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1. Study?Design?for?Multiple?Batch?Analyses??

1. 多批次分析的研究设计?

Analyses of batch effects on clinical endpoints (i.e., batch effect analyses) should be considered when drug product batches exhibit variations (e.g., a variation in chemical composition), potentially affecting clinical outcomes. These are additional analyses beyond the standard primary efficacy analyses usually performed. Standard analyses involve comparing a control group to a treatment group composed of subjects pooled across different batches. The batches that are chosen should be representative of the marketing batches and should not be too homogenous. The goal of these analyses is to quantify potential heterogeneity in clinical outcomes for subjects who receive different batches in the study. This is in principle similar to other types of subgroup analyses. 32

在药品批次显示出变异（例如化学组成变异），可能影响临床结果的情况下，应考虑对临床终点的批次效果分析（即批次效果分析）。除了通常开展的标准的主要疗效分析之外，有其它的分析。标准分析涉及对照组与不同批次汇总的受试者所组成的治疗组的比较。选择的批次应该代表上市销售批次，不应过于同质。这些分析的目的是量化在研究中接受不同批次的患者的临床结果中可能的异质性。在原理上类似于其它类型的亚组分析。32

If batch effect analyses are warranted, the sponsor should design clinical studies to facilitate these analyses, pre-specify in the protocols how these analyses will be carried out, discuss with the appropriate OND review division the pre-planned models for these analyses, and present the results of these analyses in the clinical study report. Batch effect analyses are usually exploratory, with no formal requirement of control of the Type I error rate. The remainder of this section provides more details on our recommendations for clinical study design, as well as modeling and presentation of clinical study results, to accommodate batch effect analyses.

如果批效应分析是必要的，发起方应设计临床研究来帮助这些分析，在方案中预先说明如何开展这些分析，与恰当的新药办公室审评部门讨论用于这些分析的预设模型，并在临床研究报告中呈现这些模型。批效应分析通常为探索性的，对控制第I类误差并无正式要求。本节后续部分更为详细地阐述我们对临床研究设计的建议、建模及临床研究结果呈现，以适应批效应分析。

Randomization of subjects to different batches in each site is highly recommended to facilitate batch effect analyses. For instance, a study of three different batches is conceptually similar to a study with three different randomized dosage groups and one control group. If subjects are not randomized to different batches, a direct comparison of clinical outcomes in different batches can be confounded by other effects. For example, if drug products supplied to any given site are only from one batch rather than from multiple batches, then a direct comparison of clinical outcomes in different batches is confounded with site effects on clinical outcomes.

强烈建议在每一场所将受试者随机分入不同批次中，有助于批效应分析。例如，3个不同批次的研究在概念上与不同随机化剂量组与一个对照组的研究类似。如果受试者未随机分入不同批次中，直接比较其它批次的临床效果会为其它效应所混淆。例如，如果提供给任一给定场

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32 See Section 5.7 of ICH E9 Statistical Principles for Clinical Trials. 32参见《ICH E9

临床试验统计学原理》第5.7节。

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所的药品仅来自于一个批次，而非来自于多个批次，那么来自于不同批次的临床效果直接比较会与对临床结果的场所效应相混淆。

The sponsor should also ensure that subjects randomized to a certain batch group receive study drug from the same batch for the duration of the study. In situations where this may not be possible, the batch effect analyses may only be able to estimate a batch sequence effect.

发起方应确保在研究期内，随机分入某一批次组的受试者使用来自同一批次的研究药品。当这种情况不成其为可能的情况下，批效应分析可能只能估计出批序贯效应。

With regard to modeling and presentation of results from batch effect analyses, the sponsor should include summary tables and/or forest plots displaying estimates and confidence intervals of clinical outcomes or treatment effect by batch, describe the pre-planned models used to generate these results, assess possible heterogeneity of clinical outcomes in subjects that receive different batches, and describe the statistical measures of heterogeneity and statistical tests of homogeneity used. In addition, the sponsor should provide a summary of the subjects’ baseline characteristics by batch to explore possible imbalances in the subjects’ baseline characteristics between batches and identify possible confounders of batch effect on clinical outcomes.

对于批效应结果建模和呈现，发起方应纳入显示临床结果或批次治疗效应的估计值和置信区间的汇总表和/或森林图，说明用于生成这些结果的预设模型，评价接受不同批次受试者中临床结果可能的异质性，说明所使用的异质性统计方法和同质性统计检验。此外，发起方应提交以批次划分的受试者基线特征综述，以探讨批间受试者基线特征可能存在的不平衡，并确定批间效应对临床结果的可能混淆。

2.?Dose‐Response?Effect??

2.剂量‐响应效应?

Another approach to show that clinical response to a botanical drug will not be affected by variations of different batches is to demonstrate that the drug’s effect on clinical outcomes is not sensitive to dose, while also demonstrating that the studied doses are more effective than placebo or control, or not inferior to active treatment. If a randomized, multiple-dose, parallel group design, Phase 3 study demonstrates a similar treatment effect across multiple doses, concerns about the impact of variability in chemical composition across batches may be diminished. Therefore, to facilitate the Agency’s evaluation of the effects of doses on clinical outcomes, the sponsor should summarize the results of different doses on clinical outcomes, including estimates and confidence intervals of treatment effects by dose displayed in tables and/or forest plots, in the clinical study report.

