ICH E1

• ICH E1 The Extent of Population Exposure: to Assess Clinical Safety for Drug Intended for Long-Term Treatment of Non-Life-Threatening Conditions
• ICH E1 人群暴露程度：评价无生命威胁条件下长期治疗药物的临床安全性

ICH E1 The Extent of Population Exposure: to Assess Clinical Safety for Drug Intended for Long-Term Treatment of Non-Life-Threatening Conditions

中文版

ICH E1 人群暴露程度：评价无生命威胁条件下长期治疗药物的临床安全性

The objective of this guideline is to present an accepted set of principles for the safety evaluation of drugs intended for the long-term treatment (chronic or repeated intermittent use for longer than 6 months) of non-life-threatening diseases. The safety evaluation during clinical drug development is expected to characterise and quantify the safety profile of a drug over a reasonable duration of time consistent with the intended long-term use of the drug. Thus, duration of drug exposure and its relationship to both time and magnitude of occurrence of adverse events are important considerations in determining the size of the data base necessary to achieve such goals.

For the purpose of this guideline, it is useful to distinguish between clinical data on adverse drug events (ADEs) derived from studies of shorter duration of exposure and data from studies of longer duration, which frequently are non-concurrently controlled studies. It is expected that short-term event rates (cumulative 3-month incidence of about 1%) will be well characterised. Events where the rate of occurrence changes over a longer period of time may need to be characterised depending on their severity and importance to the risk-benefit assessment of the drug. The safety evaluation during clinical drug development is not expected to characterise rare adverse events, for example, those occurring in less than 1 in 1000 patients.

The design of the clinical studies can significantly influence the ability to make causality judgements about the relationships between the drug and adverse events. A placebo-controlled trial allows the adverse event rate in the drug-treated group to be compared directly with the background event rate in the patient population being studied. Although a study with a positive or active control will allow a comparison of adverse event rates to be made between the test drug and the control drug, no direct assessment of the background event rate in the population studied can be made. A study that has no concurrent control group makes it more difficult to assess the causality relationship between adverse events observed and the test drug.

There was general agreement on the following:

1. A harmonised regulatory standard is of value for the extent and duration of treatment needed to provide the safety data base for drugs intended for long-term treatment of non-life-threatening conditions. Although this standard covers many indications and drug classes, there are exceptions.

   
   

2. Regulatory standards for the safety evaluation of drugs should be based on previous experience with the occurrence and detection of adverse drug events (ADEs), statistical considerations of the probability of detecting specified frequencies of ADEs, and practical considerations.

   
   

3. Information about the occurrence of ADEs in relation to duration of treatment for different drug classes is incomplete, and further investigations to obtain this information would be useful.

   
   

4. Available information suggests that most ADEs first occur, and are most frequent, within the first few months of drug treatment. The number of patients treated for 6 months at dosage levels intended for clinical use, should be adequate to characterise the pattern of ADEs over time.

   
   

   To achieve this objective the cohort of exposed subjects should be large enough to observe whether more frequently occurring events increase or decrease over time as well as to observe delayed events of reasonable frequency (e.g., in the general range of 0.5%-5%). Usually 300-600 patients should be adequate.

   
   

5. There is concern that, although they are likely to be uncommon, some ADEs may increase in frequency or severity with time or that some serious ADEs may occur only after drug treatment for more than 6 months. Therefore, some patients should be treated with the drug for 12 months. In the absence of more information about the relationship of ADEs to treatment duration, selection of a specific number of patients to be followed for 1 year is to a large extent a judgement based on the probability of detecting a given ADE frequency level and practical considerations.

   
   

   100 patients exposed for a minimum of one-year is considered to be acceptable to include as part of the safety data base. The data should come from prospective studies appropriately designed to provide at least one year exposure at dosage levels intended for clinical use. When no serious ADE is observed in a one-year exposure period this number of patients can provide reasonable assurance that the true cumulative one year incidence is no greater than 3%.

   
   

6. It is anticipated that the total number of individuals treated with the investigational drug, including short-term exposure, will be about 1500. Japan currently accepts 500-1500 patients: the potential for a smaller number of patients is due to the post-marketing surveillance requirement, the actual number for a specific drug being determined by the information available on the drug and drug class.

