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provided or referenced in the IND, the sponsor should provide a comparison of the investigational botanical drug product to be used in the IND and the botanical drug product(s) used in the referenced studies (e.g., chemical identification and quantification of active or chemical constituents in the drug substance, drug product composition and formulation). Likewise, when the source and manufacturing process of the botanical raw material, drug substance, or drug product are changed during development, the sponsor should provide a comparison of the previous and new sources and manufacturing processes, because seemingly minor changes in the source and/or process may result in a meaningful difference in the clinical effects and raise the question about the applicability of earlier pharmacological, nonclinical, and clinical data.

如果在研究用新药申请（IND）中提供或引用了之前可用的非临床和/或临床数据，发起方应提供在研究用新药申请（IND）所使用的研究用植物药品和所引用的研究中所采用的植物药品（例如，原料药活性成分或化学成分的化学鉴定和定量检测，药品组成和处方）的比较。同样地，在研发期间，当植物原药材、原料药或药品的供货来源和制造工艺发生变更时，发起方应提供之前和新来源及制造工艺的比较，原因在于供货来源和/或工艺上看似微小的变更可能导致临床效果上有意义的变化，并提出之前的药理学、非临床和临床数据适用性的问题。

If there is uncertainty about whether different batches of the drug substance are similar, bridging studies (e.g., chemical identification and quantification of active or chemical constituents in the drug substance, biological assay, and/or other nonclinical studies) may be warranted to demonstrate that the drug substances used in various stages of development are sufficiently similar to justify reliance on previous nonclinical and clinical testing results. Sufficient quantities of the botanical raw material and drug substance from the different batches should be retained for future chemical characterization and/or pharmacological/toxicological testing.

如果对不同批次原料药是否相似存在不确定性，桥接研究（例如，原料药活性或化学成分的化学鉴别，生物检定，和/或其它非临床研究）可提供保证证明在不同研发中所使用的原料药充分相似，说明之前的非临床和临床检验结果可靠性是合理的。应保存足够量的来自于不同批次的植物原药材与原料药，用于将来的化学表征和/或药理学/毒理学检验。

The sponsor should also refer to Section VI.G below regarding the applicability of the fixed-dose combination rule to the investigational botanical drug.

涉及研究用植物药固定剂量复方药品适用性，发起方还应参考下文第VI节。

Phase 3 studies should provide pivotal support for an NDA submission. Thus, it is important that the sponsor reviews Section VI of this guidance regarding the information recommended for botanical-specific contents in an NDA submission to ensure that the necessary information will be collected with appropriate technologies and well-designed studies during this phase.

3期研究应为新药申请（NDA）提交提供关键性支持。因此，发起方仔细阅读本指南第VI节涉及就新药申请提交中植物药特定内容所建议的信息，对于确保在该期使用适用技术和设计周到的研究收集所需资料，是非常重要的。

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B.?Description?of?Product?and?Documentation?of?Prior?Human?Experience?B.?产品说明和既往人体体验文件记录?

This information should have been submitted to the IND in support of Phase 1 and Phase 2 clinical studies in accordance with § 312.23. See Section V.A of this guidance for details.

依据§ 312.23，该资料应提交至研究用新药申请（IND）以支持1期和2期临床研究。详见本指南第V.A节。

C.?Chemistry,?Manufacturing,?and?Controls?C.化学、制造和控制?

To support Phase 3 clinical studies of a botanical drug product, the sponsor should provide information under the same categories outlined in Section V.B in accordance with § 312.23; however, more detailed information should be provided to support these studies, as described below.

为支持植物药品的3期临床研究，依据§ 312.23，发起方应提供V.B节中所概述的类别的资料；然而，应提供更为详尽的信息支持这些研究，如下所述。

1. Botanical?Raw?Material??

1. 植物原药材?

To ensure quality and therapeutic consistency, it is important to select representative raw material batches (i.e., raw material from three or more representative cultivation sites or farms) for the manufacturing of the clinical drug substance for multiple batch Phase 3 studies. The sponsor should establish large growing regions with three or more cultivation sites or farms whose locations are purposefully selected to be representative of the regions for each of the botanical raw materials following the principles of Good Agricultural and Collection Practices (GACP).19 This will help reduce the likelihood of an insufficient supply of the botanical raw material post-NDA approval.

为确保质量与疗效一致，对于用于3期研究的临床原料药制造，选择具有代表性的原药材批次（即3个或更多的具有代表性的种植场地或农场）是非常重要的。发起方应建立具有3个或

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19

See the World Health Organization’s “WHO guidelines on good agricultural and collection practices (GACP)

for medicinal plants” at http://whqlibdoc.who.int/publications/2003/9241546271.pdf and the European Medicines Agency’s “Guideline on Good Agricultural and Collection Practice (GACP) for Starting Materials of Herbal Origin” at

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003362.pdf.

