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EMA/572054/2016# q' a$ @5 C: U0 r4 T: C3 k. [. ^
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Product- or Population-Specific C**iderati** IV: Paediatric population
产品或人群特异性考虑因素IV：儿科人群
P.IV.A. Introduction
P.IV.A. 介绍
The paediatric population is defined in the European Union (EU) as that group of the population between birth and 18 years of age. The paediatric population encompasses several subsets. In accordance with current guidelines1,2, the applied age classification of paediatric patients is:
欧洲联盟(EU)将儿科人群定义为出生至18岁之间的人群。儿科人群包括几个亚集。根据现行指南，儿科患者的应用年龄分类为：
) e7 N8 a- @+ \: ~% A" ^• preterm newborn neonates: from day of birth through the expected date of delivery plus 27 days;
•早产新生儿：从出生日到预计分娩日期加27天；
• term and post-term neonates: from day of birth plus 27 days;
! e) O) e I6 H' I1 Z0 j7 i•足月和足月新生儿：从出生日起加27天；
• infants (or toddlers): from 1 month (28 days) to 23 months;
8 \8 O' y! {4 f$ h3 B( c, |' j) y•婴儿(或幼儿)：从1个月(28天)到23个月；
• children: from 2 years to 11 years; and
6 e( w y! j: y4 M* j: b7 M•儿童：2岁至11岁；和
• adolescents: from 12 years to less than 18 years.
•青少年：从12岁到不到18岁。
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Adverse reacti** to medicinal products in the paediatric population need specific evaluation, as they may substantially differ – in terms of frequency, nature, severity and presentation – from those occurring in the adult population (see P.IV.A.1.). The importance of performing tailored pharmacovigilance research in the paediatric population3 has been recognised and established. Collection of pharmacovigilance data should take into account that in the paediatric population medicines have different utilisation patterns and are often used off-label, i.e. intentionally used for a medical purpose not in accordance with the terms of the marketing authorisation.
儿科人群对药品的不良反应需具体评估，因为儿科人群疾病在发病频率，性质，严重程度和临床表现等方面可能与**人群中的发生情况不同(见P.IV.A.1.)。 已经认识到并建立了在儿科人群中进行定制的药物警戒研究的重要性。药物警戒数据的收集应考虑到在儿科人群中药物具有不同的使用模式并且经常在标签外使用，即故意用于不符合上市许可条款的医学目的。
' F% W2 e' d! S- o7 LRegulation (EC) No 1901/2006 of the European Parliament and of the Council on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC and Regulation (EC) No 726/2004, referred to as the ‘Paediatric Regulation’, puts particular emphasis on the collection of safety data in the paediatric population, including data on possible long-term adverse effects. As mandated by this Regulation, the European Medicines Agency (the ‘Agency’) issued the Guideline on the Conduct of Pharmacovigilance for Medicines Used in the Paediatric Population (EMEA/CHMP/PhVWP/235910/2005 rev 1), which came into effect in 2007 with the implementation of the Paediatric Regulation.
欧洲议会和理事会第1901/2006号条例，关于儿科用药和修订法规(EEC)No 1768/92，指令2001/20/EC和法规(EC)No 726/2004，转介作为“儿科监管”，特别强调收集儿科人群的安全性数据，包括可能的长期不良反应数据。根据该法规的要求，欧洲药品管理局(“药品管理局”)颁布了“儿科人群药物药物警戒行为指南”(EMEA / CHMP / PhVWP / 235910/2005 rev 1)，该指南于 2007年实施了儿科监管。
, Y7 b7 ^$ l) a6 eSince the Paediatric Regulation came into force, a number of changes in the scientific and regulatory environment have had direct c**equences for the conduct of pharmacovigilance in the paediatric population, in particular the following:
自“儿科条例”生效以来，科学和监管环境的一些变化对儿科人群的药物警戒行为产生了直接影响，特别是以下方面：
7 n. Z Y g3 j# ^* E. T• the development of new paediatric medicines – as well as the ‘paediatric’ development of medicines that were already marketed – have both increased; this is reflected by a growing number of paediatric indicati** for innovative medicines, newly authorised paediatric age-specific formulati** and new paediatric indicati** for medicines with an existing marketing authorisation for adults4;
$ K. H) J- e* a) v•开发新的儿科药物 – 以及已经上市的药物的‘儿科‘开发 – 都增加了；这反映在越来越多的创新药物的儿科适应症，新授权的儿科年龄特异性配方和新的儿科适应症药物上，现已获得**上市许可；
9 k' G/ y1 {( v W w6 g• new pharmacovigilance legislation, i.e. Directive 2010/84/EU amending Directive 2001/83/EC (the latter is referenced in this guidance as DIR) and Regulation (EU) No 1235/2010 amending Regulation (EC) No 726/2004 (the latter is referenced as REG), came into force in July 2012,providing for strengthened pharmacovigilance processes for all medicines, irrespective of their authorised indication(s) and population(s).
