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assessment of botanical drugs are no different from those for nonbotanical drugs.21 Doses used in toxicology studies should follow the principles in ICH 724 M3(R2).
总体上，对于晚期临床研究，植物药的全身药理学/毒理学评价与用于非植物药的相应评价并无差异。21 用于毒理学研究的剂量应符合ICH 724 M3(R2)中的原则。
The sponsor should reach agreement with the appropriate OND review division about the methods it plans to use for arriving at acceptable dose levels in safety pharmacology (see ICH S7A and S7B) 22 and toxicology studies. In principle, the highest dose used in toxicology studies should produce some measurable toxicity. This toxicity information can be used to inform safety monitoring during human studies.
发起方应与恰当的新药办公室审评部门就计划采用达到安全药理学（参见ICH S7A和S7B）
22
和毒理学研究中可接受剂量水平的方法达成一致。原则上，毒理学研究中采用的最高剂量应
产生某种程度上可测量的毒性。这一毒理学资料可用于为人体研究中的安全性监测提供信息。
2.?Nonclinical?Pharmacokinetic/Toxicokinetic?Studies?
2.非临床药代动力学/毒代动力学研究?
Because a botanical drug product usually consists of more than one chemical constituent, it may be technically challenging to use standard pharmacokinetic measurements to substantiate the systemic exposure of a botanical drug in animals. Monitoring representative chemical constituent(s) in a botanical drug product using a sensitive analytical method can provide information regarding systemic exposure. If feasible, chemical constituents of a drug product that contribute to toxicity or pharmacology should be assessed in the pharmacokinetic/toxicokinetic studies. The sponsor should also attempt to determine the metabolic fates of these chemical constituents.
Pharmacokinetic/toxicokinetic information collected during the toxicity studies may help the sponsor to interpret the studies’ outcomes.23
由于植物药品通常含有一个以上的化学成分，使用标准的药代动力学测量方法在动物中证实全身接触量可能在技术上本身就是一个挑战。采用灵敏的分析方法监测植物药品中具有代表性的化学成分可提供全身接触量相关的信息。如果可行，应在药代动力学/毒代动力学研究中评价对毒性或药理学造成影响的药品化学成分。发起方还应努力确定这些化学成分的代谢结果。在这些毒性研究中收集的药代动力学/毒代动力学资料有助于发起方解析研究结果。23
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21 See ICH M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals.
21 参见ICH M3(R2)《用于人体临床试验开展和药品上市批准的非临床安全性研究》。 22 See ICH S7A Safety Pharmacology Studies for Human Pharmaceuticals and S7B Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals.
22参见《ICH S7A人用药品安全药理学研究》及《ICH S7B人用药品造成的心室复极推迟（QT间期延长）可能性的非临床评估》。
23 See ICH S3A Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies and S3B
Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies.
23 参见《ICH S3A毒代动力学：毒性研究中的全身接触量》及《ICH S3B:药代动力学：重复剂量组织分布研究指南》。
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3.?Reproductive?Toxicology??
3.?生殖毒性?
For most botanical drug products, prior human experience may be a less reliable indicator of reproductive safety than are specialized animal toxicology studies. In the absence of documented reproductive safety data in humans or animals, reproductive toxicology studies are normally conducted per recommendations provided in ICH guidelines (same as for nonbotanical drugs). 24
对于绝大部分的植物药品，在生殖安全性方面，与专门的动物毒性研究相比，既往人体体验可能是一个可靠性较小的指标。在缺乏经过证明的人体及动物安全性数据情况下，生殖毒性研究通常依照ICH指南（与用于非植物药的相同）中提出的建议开展。24
4.?Genotoxicity?Studies??
4.?遗传毒性研究?
A complete assessment of genetic toxicity may be warranted prior to Phase 3 clinical studies if these assessments have not been conducted earlier. See ICH S2(R1) for the definition of a standard battery of genotoxicity tests. 25 Interpretation of the results of this standard battery of tests and the determination of the need for additional tests should be no different for botanical and nonbotanical drugs. 26
如果之前没有开展评价，应在3期临床研究前开展全面的遗传毒性评价以提供保证。遗传毒性标准组合的规定，请参见ICH S2(R1)。25对于植物药和非植物药，该标准组合检验结果解析以及需要开展额外检验的必要性的确定并无区别。26
5.?Carcinogenicity?Studies??
5.致癌性研究?