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更多有目的选择的种植场地或农场的大型种植区域，作为每个符合良好种植和采收规范（Good Agricultural and Collection Practices，GACP）原则的植物原药材产地的代表。19 这将有助于减少新药申请批准后植物原药材供应不足的可能性。

The sponsor should provide information on additional work performed to characterize the botanical raw material(s) (e.g., chemical identification of each botanical raw material by a spectroscopic or chromatographic method, and authentication of each botanical raw material by a DNA fingerprinting method as necessary), updates on the quality control tests and analytical procedures applied by the botanical raw material supplier, and the proposed acceptance criteria, with the goal of working toward final development in preparation for an NDA submission.

发起方应提供所开展的表征植物原药材的其它工作的资料（例如，通过分光光度或色谱法对每一种植物原药材的鉴别，如果需要，通过DNA指纹法确认每种植物原药材），质量控制检验及植物原药材供应商所采用的分析规程更新，提出的可接受标准，目标是致力于为新药申请提交做准备的最终研发。

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

2．植物药原料药与药品?

For the drug substance and drug product, the sponsor should provide updates (as necessary) on additional work conducted to improve characterization of the botanical drug and its active constituents. The sponsor should establish specifications (with interim acceptance criteria) that can be finalized during the NDA review based on the results of Phase 3 clinical studies. In addition, pharmaceutical development of the drug substance and drug product should be well advanced so that no significant changes of the botanical raw material(s) and manufacturing processes will be needed during Phase 3 clinical studies to support the marketing application. For example, a robust manufacturing process for the drug substance and drug product should be established and demonstrated to ensure that the clinical study materials and the to-be-marketed materials are consistent, so bridging studies may not be necessary to support the marketing application (see Section V).

对于原料药与药品，发起方应提供为提高植物药及其活性成分表征所开展的额外工作更新（如果必要）。发起方应建立能够在新药申请审评期间依据3期临床研究结果最终决定的质量标准（带有临时性的可接受标准）。此外，原料药和药品的制药研发应具有很好的前瞻性，因此在3期临床研究中，将不需要植物原药材和制造工艺的重大变更支持上市申请。例如，应建立针对原料药与药品的可靠稳定的制造工艺，并证明能够确保临床研究材料和将要上市的材料是一致的，因此勿需桥接研究支持上市申请（参见第V节）。

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参见世界卫生组织《WHO药用植物良好种植和采集规范（GACP）指南》，网址：

http://whqlibdoc.who.int/publications/2003/9241546271.pdf，以及欧洲药品管理局《草药来源起始物料良好种植和采集规范（GACP）指南》，网址

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003362.pdf。

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D.?Nonclinical?Safety?Assessment?D．非临床安全性评价?

Toxicity data from standard toxicology studies in animals should generally be provided to support late-phase clinical studies.20 A botanical drug product in Phase 3 clinical studies will generally be assessed with the same overall nonclinical review standards as any other new drug under development in accordance with § 312.23(a)(8).

通常应提交来自于在动物中开展的标准毒理学研究的毒性数据支持晚期临床研究。20 3期临床研究中的植物药品一般将以与其它处于符合§ 312.23(a)(8)的研发中的新药一样的非临床审评标准评价。

Certain changes in formulation could affect whether previously performed pharmacology or toxicology studies are applicable to the new formulation, and in some cases may warrant the submission of nonclinical bridging studies. The sponsor should discuss all proposed formulation changes with the appropriate OND review division to determine whether the changes would warrant bridging or other types of studies.

处方上的某些变更可对之前开展的药理学或毒理学研究是否适用于新处方造成影响，在一些情况下，可能需要提交非临床桥接研究加以保证。发起方应与恰当的新药办公室（OND）审评部门讨论所有提出的处方变更，决定是否需要桥接或其它类型的研究保证变更。

The sponsor should consider the following points when preparing a nonclinical

pharmacology/toxicology development plan for a botanical drug product that is intended to be used in Phase 3 clinical studies. If questions arise during any stage of botanical drug product development, the sponsor is encouraged to consult the appropriate OND review division.

在编制拟用于3期临床研究的植物药品非临床药理学/毒理学研发计划时，发起方应考虑下列要点。如果植物药研发的任何阶段出现问题，鼓励发起方向恰当的新药办公室（OND）审评部门咨询。

1. General?Pharmacology/Toxicology?

1. 全身药理学/毒理学?

In general, for late-phase clinical studies, the recommendations for general pharmacology/toxicology

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See the ICH joint safety and efficacy guidances at

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065006.htm and the ICH safety guidances at

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065007.htm. 20 参见ICH安全性与有效性联合指南，网址：

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065006.htm,以及ICH安全性指南，网址：

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065007.htm。

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