•新的药物警戒立法，即指令2010/84 / EU，修订指令2001/83 / EC(后者在本指南中称为DIR)和法规(EU)No 1235/2010，修订法规(EC)No 726/2004(后者被称为REG)，于2012年7月生效，为所有药物提供加强的药物警戒程序，不论其是什么适应症和人群。
: M3 o; Z5 }) w9 d: {1 TThis pharmacovigilance legislation introduced changes that are relevant for the paediatric population. In particular the extended definition of adverse reaction now acknowledges that adverse reacti** may arise from use of the product within or outside the terms of the marketing authorisation or from occupational exposure [DIR Art 101(1)]. Use outside the marketing authorisation includes off-label use, overdose, misuse, abuse and medication errors (see GVP Annex I), which are all important aspects related to the pattern of utilisation of medicines in the paediatric population (see P.IV.A.1.4.).
该药物警戒立法引入了与儿科人群相关的变化。特别是不良反应的扩展定义现在承认，在上市许可条款或职业暴露条款之内或之外使用该产品可能产生不良反应[DIR Art 101(1)]。在营销许可之外使用包括标签外使用、过量使用、错用、滥用和药物错误(参见GVP附件I)，这些都是与儿科人群中药物利用模式相关的重要方面(参见P.IV.A.1.4.)# n! Z% Z: V0 r) d+ N
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C**equent to these changes, the previous guideline EMEA/CHMP/PhVWP/235910/2005 rev 1 needed to be updated, and revised guidance is now provided in this Product-Specific C**iderati** Chapter P.IV of the Good Pharmacovigilance Practices (GVP). This guidance should be read in conjunction with Title IV of the Paediatric Regulation and its Article 34, Regulation (EC) No 726/2004 and Directive 2001/83/EC.
由于这些变化，之前的指南EMEA / CHMP / PhVWP / 235910/2005 rev 1需要更新，现在在本产品特定注意事项第IV章“良好药物警戒实践(GVP)”中提供了修订指南。本指南应结合儿科监管标题IV及其第34条，法规(EC)No 726/2004和指令2001/83/EC一并阅读。
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The creation of this guidance as a GVP C**iderati** Chapter, aims at integrating paediatric pharmacovigilance within the structures and processes for pharmacovigilance overall. P.IV therefore applies in conjunction with the GVP Modules I to XVI on pharmacovigilance processes in the EU and does not replace these GVP Modules or introduce regulatory requirements in addition to those already covered in existing Modules. This Chapter provides guidance on how to make best use of the pharmacovigilance tools and processes to address the needs and specific challenges of the paediatric population, and supports the interpretation of how regulatory requirements should be adapted to target this specific population.
作为GVP注意事项章节创建本指南旨在整合儿科整体上药物警戒的结构和过程中的药物警戒。因此，P.IV与GVP模块I至XVI一起应用于欧盟的药物警戒过程，除了现有模块中已涵盖的那些之外，不会取代这些GVP模块或引入法规要求。本章提供了如何充分利用药物警戒工具和流程来解决儿科人群的需求和具体指导，并支持解释如何调整监管要求以针对特定人群。
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The guidance contained in this Chapter is addressed to marketing authorisation applicants and holders, and to the competent authorities in the Member States and the Agency. Additionally it will be of interest to parents/carers, healthcare professionals, patient/c**umer organisati**, healthcare professional organisati**, organisati** of national healthcare systems in Member States as well as sp**ors of clinical studies.
