethnic Factors in the Acceptability of Foreign Clinical Data: Questions and Answers.
14See § 312.23(c).
13相关指南文件的实例包括《行业指南与FDA员工指南：FDA受理未按照研究用药物（IND）申请开展的国外临床研究》，以及《行业指南：E5—国外临床数据可接受性的族群因素问答》。
14参见§ 312.23(c)。
proposed in the IND study,
? 等同于研究用药物（IND）研究中拟采用剂量的原药材或传统制剂量的说明，
? Comparison of the identity of the investigational botanical drug with traditional preparations described in the literature, and/or
? 研究用植物药与文献中说明的传统制剂的鉴别比较，和/或
? Comparison of the clinical settings in which the drugs have been used with the setting(s) in which they are proposed to be used.
? 药品使用的临床情况与拟使用的情况的比较。
The Agency will determine the relevance of prior human experience with traditional preparations to the assessment of botanical drugs’ safety in clinical studies proposed under INDs on a case-by-case basis.
FDA将根据具体情况确定既往人体体验与传统制剂与拟采用的按照研究用新药申请（IND）的临床研究中的植物药安全性评价的相关性。
B. Chemistry, Manufacturing, and Controls
B.化学、制造和控制
The amount of CMC information to support clinical studies conducted under an IND depends on a number of factors, including the botanical drug’s marketing history and the phase of development. The use of botanical drugs in foreign markets may provide useful human experience; however, the relevance of such experience to determining the amount of CMC information needed for early-phase clinical studies depends on the integrity of the control measures and the quality of the foreign manufactured botanical drug. Provided below is an overview of the CMC information that is recommended to support early-phase clinical studies for a botanical drug. More detailed CMC information will be warranted to proceed into late-phase clinical studies (see Section VI).
用于支持按照临床用药物申请（IND）开展的临床研究的化学、制造和控制（CMC）资料量取决于多个因素，包括植物药的上市历史和研发阶段。国外市场的植物药应用可提供有用的人体体验；然而，这种体验与决定用于早期临床研究所需的化学、制造和控制的资料量取决于控制措施的完整性和国外制造的植物药的质量。以下提供建议用于支持植物药早期临床研究的化学、制造和控制（CMC）资料概览。进入晚期临床研究将需要更为详细的化学、制造和控制（CMC）资料保证（参见第VI节）。
1. Botanical Raw Materials (§ 31
2.23(a)(7)(i))
1. 植物原药材(§ 31
2.23(a)(7)(i))
A botanical drug substance can be derived from one or more botanical raw materials of the same or different plant species. The following recommendations apply to each individual botanical raw material