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对所宣称的疗效的影响，来自于动物疾病模型的非临床数据或体外测定药理学数据将是有用的。

VII.?NDAS?FOR?BOTANICAL?DRUG?PRODUCTS?VII．植物药品新药申请?

The pre-NDA meeting is of particular importance for botanical drug products, given their unique characteristics and considerations. The pre-NDA meeting should be held sufficiently in advance of (e.g., more than 2 months before) the planned NDA submission to allow the applicant enough time to meaningfully respond to the Agency’s feedback. In accordance with the Prescription Drug User Fee Act (PDUFA V) performance goals,35 the Agency and applicant will agree on the content of a complete application for the proposed indication(s) at the pre-NDA meeting. Agreements and discussions will be summarized at the conclusion of the meeting and reflected in the Agency’s meeting minutes.

考虑到植物药品的特性和注意事项，对于植物药品，新药申请前会议（the pre-NDA meeting）尤为重要。新药申请前会议应在计划的新药申请提交前足够提前（例如，提前超过2个月），使得申请人由足够时间对FDA的反馈做出回复。为符合处方药生产商付费法案（the Prescription Drug User Fee Act，PDUFA V）所规定的绩效目标，35FDA和申请人应在新药申请前会议上就针对提出的适应症的完整申请达成一致。会议结束时总结达成一致和讨论内容，并以FDA会议纪要形式反映。

Submission requirements for an NDA for a botanical drug product are generally no different from those for other drug products. For instructions and advice on submitting NDAs (applicable to all drug products), the applicant should refer to existing Agency regulations and FDA guidances. The applicant should submit an NDA for a botanical drug product in the Electronic Common Technical Document (eCTD) format. 36 Issues specific to NDAs for botanical drug products are discussed in this section. Refer to previous sections of this guidance for details on data to be acquired and the studies to be conducted to collect such data during the IND process.

针对植物药品的新药申请提交要求与针对其它药品的要求总体上并无差别。提交新药申请（适用于所有药品）的说明和建议，申请人应参考现行FDA法规和FDA指南。申请人应以电子版通用技术文件（eCTD）36形式提交新药申请。本节讨论植物药新药申请的具体议题。所要求的数据细节和在研究用新药申请（IND）过程中开展研究收集这些数据的细节，可参考本指南前述节。

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35 See PDUFA Reauthorization Performance Goals and Procedures for Fiscal Years 2013 through 2017 at

http://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm270412.pdf. 35

参见2013-2017财年处方药生产商付费法案（PDUFA）重新授权绩效目标和规程，网址：http://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm270412.pdf。

36 For information about a Common Technical Document (CTD), see the Guidance for Industry on M4:

Organization of the CTD. For information about an Electronic Common Technical Document, see the FDA web page eCTD Basics and Getting Started.

36 For information about a Common Technical Document (CTD), see the Guidance for Industry on M4:

Organization of the CTD. For information about an Electronic Common Technical Document, see the FDA web page eCTD Basics and Getting Started. 通用技术文件（CTD）相关信息，参见《行业指南M4: 通用技术文件（CTD）指南》。电子版通用技术文件（eCTD）相关信息，参见FDA网页：电子版通用技术文件（eCTD）基础及入门（eCTD Basics and Getting Started）。

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A. Description?of?Product?and?Documentation?of?Prior?Human?Experience??A. 产品说明及既往人体体验证明?

All information provided in the IND should be submitted in the NDA. Refer to Sections V.A.1 and 2. If more recent human experience exists for the botanical drug (e.g., based on a similar drug product marketed in foreign countries), an updated summary also should be provided in the NDA.

研究用新药申请（IND）中提供的信息均应在新药申请中提交。参见第V.A.1和2节。如果植物药具有其它的近期人体体验（例如，居于在美国以外的国家上市销售的类似药品），还应在新药申请中提交经过更新的综述。

B.?Quality?Control??B.质量控制?

Because the drug substance’s active constituents may not be unequivocally identified, the technical challenges for quality control are to determine a botanical drug’s identity and ensure its consistency of strength. A botanical drug product’s quality control should consider a totality-of-the-evidence approach as outlined in Sections III.B and VII.F. It should extend to the raw material(s) and may require additional measures such as

biological assays and/or information on the effect of variations on clinical outcomes from a multiple batch clinical study.

由于原料药多种活性成分可能未明确鉴定，质量控制的质量挑战在于确定药物的鉴别特征并确保其规格一致。植物药品的质量控制应考虑第III.B和VII.F节概述的证据汇总方法。植物药品质量控制应延伸至原药材，并可能要求诸如生物检定和/或来自于多批次临床研究的变异对临床结果的影响的资料。

1. Botanical?Raw?Material?

1. 植物原药材?