本章中包含的指南适用于上市许可申请人和持有人，以及成员国和机构的主管当局。 此外，父母/护理人员，医疗保健专业人员，患者/消费者组织，医疗保健专业组织，成员国的国家医疗保健系统组织以及临床研究的赞助商都会对此感兴趣。
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This guidance is addressed primarily to cover medicines with a paediatric indication or those with an adult indication and ongoing paediatric development, but also to medicines with an adult indication for which there is evidence of use in the paediatric population.
该指南主要针对具有儿科适应症的药物或具有**适应症和正在进行的儿科发育的药物，以及具有**适应症的药物，其中有证据表明在儿科患者中使用。
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The paediatric use of vaccines and the safety surveillance of paediatric outcomes after exposure to medicines in utero are outside the scope of P.IV., as such guidance is covered by GVP P.I and GVP P.III.
小儿使用疫苗和在子宫内接触药物后对小儿的安全监测超出了P.IV.的范围，因为GVP P.I和GVP P.III涵盖了这种指导。
- e; E' o! X$ E2 NP.IV.A.1. Pharmacovigilance aspects specific to the paediatric population' N6 q4 b2 g! C
P.IV.A.1.儿科人群特有的药物警戒方面
P.IV.A.1.1. Susceptibility to adverse reacti**
P.IV.A.1.1.易感不良反应
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Due to growth and maturation, the susceptibility of paediatric patients to adverse reacti** may substantially differ from adults. Various factors account for this difference and include, but are not limited to:
由于生长和成熟，儿科患者对不良反应的易感性可能与**显着不同。各种因素解释了这种差异，包括但不限于：
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• changes in physiology during growth and development (ontogeny), that may lead to different pharmacodynamic and pharmacokinetic parameters in the paediatric subjects compared to adults having an impact on the safety profile of the medicine;
•生长和发育过程中的生理变化(个体发育)，与可能影响药物安全性的成年人相比，可能导致儿科患者的药效学和药代动力学参数不同；
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• immaturity of some organ systems (e.g. skin, airways, kidneys, liver, gastro-intestinal system, brain and blood-brain-barrier, immune system, bones, drug transporters) that may increase the vulnerability to adverse reacti** and their sequelae;
•某些器官系统(如皮肤、气道、肾脏、肝脏、胃肠系统、脑和血脑屏障、免疫系统、骨骼、药物转运体)的不成熟，可能增加不良反应及其后遗症的易感性；
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• changes in body mass and composition that may lead to a narrowing of the therapeutic window and an increased susceptibility to dose-related adverse reacti**;
•体重和组成的变化可能导致治疗窗口缩小，并增加对剂量相关不良反应的易感性；
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• increased sensitivity to pharmacologically active excipients5 that may lead to an increased risk of adverse reacti**.
•对药理活性辅料的敏感性增加，可能导致不良反应风险增加。
5 j ?! F* @( NWithin the paediatric population itself, the different maturation milestones might alter the susceptibility to specific adverse reacti** across the various paediatric sub-populati** (e.g. (pre)term neonates to toddlers or pre-/post-pubertal children).
在儿科人群中，不同的成熟里程碑可能改变对各种儿科亚群[例如(前)足月新生儿到幼儿或青春期前/后儿童的特定不良反应的易感性]。
9 g. @0 S7 L( U8 |4 ]4 \) NMoreover, effects on developing organs and organ systems – e.g. on skeletal growth, **ual maturation, neurobehavioral development6 – may only become obvious, visible or identifiable with significant delay after exposure or long-term use (i.e. in adolescence or adulthood).
此外，对发育器官和器官系统的影响– 例如关于骨骼生长，性成熟，神经行为发育– 可能仅在暴露或长期使用后(即在青春期或成年期)显着延迟，可见或可识别。
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These c**iderati** highlight the importance of taking into account aspects related to organ maturation, developmental physiology and developmental pharmacology7 when planning pharmacovigilance activities for the paediatric population. C**iderati** for long-term follow-up should carefully take these factors into account.