   
   

7. There are a number of circumstances where the harmonised general standards for the clinical safety evaluation may not be applicable. Reasons for, and examples of, these exceptions are listed below. It is expected that additional examples may arise. It should also be recognised that the clinical data base required for efficacy testing may be occasionally larger or may require longer patient observation than that required by this guideline.

   
   

   Exceptions:

   1. Instances where there is concern that the drug will cause late developing ADEs, or cause ADEs that increase in severity or frequency over time, would require a larger and/or longer-term safety data base. The concern could arise from:
   1. data from animal studies;
   2. clinical information from other agents with related chemical structures or from a related pharmacologic class;
   3. pharmacokinetic or pharmacodynamic properties known to be associated with such ADEs.
   2. Situations in which there is a need to quantitate the occurrence rate of an expected specific low-frequency ADE will require a greater long-term data base. Examples would include situations where a specific serious ADE has been identified in similar drugs or where a serious event that could represent an alert event is observed in early clinical trials.
   
   
   3. Larger safety data bases may be needed to make risk/benefit decisions in situations where the benefit from the drug is either (1) small (e.g., symptomatic improvement in less serious medical conditions) or (2) will be experienced by only a fraction of the treated patients (e.g., certain preventive therapies administered to healthy populations) or (3) is of uncertain magnitude (e.g., efficacy determination on a surrogate endpoint).
   
   
   4. In situations where there is concern that a drug may add to an already significant background rate of morbidity or mortality, clinical trials may need to be designed with a sufficient number of patients to provide adequate statistical power to detect prespecified increases over the baseline morbidity or mortality.
   
   
   5. In some cases, a smaller number of patients may be acceptable, for example, where the intended treatment population is small.
   
   

8. Filing for approval will usually be possible based on the data from patients treated through 6 months. Data on patients treated through 12 months must be submitted as soon as available and prior to approval in the United States and Japan but may be submitted after approval in the E.C.. In the U.S. the initial submission for those drugs designated as priority drugs must include the 12-months patient data.

ICH E1 人群暴露程度：评价无生命威胁条件下长期治疗药物的临床安全性

English Version

ICH E1 The Extent of Population Exposure: to Assess Clinical Safety for Drug Intended for Long-Term Treatment of Non-Life-Threatening Conditions

本指导原则的目的在于提出一套用于非危及生命性疾病长期治疗（超过6个月的慢性或间断使用）药物的安全性评估原则。在药物临床研发期间的安全性评价要求能定性和定量地描述与药物预期长期使用时间相一致的一段合理时间内药物的安全性特征。因此，在确定达到上述目标所必需的数据库规模时，药物暴露的持续时间及其与不良事件发生的时间和严重程度的关系是考虑要点。

为达到这一指导原则的目的，区分与药物不良事件相关的临床数据是来源于较短期的暴露研究还是较长期的暴露研究是相当有用的；长期暴露研究通常是非同期对照研究。要求很好地描述短期不良事件发生率（约1%的3个月累积发生率）。如果发生率在一段较长的时间内是变化的，这些不良事件应该根据它们的严重程度及其对药物风险-获益评估的重要性来描述。药物临床开发期间的安全性评价并不要求描述罕见不良事件的特征，例如发生率小于千分之一的事件。

临床研究设计能显著地影响对药物与不良事件之间的因果关系的判断。安慰剂对照试验允许将药物治疗组的不良事件发生率与被研究患者人群中不良事件的背景发生率直接比较。尽管一个使用阳性或活性对照的研究允许比较受试药物与对照药物间的不良事件发生率，但不能直接评价被研究人群中的不良事件的背景发生率。不设同期对照组的研究会使受试药物与观察到的不良事件之间的因果关系的评估变得更加困难。

以下是总体协定：

1. 一个协调的监管标准对于为预期用于非危及生命性疾病长期治疗的药物提供安全性评价数据库所必需的治疗程度和持续时间是相当有价值的。尽管这一标准涵盖许多适应症和许多药物类别，但仍存在例外情况。