证明对植物药临床响应将不受不同批次变异影响的另外一种方法是证明药物对临床结果的影响对剂量不敏感，同时也证明所研究的剂量比安慰剂或对照更有效，或者不比积极治疗劣效。如果随机化、多剂量、平行组设计的3期临床研究证明所剂量间存在类似的治疗效应，对批间变异的担心可能会减少。因此，为促进FDA对剂量对临床效果影响的评价，发起方应在临床研究报告中归纳不同剂量对临床结果影响的结果，包括以图表和/或森林图表示剂量对治疗效果作用的估计值和置信区间。

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3.Clinical?Studies?of?Botanical?Drugs?for?Serious?Conditions?

3.用于严重疾病的植物药品的临床研究?

While extensive anecdotal human experience for some botanical drugs may exist, not knowing the active constituent(s) and/or mechanisms of action may cast doubt on the drug’s presumed efficacy. Lack of scientifically reliable and relevant data to support efficacy may raise ethical concerns for clinical studies evaluating the botanical drug alone, especially for serious conditions. In these cases, an “add-on to standard care versus standard care” design is preferred to a “stand-alone versus control” design in clinical studies for serious conditions. However, add-on designs present the possibility of an adverse interaction between the standard of care and the botanical drug. If such an interaction is possible and strong evidence is available to support the presumed efficacy of the botanical drug alone, alternative designs (e.g., adding a third arm of botanical drug alone) should be considered.

尽管一些植物药可能存在广泛的口碑相传的人体体验，但不了解活性成分和/或作用机制可能会造成对药物所谓的疗效的怀疑。支持疗效的科学可靠和相关数据缺乏，会引起单独评价植物药的临床研究的伦理学问题，尤其是对于严重病症。在这种情况下，对于严重病症的临床研究，优先采用“标准治疗附加方法对比标准治疗”设计，而非“单独对比对照”设计。然而，附加设计会出现治疗标准与植物药间不良相互作用的可能性。如果可能存在这样的相互作用，并有强烈的证据支持植物药单独使用的所谓疗效，应考虑多种替代设计（例如，增加单独使用植物药的第三臂）。

4.?Other?Study?Design?Issues??

4.?其它研究设计问题?

When the rationale for developing certain botanical drug products is based on prior clinical experience in alternative medical systems (e.g., Ayurveda, traditional Chinese medicine, Unani, Sidha, and other herbal medicine and pharmacognosy textbooks), the sponsor may propose to incorporate traditional practices into their clinical protocols. For example, patients may be selected or grouped based on alternative medical theory or practice and treated with specific botanical regimens accordingly, or the final dosage form may be prepared by individual patients according to traditional Chinese or Indian methods.

在研发某种植物药品的基本原理是基于替代医学体系（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）的既往临床体验时，发起方可提出将传统实践整合到他们的临床方案中。例如，可根据替代医学理论或实践选择患者或分组，并相应地使用特定的植物疗法治疗，或成品剂型可由单个患者根据中国或印度的传统方法制备。

These unconventional measures should be considered individually and could be acceptable if they will

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help ensure or enhance the therapeutic effect for an acceptable indication and can be described and translated into practical instructions for use in the labeling for patients and healthcare providers in the United States. The sponsor contemplating such approaches should consult with the appropriate OND review division.

如果这些非常规方法将有助于加强对认可的适应症的疗效，并能翻译为针对美国患者或医疗人员的标签使用说明，应个别考虑这些非常规方法。 The sponsor contemplating such approaches should consult with the appropriate OND review division.考虑这种方法的发起方应向恰当的新药办公室（OND）审评部门咨询。

G.?Applicability?of?Combination?Drug?Regulations??G.复方药品法规的适用性?

For a fixed-combination drug product, current regulations require sponsors to demonstrate each component’s contribution toward overall efficacy and/or safety. 33However, these regulations generally do not apply to naturally derived mixtures, such as those found within a single botanical raw material. Botanical drug products derived from a single botanical raw material are generally not considered fixed-combination drugs because the entire botanical mixture generally is considered to be the active ingredient.

对于固定剂量复方药品，现行法规要求发起方证明每种成分对总体疗效和/或安全性的贡献。33 然而，这些法规通常不适用于天然来源混合物，例如在单个植物原药材中发现的天然来源混合物。由于整体的植物混合物通常被认为是活性成分，因此来源于单个植物原药材的植物药品通常不被认为是固定剂量复方药品。

Botanical drug products derived from multiple botanical raw materials are currently considered fixed-combination drugs. However, the Agency recognizes that demonstrating each botanical raw material’s contribution to efficacy and safety in a product with multiple botanical raw materials may not always be feasible. The Agency is currently reviewing the requirements for fixed-combination drugs and how they should be applied to botanical drug products.

来源于多个植物原药材的植物药品目前被认为是固定剂量复方药品。然而，FDA认识到证明每个植物原药材对多个植物原药材药品的疗效和安全性的贡献通常并不可行。FDA目前正在审查针对固定剂量复方药品的要求以及如何将这些要求应用到植物药品。

Until the Agency issues further guidance or policy specific to the application of these regulations to fixed-combination botanical drug products, nonclinical data from animal disease models or

pharmacological in vitro assays may be useful to show the contribution of individual components34 to the claimed effects.

在FDA发布具体用于固定剂量复方植物药的进一步指南或政策之前，对于证明单个成分34

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33 See §300.50 and 330.10(a)(4)(iv). 33

参见§300.50 and 330.10(a)(4)(iv)。

34 In this context, a component refers to a mixture derived from a specific botanical raw material. 34 在这种情况下，一个成分指源于一种特定的植物原药材的一种混合物。

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