这些考虑突出了在计划时考虑与器官成熟，发育生理学和发育药理学相关的方面的重要性
针对儿科人群的药物警戒活动。长期随访的考虑因素应仔细考虑这些因素。
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P.IV.A.1.2. Limited numbers of subjects in paediatric clinical trials
P.IV.A.1.2.儿科临床试验中受试者数量有限
9 @! p/ u; K" X" x+ [Clinical trials conducted in adults have known limitati** in generating safety data. Trials often are limited in size and in duration, might exclude high-risk populati** and have limited statistical power to detect rare, but potentially serious, adverse reaction that will only be detected in the real-world setting. These limitati** are even more relevant for paediatric clinical trials.
**进行的临床试验已知在生成安全性数据方面存在局限性试验的规模和持续时间通常有限，可能排除高风险人群，有限的统计能力来检测罕见但可能严重的不良反应，这种反应只能在现实环境中检测到，这些限制与儿科临床试验更为相关。
- O9 h+ b* d9 y6 G/ zDue to the small numbers of patients that is generally possible to enrol, paediatric clinical trials often have a sample size that is not statically-powered for dem**tration of efficacy and cannot gather a sufficient number of participants for collecting precise information on the incidence of adverse reacti**, particularly in some paediatric age sub-groups. Adverse reacti** that are rarer than ‘common’, i.e. occur at a frequency of less than 1/1008, may not be detectable in clinical trials. Also, the duration of such trials is usually limited, and adverse reacti** that have a long latency between exposure and **et might not be adequately captured.
由于通常可以招募的患者人数较少，因此儿科临床试验的样本量通常不具有静态功效以证明疗效，并且无法收集足够数量的参与者来收集关于不良反应发生率的准确信息。特别是在一些儿科年龄分组。在临床试验中可能检测不到比“常见”更罕见的不良反应，即以小于1/1008的频率发生的不良反应。此外，这些试验的持续时间通常是有限的，并且可能无法充分捕获在暴露和发作之间具有长潜伏期的不良反应。
# o& F; P0 A# ^1 AOverall, this means that the safety data collected for neonates, infants, children and adolescents for a given medicine in comparison to what is generally available for adults at the time of granting the marketing authorisation, can be particularly limited.
总的来说，这意味着与给予上市许可时**通常可获得的安全性数据相比，针对给定药物的新生儿、婴儿、儿童和青少年收集的安全性数据可能特别有限。
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P.IV.A.1.3. Medication errors
P.IV.A.1.3.用药错误% N6 c2 l1 I, `- D$ C, a/ u
A medication error is an unintended failure in the drug treatment process that leads to, or has the potential to lead to, harm to the patient (see GVP Annex I). Medication errors can occur at the time of prescribing, storing, dispensing, preparing as well as administering a medicine.
药物错误是药物治疗过程中的意外失败，导致或有可能导致对患者的伤害(参见GVP附录I)。在处方、储存、分配、准备以及施用药物时可能发生药物错误。
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Historically, there has been limited development of medicines for paediatric patients, leading to the absence of specific paediatric dosing guidance in the product information, and scarcity of ageappropriate pharmaceutical forms or presentati**. Due to the limited availability of medicines with an authorised paediatric indication and/or with an age-appropriate pharmaceutical form, paediatric patients may be treated at dosages that are inferred from adult patients, solely based on weight c**iderati**, or with inappropriate pharmaceutical forms (e.g. tablets instead of syrups or drops).Such widespread practice of off-label use (see P.IV.A.1.4.) was, and still is, associated with a risk of medication errors. Since these medication errors might lead to the administration of inappropriate doses (such as overdose or sub-therapeutic dose), paediatric patients are exposed to a higher risk of developing adverse reacti** than adults9,10.