   
   

2. 药物临床安全性评价的监管标准应基于以往对药物不良事件（ADE）的发生及观察经验、测定特定频率ADE概率的统计学考虑以及实际的考虑。

   
   

3. 不同种药物的与治疗持续时间相关的ADE的发生信息仍不完整，为获得这些信息而进行的深入研究是有益的。

   
   

4. 已获知的信息显示极大部分ADE在药物治疗的最初几个月首次出现，而且最为频繁；以临床预期使用的剂量水平治疗一定数量的患者共6个月，患者的数量应足以描述这段时期内ADE的特征。

   
   

   为达到这一目的，接受药物暴露的受试者组应足够大以观测较频繁发生的事件随时间是否增加或减少，同时观察合理频率(例如，总体范围为0.5%~5%)下延迟发生的事件。足够的患者数量通常为300~600例。

   
   

5. 有一点值得注意，即尽管通常不常见，一些ADE随时间的延长其频率和强度也增加；一些严重ADE可能仅在药物治疗6个月后发生。因此，一些患者的治疗时间应持续至12个月。在没有更多的关于ADE与治疗持续时间关系的相关信息时，选择一定数量的患者，使他们的随访持续至1年，在很大程度上是根据测定特定的ADE频率水平的概率和实际考虑而作出的判断。

   
   

   100 名患者接受药物暴露至少1年作为安全性评价数据库的一部分是可以接受的；数据应来源于前瞻性研究，这些研究应经过适当设计提供在临床预期使用剂量水平至少1年的药物暴露。在1年的药物暴露期间如果没有观测到严重ADE，那么这一患者数量可以提供合理的保证，保证1年累积真实发生率不大于3%。

   
   

6. 经研究药物治疗的个体总数（包括短期暴露）的期望值约为1500例。目前日本接受500~1500例患者：较少的患者数量存在的可能性是由于上市后药物的监测要求；对特定药物而言，实际病例数是由与药物及药物类别有关的已获知的信息决定的。

   
   

7. 有些情况临床安全性评价的协调的总体标准并不适用。这些例外情况的原因和实例见下文。预计其他的实例也可能出现。应被认识的一点是有效性验证所要求的临床数据库，偶尔可能比这一指导原则中要求的更大或要求对患者观察更长时间。

   
   

   例外情况：

   1. 当有顾虑药物将导致迟发ADE或随时间的延长ADE的强度或频率增加时，需要更大和/或更长期的安全性数据库。这些顾虑可能来源于：
   1. 动物研究数据；
   2. 其他化学结构相关或药理学分类相关的药品的临床信息；
   3. 已知与上述ADE有关的药代动力学或药效学特征。
   2. 当需要对一个预期低频率的特定ADE的发生率作定量描述时，需要一个较长期的数据库；这种情况包括在相似药物中发生的一种特定的且已确定的严重ADE；或者在早期临床试验中观察到可能代表警告事件的一个严重事件。
   
   
   3. 当药物获益（1）太小（例如，在非严重疾病条件下的症状改善）；或者（2）仅有一部分接受治疗的患者能够体验（例如，对健康人群的某些预防性治疗）；或者（3）大小仍未确定（例如，以替代终点进行疗效确定）时，在决定风险/获益关系时需要较大的数据库。
   
   
   4. 当药物可能增加疾病本身就存在的显著的背景死亡率或发病率时，临床试验可能需要足够的患者数量以提供适宜的统计学效力，从而能检测到发病率或死亡率比基线条件下有预期设定的增加。
   
   
   5. 在一些条件下较少的患者数量是可以接受的，例如，预期的治疗人群数量较小时。
   
   

8. 根据治疗6个月的患者数据提出新药许可申请通常是合理的；在美国和日本，经12个月治疗的患者数据一经获得必须立刻提交，并且必须在获得新药许可之前提交，但在欧洲国家，12个月数据的提交可以在获得新药许可之后。在美国，那些被认定为优先药物（priority drugs)的药物，其首次递交的申请中必须包括经12个月治疗的患者数据。