Contains Nonbinding Recommendations
Draft — Not for Implementation 包含不具约束力的建议 草案 — 不用于实施
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. 6 To 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.7 Therefore, 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
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21 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). 7 See 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)。
北京大学药物信息与工程研究中心?comments@cpier.pku.edu.cn?
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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。
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See section 503(b)(1) of the FD&C Act.
参见《联邦药品、食品与化妆品法案》第503(b)(1)节。
北京大学药物信息与工程研究中心?comments@cpier.pku.edu.cn?
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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.10 If 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 consultations11 are 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
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In this guidance, “sponsor” refers to anyone who submits an IND and “applicant” refers to anyone who submits an NDA.
10 CDER updates guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance web page at
www.fda.gov/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: www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm。
11 See 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》。
北京大学药物信息与工程研究中心?comments@cpier.pku.edu.cn?
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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.12 In 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. V.
INDS?FOR?PHASE?1?AND?PHASE?2?CLINICAL?STUDIES?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
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Examples 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》。
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