从历史上看，儿科患者的药物开发有限，导致产品信息中缺乏特定的儿科剂量指导，以及年龄适当的药物形式或表现形式的缺乏。 由于具有授权儿科适应症和/或适合年龄的药物形式的药物供应有限，儿童患者可以从**患者推断的剂量进行治疗，仅基于体重考虑，或使用不适当的药物形式(例如 片剂代替糖浆或滴剂)。这种标签外使用的普遍做法(参见P.IV.A.1.4)过去和现在仍然存在药物错误的风险。由于这些用药错误可能会导致给药剂量不合适(如过量或亚治疗剂量)，因此儿科患者发生不良反应的风险高于**。
6 u4 Z" Y. i3 \6 d b* pFurthermore, the c**equences of such medication errors in can also be much more serious particularly in the most vulnerable paediatric age sub-groups such as neonates.
此外，这种用药错误的后果也可能更加严重，特别是在最脆弱的儿科年龄亚组如新生儿。
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It is expected that increased availability of new products with specific paediatric indicati** and ageappropriate form and presentati** (see P.IV.A.1.) will reduce adverse reacti** deriving from medication errors in the future.
预计具有特定儿科适应症和年龄适当的形式和表现的新产品的可用性增加(参见P.IV.A.1.)将减少未来药物错误引起的不良反应。# a6 C" C# ]: t1 A# H$ Y
The Pharmacovigilance Risk Assessment Committee (PRAC) Good Practice Guide on Risk Minimisation and Prevention of Medication Errors 11 provides guidance on the systematic assessment and prevention of medication errors throughout the product life-cycle and contains additional c**iderati** applicable to paediatric patients. These include calculation tables in educational material, appropriate dispensing devices and presentati** and recommendati** for enhanced communication between healthcare professionals, patients and their parents/carers. Advice on appropriate prescribing, storing, dispensing, preparing and administration of medicines, as well as monitoring of patients is also provided. Such strategies and measures for risk minimisation and prevention of medication errors should be c**idered when developing paediatric medicines or risk management plans.
药物警戒风险评估委员会(PRAC)关于风险最小化和预防药物错误的良好实践指南提供了有关在整个产品生命周期中系统评估和预防用药错误的指导，并包含适用于儿科患者的其他注意事项。这些包括教育材料中的计算表，适当的分配设备和演示以及增强医疗保健专业人员，患者及其父母/护理人员之间的沟通的建议。还提供了关于药物的适当处方、储存、分配、准备和管理以及患者监测的建议。应采取此类风险最小化和预防用药错误的策略和措施在制定儿科药物或风险管理计划时考虑。
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P.IV.A.1.4. Off-label use
P.IV.A.1.4.标签外使用
1 H% M* u- X; ^" _( ^6 c6 qOff-label use indicates situati** where a medicinal product is intentionally used for a medical purpose not in accordance with the terms and conditi** of the marketing authorisation. Relevant cases are where the use of a medicine is indicated solely for adults, but is nonetheless used in paediatric subjects (possibly with a different dosage, different route of administration and/or to treat a specific paediatric condition) (see GVP Annex I), or when a paediatric indication exists that is limited to some paediatric age sub-groups, but the product is also used in other age sub-groups (e.g. a medicine is indicated only in adolescents but is used also in children).
标签外使用表示医疗产品故意用于医疗目的而不符合上市许可的条款和条件的情况。相关病例是仅针对**使用药物的情况，但仍然用于儿科受试者(可能具有不同的剂量，不同的给药途径和/或治疗特定的儿科疾病)(见GVP附件I)，或者当存在仅限于某些儿科年龄亚组的儿科适应症时，该产品也用于其他年龄亚组(例如，药物仅在青少年中指示，但也在儿童中使用)。
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Off-label use of medicines in paediatric patients has been a common practice, due to the fact that paediatric-specific medicinal products were not available, but necessary therapy could not be withheld. With the developments described in P.IV.A., the situation nowadays has improved, but there are still a number of medical conditi** where the need for specific paediatric medicines is not met and off-label use continues.
由于没有儿科专用药品这一事实，儿科患者的标签外药物使用已成为常见做法，但不能拒绝必要的治疗。随着P.IV.A.中描述的发展，现在的情况有所改善，但是仍然存在许多医疗条件，其中不满足对特定儿科药物的需求并且标签外使用仍在继续。
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Such off-label use, as discussed above, might expose paediatric patients to an increased risk of medication errors and of adverse reacti**. Therefore, it is relevant that important risks arising from off-label use in paediatric patients are addressed appropriately (see P.IV.B.1.).