A botanical drug product’s quality control should start with the raw material(s) and should be described in the NDA. Specific information on medicinal plants (e.g., verification of authenticity with morphology, macroscopic and microscopic analysis, and chemical analysis), agricultural practices (e.g., growing, harvesting, and storage conditions), geographic locations, and collection and processing methods should be identified. The applicant should establish GACP and summarize the related procedures for each of the botanical raw materials when submitting an NDA. The general GACP principles established by the World Health Organization (WHO), European Medicines Agency

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(EMA), or the regulatory body of the botanical raw material growing region should be referenced. DNA fingerprinting may be warranted in cases of complicated taxonomy and when identification issues related to the botanical raw material exist. For example, if multiple related plant species have been used to produce a particular botanical raw material, the DNA fingerprint may provide more plant-specific characteristics for identification than would other methods. In addition, the applicant should describe approaches used to minimize contamination, deterioration, and variations. The same methods should be used to collect and process the raw material(s) for manufacturing the botanical drug substance tested during early-phase clinical studies and the drug substance tested during late-phase clinical studies. Making changes to these collection and

processing methods during clinical development could change the chemical profile of the drug substance in the resulting botanical drug product and may warrant bridging studies to justify reliance of previous clinical testing results. Also see Sections V.A.1 and B.1.

植物药品质量控制应该始于原药材并应在新药申请中加以说明。应确定药用植物的具体资料（例如通过形态学、外观与显微分析、以及化学分析的真品验证），种植规范（例如种植、采收和贮存条件），地理位置，采集与加工方法。申请人应制定良好种植与采收规范（GACP），并在提交新药申请时概述每种植物原药材的响应规程。应引用世界卫生组织（WHO）、欧洲药品管理局（EMA）或植物原药材种植地区的监管机构制定的通行的良好种植与采收规范（GACP）原则。在存在分类复杂和植物原药材相关的鉴别问题的情况下，可能需要DNA指纹法提供保证。例如，如果使用多种相关的植物物种制成一种特殊的植物原药材，对于鉴别，DNA指纹可能比其它方法提供更多的植物专属特征。此外，申请人应说明所采用的最长程度减少污染、变质和变异的方法。早期研发研究中检测的原料药所采用的原药材采集、加工方法，与用于晚期研发研究中检测的原料药的相关方法应采用同样的方法。在临床研发期间对这些采集和加工方法做出变更会改变相应的植物药品中的原料药的化学特征谱，可能需要桥接研究保证证明之前的临床检验结果的可靠性是合理的。同时参见第V.A.1和B.1.节。

2.?Botanical?Drug?Substance?and?Drug?Product?

2.植物原料药和药品?

a. Identity a. 鉴别

Because of inherent difficulties in characterizing all chemical constituents in botanical drugs, establishing their identity relies not only on chemical characterization of molecules in the mixture, but also on other aspects, including control of the raw material(s) at the medicinal plant level, characterization of relative potency and activity by a biological assay, and/or clinically relevant specifications based on results of the multiple-batch clinical studies. Nevertheless, the applicant should evaluate the current and emerging technologies and develop orthogonal analytical methods to provide adequate identification and quantification of the active or chemical constituents in a botanical drug.

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When the active constituents are not known and the botanical mixture cannot be fully characterized, the applicant may then select a characteristic profile of chemical constituents (which shows sensitivity to changes in the quality of the raw material(s) and/or manufacturing conditions for drug substance and product) for identity testing.

由于表征植物药中所有化学成分的固有困难，建立其鉴别特性不仅有赖于对混合物中多种分子的化学表征，还有赖于其它方面，包括在药用植物水平上的原药材控制，通过生物检定方法表征相对含量和活性，和/或基于多批次临床研究结果的临床相关质量标准。此外，申请人应评价当前和新兴技术，并开发正交分析方法对植物药中的活性或化学成分做成分鉴定和定量检测。在活性成分未知以及植物混合物不能完全表征的情况下，申请人可选择用于鉴定检验的化学组分特征谱（显示对原药材质量和/或原料药及药品制造条件变化的灵敏性）。

b. Chemical Characterization b.化学表征

The multiple analytical methodologies used for chemical characterization of the botanical drug should be fully described in the NDA. The NDA should include all chemical tests performed to qualitatively and quantitatively characterize active or chemical constituents, as well as provide data to address mass balance.

新药申请（NDA）中，应对用于化学表征的多种分析方法做充分阐述。新药申请应包括定性、定量表征活性或化学成分的所有化学检验，同时提供表明解决质量平衡的数据。

c. Manufacturing Processes c. 制造工艺

The applicant should provide information about all of the sites that will be used to manufacture the drug substance and drug product for commercial distribution. These should be the same manufacturing sites that produced the drug substance and drug product used in Phase 3 clinical studies, to provide consistency. Changes in manufacturing sites should be avoided, especially during late-phase clinical development. The NDA should include full manufacturing information, including manufacturing equipment used, in-process controls, and testing.

申请人应提供所有将用于制造用于商业销售的原料药与药品工厂的资料。这些（工厂）应该是与生产用于3期临床研究的原料药和药品同样的制造厂，以提供一致性。应避免制造工厂变更，尤其在晚期临床研发期间。新药申请应包括完整的制造资料，包括所使用的制造设备、中间过程控制和检验。

The drug substance and drug product manufacturing processes should be finalized, and in-process controls and testing should be established.

原料药和药品制造工艺应该是最终定下来的，并应建立中间过程控制和检测。

d. Biological Assay d．生物检定

In cases where chemical testing alone may not be sufficient to ensure quality and thus therapeutic consistency, the applicant should include a biological assay in the release specifications and stability

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