Carcinogenicity studies are typically submitted with an NDA. To meet this goal, dose range finding studies and the carcinogenicity studies should generally be conducted during the IND phase. The indication and duration of the intended use of the botanical drug product will influence the need for
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24 See ICH S5A Detection of Toxicity to Reproduction for Medicinal Products, S5B Detection of Toxicity to
Reproduction for Medicinal Products: Addendum on Toxicity to Male Fertility, and ICH M3(R2), supra note 21. 24参见《ICH S5A 药品生殖毒性检测》，《ICH S5B 药品生殖毒性检测：雄性生育力附录》，及ICH M3(R2)，见上文注释21。
25 See ICH S2(R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use. 26 See § 312.23(a)(8)(ii)(a).
25 参见《ICH S2(R1) 拟用于人体使用的药物的生殖毒性检测与数据解读》。 26 参见§ 312.23(a)(8)(ii)(a)。
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carcinogenicity studies and their timing relative to clinical development. 27 Protocols for carcinogenicity studies should be submitted to the Agency for review under Special Protocol
Assessment28 and for concurrence prior to the initiation of such studies to ensure that the dose selection and study design are acceptable. In particular, these protocols should identify the rationale for selecting the high dose for the carcinogenicity study. 29
致癌性研究通常随新药申请（NDA）提交。为达到这一目标，通常应在研究用新药申请（IND）阶段开展致癌性研究。植物药品拟定使用的适应症和持续时间将影响开展致癌性研究的需求及与临床研发相关的时机。27应向FDA提交致癌性研究方案，依照《特别方案评价》（Special Protocol Assessment）28 审查，在该研究启动前取得同意，以确保剂量选择和研究设计可以接受。特别是，这些方案应确定用于致癌性研究的高剂量选择的合理性。29
6.?Other?Toxicity?Studies??
6.其它毒性研究?
In general, recommendations for special pharmacological/toxicological studies (e.g., studies that are used to identify potential biomarkers or provide mechanistic
understanding) for botanical drugs are not different from those for nonbotanical drugs. 30
一般来讲，对于植物药，针对具体药理学/毒理学研究的建议（例如，用于确定潜在的生物标志物或提供机制了解）与非植物药没有差别。30
7.?Regulatory?Considerations??
7.?监管考虑要点?
Nonclinical pharmacological and toxicological studies that the sponsor conducts as part of botanical drug development and to support safety should generally be performed in accordance with regulations governing good laboratory practices under 21 CFR Part 58. Both the botanical drug substance and drug product should be manufactured to achieve adequate batch-to-batch consistency as outlined in this guidance’s CMC sections. If changes occur in the botanical drug substance or botanical drug product during clinical development, nonclinical bridging studies may be needed to comply with 21 CFR 312.23(a)(8)(ii)(a).
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27 See Environmental Assessment Guidance, supra note 18. Also, see ICH S1A The Need for Long-Term Rodent
Carcinogenicity Studies of Pharmaceuticals and S1B Testing for Carcinogenicity in Pharmaceuticals. 28 See the Guidance for Industry on Special Protocol Assessment.
29 See ICH S1C(R2) Dose Selection for Carcinogenicity Studies of Pharmaceuticals.
27参见环境评价指南，见上文注释18。同时参见《ICH S1A 药品开展长期啮齿类毒性研究的需要》和《ICH S1B 药品致癌性检验》。
28参见《行业指南：特别方案评价》。
29参见《ICH S1C(R2) 药品致癌性研究的剂量选择》。 30 See Environmental Assessment Guidance, supra note 18. 30 参见环境评价指南，见上文注释18。
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依照21 CFR Part 58，发起方开展的作为植物药研发一部分和支持安全性的研究一般应符合药物非临床管理规范的规定。植物原料药和药品制造应实现充分的本指南化学、制造、控制节所概述的批间一致性。如果在临床研发期间，植物药原料药或植物药品发生变更，可能需要开展非临床桥接研究以符合21 CFR 312.23(a)(8)(ii)(a)。
E.?Clinical?Pharmacology??E.临床药理学?
To support Phase 3 clinical studies of a botanical drug product, regardless of its marketing experience in the United States or other countries, the sponsor should provide the dose selection rationale (including a description of the human pharmacokinetic and pharmacodynamic relationships for both efficacy and safety, if available). This information should be provided in addition to the information recommended in Section V.D. It may be useful for the sponsor to perform clinical trial simulations prior to conducting Phase 3 clinical studies, if feasible. The sponsor is encouraged to meet with the Agency to reach agreement on the sponsor’s planned clinical pharmacology development programs prior to Phase 3.
为支持植物药品的3期临床研究，不论其在美国或其它国家的上市体验如何，发起方应提供剂量选择理由（包括让有效性和安全性人体药代动力学和药效学关系，如果可用）。除了第V.D.节所建议的资料外，应提供该资料。如果可行，在开展3期临床研究前，发起方开展临床试验模拟可能是有用的。鼓励发起方与FDA开会，在3期研究之前就发起方计划的药理学研发计划达成一致。
F.?Clinical?Considerations??F.临床考虑要点?
Phase 3 clinical studies of botanical drugs have the same purpose as Phase 3 clinical studies of nonbotanical drugs. Many general and therapeutic area-specific guidance documents are available on the FDA Drugs guidance web page. 31Special considerations for Phase 3 clinical studies of botanical drugs are summarized as follows:
植物药3期临床研究与非植物药3期临床研究目的相同。FDA指南网页上多份通用和具体治疗域的指南文件。31 植物药3期临床研究具体考虑总结如下：
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31 See www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 31
参见www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm。
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