如上所述，这种标签外使用可能使儿科患者暴露于药物错误和不良反应的风险增加。因此，适当地解决儿科患者标签外使用产生的重要风险(见P.IV.B.1.)
4 F( \0 D% _# CP.IV.A.1.5. Clinical presentation of adverse reacti**
P.IV.A.1.5.临床表现不良反应
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Signs and symptoms of adverse reacti** and their clinical course may be different in paediatric patients compared to adults. This is also true among the various paediatric age sub-groups. N**pecific symptoms, such as vomiting and diarrhoea as well as sleepiness or variation in the intensity and pattern of crying, can be the only manifestati** of some adverse reaction observed in neonates, infants and toddlers. Moreover, symptoms that are dependent on patient communication ability (e.g.nausea, pain, mood alterati**) in younger or mentally disabled children12 might be under- or misreported.
与**相比，儿科患者的不良反应的症状和体征及其临床过程可能不同。在各种儿科年龄组中也是如此。非特异性症状，例如呕吐和腹泻以及嗜睡或强度和哭泣模式的变化，可能是在新生儿，婴儿和幼儿中观察到的一些不良反应的唯一表现。此外，依赖于年轻或智障儿童患者沟通能力(例如恶心、疼痛、情绪改变)的症状可能会被低估或误报。
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This means that the clinical presentation of adverse reacti** can be non-specific and be misinterpreted as the manifestation of a pre-existing condition. As such these reacti** will be less likely to be suspected and reported.
这意味着不良反应的临床表现可能是非特异性的被误解为先前存在的条件的表现。因此，这些反应不太可能被怀疑和报告。
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Aspects relating to the modalities of presentation of adverse reacti** in the paediatric population (see P.IV.B.5.) need to be taken into account when choosing the most appropriate search terms for performing signal detection (e.g. Lowest Level Terms and Preferred Terms when performing Standardised MedDRA Queries (SMQs)). This is also important when planning pharmacovigilance activities that might involve an active role of the paediatrician and of parents/carers, as they should be enabled to interpret particular signs and symptoms (e.g. crying and pain).
在选择最适合执行信号检测的搜索术语时，需要考虑与儿科人群中不良反应呈现方式有关的方面(参见P.IV.B.5.)(例如最低级别术语和首选术语)执行标准化MedDRA查询(SMQ)时。在规划可能涉及儿科医生和父母/照顾者的积极作用的药物警戒活动时，这也很重要，因为他们应该能够解释特定的体征和症状(例如哭泣和疼痛)。
# c" i! }4 m/ r6 ]2 HP.IV.B. Structures and processes
P.IV.B.结构和过程
P.IV.B.1. Risk management plan (RMP)
P.IV.B.1.风险管理计划(RMP)6 r# F" m8 j/ I$ z3 T. I
The current requirements for risk management plans (RMP) in GVP Module V and the Guidance on the format of the risk management plan (RMP) in the EU – in integrated format13 includes c**iderati** for the paediatric population. Methods used to minimise risk of adverse reacti** in the adult population should be evaluated and adapted to paediatric patients, taking into account the aspects specific to the paediatric population (P.IV.A.1.).
GVP模块V中的风险管理计划(RMP)的当前要求和欧盟风险管理计划(RMP)格式的指南–以综合格式包括对儿科人群的考虑。考虑到儿科患者特有的方面(P.IV.A.1.)，应评估并适应儿科患者的方法，以尽量减少**人群中不良反应的风险。
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In terms of pre-clinical evidence, results of juvenile animal toxicology studies can have a predictive value in terms of effects in the paediatric population and can support prioritising pharmacovigilance research questi** (e.g. accumulation of active substance in some organs of the animals tested, impairment in some behavioural tests).
就临床前证据而言，幼年动物毒理学研究的结果可以对儿科人群的影响具有预测价值，并且可以支持优先考虑药物警戒研究问题(例如，在测试动物的某些器官中活性物质的积累，一些行为测试)。
1 c/ f* @4 m4 J* ^! H; z+ fRegarding existing clinical data, the knowledge gained from studies in the adult population should support in the identification of important potential risks, in the characterisation of the safety profile as well as the description of tools to reduce the risk related to the use of the product14 in the paediatric population.
关于现有的临床数据，从**人群的研究中获得的知识应该有助于识别重要的潜在风险，确定安全概况的特征以及降低与使用产品有关的风险的工具的描述儿科人群。
% b3 t5 \) |% SSometimes no previous clinical or real-world data from adults are existing: this might happen when a medicine is authorised exclusively for paediatric patients or when it is authorised for adult and paediatric patients at the same time.
有时，不存在来自**的先前临床或真实数据：当专门为儿科患者授权药物或同时授权**和儿科患者时，可能会发生这种情况。
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Conversely, a paediatric indication might be added after c**iderable post-marketing experience has been gained in adults. Therefore, the amount of available evidence can vary greatly.
相反，在**获得相当大的上市后经验后，可能会增加儿科适应症。因此，现有证据的数量可能差别很大。
" P' ?9 O# K; W3 e2 ?Particularly important aspects to be c**idered for paediatric patients for the purpose of risk identification and characterisation include:
为了风险目的，儿科患者需要考虑的特别重要的方面识别和表征包括：9 A6 H. i0 _. C1 b* D7 q ~5 B$ Y
• age-related shifts in the interaction of the medicinal product with its target organs or tissues;
•药物与其靶器官或组织相互作用的年龄相关变化；
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•ontogeny of the absorption, distribution, metabolism and excretion (ADME), including disposition in intra-individual structures (such as the blood-brain barrier), of an active substance;
•吸收、分布、代谢和排泄(ADME)的个体发生，包括活性物质在个体内结构(例如血脑屏障)中的处置；. Z7 n! W4 [& f9 v0 y
• potential adverse reacti** due to different exposure to (different) metabolites as opposed to the adult age;
•与成年人相比，由于不同的(不同)代谢物接触而产生的潜在不良反应；
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• long-term effect on developing reproductive and neurodevelopmental systems;
•对发展生殖和神经发育系统的长期影响；
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• effects on bone and cartilage during active growth phase;
•在活跃生长阶段对骨骼和软骨的影响；
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• impact on maturation of the immune system in the pathogenesis of known adverse reacti** and effect of transition from passive maternal immunity to maturing immune systems in infants.
•在已知不良反应的发病机制中对免疫系统成熟的影响以及婴儿从被动母体免疫向成熟免疫系统过渡的影响。
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Evaluation of these aspects can help in assessing whether a risk of adverse reacti** for a given medicine might differ from the adult population and whether its pharmacological properties suggest any possibility of developmental risk.
对这些方面的评估有助于评估给定药物的不良反应风险是否可能与成年人群不同，以及其药理学特性是否表明存在发育风险的可能性。
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Similarly, when it is anticipated that a subgroup of the paediatric population is likely not to be different from the adult population (e.g. post-pubertal children, children above a certain age and/or weight), this should be supported by evidence and discussed at the time of the initial marketing authorisation application.
同样，当预计儿科人群的一个亚组可能与成年人群不同时(例如，青春期后的儿童，超过一定年龄和/或体重的儿童)，这应得到证据的支持，并在初始上市授权申请的时间。6 _5 d8 d/ W4 v7 \' h
If a specific paediatric risk is highlighted and is included as a safety concern in the RMP – in line with the guidance provided in GVP Module V – c**ideration should be given as to whether a paediatric post-authorisation safety study (PASS) (see P.IV.B.4.) would be appropriate for further characterising this risk.
如果突出显示特定的儿科风险并将其列为RMP中的安全问题–根据GVP模块V中提供的指导–应考虑是否进行儿科授权后安全性研究(PASS)(参见P. IV.B.4.)适合进一步表征这种风险。
In the case of a development of a medicine to treat rare diseases in paediatric patients for which paediatric data are lacking, or very limited, registries or other means of long-term data collection could be c**idered by the marketing authorisation holder to enable the conduction of appropriate PASS to follow-up and appropriately document long-term safety.
在开发治疗儿童患者罕见疾病的药物的情况下，儿童数据缺乏或非常有限，上市许可持有人可以考虑登记或其他长期数据收集手段，以便适当的PASS(上市后药品的安全习性研究)跟进并适当记录长期安全性。
) E, ]: f3 R; G+ R2 NIn these cases, high level planning of paediatric registries and related PASS should already be c**idered at the time of submission of a PIP (see P.IV.C.2.), to promote continuity in the generation of safety data between the pre- and post-authorisation phase (as already highlighted in P.IV.B.4.).
在这些情况下，在提交PIP时应该考虑儿童登记处和相关PASS(上市后药品的安全习性研究)的高级别规划(见P.IV.C.2)，以促进预先生成安全数据的连续性。 和授权后阶段(如P.IV.B.4中强调的)。
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The c**ultation of specialist networks (e.g. the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)23) and, where appropriate, the paediatric clinical trial networks (e.g. the European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA)24) could be helpful to address specific aspects related to design and conduct ofPASS in paediatrics. The applicants/marketing authorisation holder in the EU is also encouraged to request scientific advice (SA) from the Agency on specific aspects of PASS protocols, especially for complex or controversial issues or for innovative approaches or methodologies including those for paediatric studies25.
专家网络的咨询(例如欧洲药物流行病学和药物警戒中心网络(ENCePP))以及适当的儿童临床试验网络(例如欧洲药品管理局的欧洲儿童研究网络(Enpr-EMA))可能有助于解决与儿童的PASS设计和实施相关的具体方面。还鼓励欧盟的申请人/上市许可持有人向机构请求关于PASS协议特定方面的科学建议(SA)，特别是针对复杂或有争议的问题或创新方法或方法，包括儿童研究。
' k; H' Y' |/ WP.IV.C.6. Signal management within the EU regulatory network
P.IV.C.6. 欧盟监管网络内的信号管理
In addition to the guidance in P.IV.B.5., ICSRs for paediatric patients should be analysed by means of tools provided by EudraVigilance separately from ICSRs for adult patients (e.g. electronic Reaction Monitoring Reports (eRMRs)26).
除了P.IV.B.5.中的指导，儿童患者的ICSR(个例安全性报告)应通过欧盟药物警戒监管系统提供的工具与**患者的ICSR(个例安全性报告)分开进行分析(例如电子反应监测报告(eRMR))。
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It is recommended that statistics of disproportionate reporting (see GVP Module IX Addendum I) are calculated using only ICSRs about paediatric patients to increase the ability to detect paediatric signals of disproportionate reporting (SDR) from appropriate databases, i.e. EudraVigilance in the EU. Sub-group analysis by age and comparison of the disproportionality statistics in paediatric patients versus adults (if applicable, depending on the size of the data set) can help to determine whether or not a suspected adverse reaction is likely to be more frequent in paediatric patients.
建议不仅使用有关儿童患者的ICSR(个例安全性报告)计算不成比例报告的统计数据(参见GVP(药物警戒管理规范)模块IX附录I)，以提高从适当数据库(即欧盟药物警戒监管系统)去比例化报告统计值(SDR)的儿童信号的能力。按年龄进行分析，并比较儿童患者与**的不成比例统计数据(如果适用，取决于数据集的大小)，有助于确定儿童患者是否可能更频繁地发生疑似不良反应。
0 Z, a7 D% i( ?) y8 BP.IV.C.7. Safety communication in the EU
P.IV.C.7. 欧盟的安全通信
Further to the guidance in P.IV.B.5., children and their families in the EU can be c**ulted by the marketing authorisation holder in the EU as well as by the Agency and competent authorities in Member States through the established young person advisory groups for the preparation and revision of safety communication and educational materials for additional RMMs (see Principles on the Involvement of Young Patients and C**umers Within EMA Activities27). The Enpr-EMA Working Group on Young Pers** Advisory Groups (YPAGs) currently works on resources and on establishing a framework of interaction, which will become available for the Agency and the EU regulatory network as well as marketing authorisation holders in the EU.
继P.IV.B.5.中的指导，欧盟的上市许可持有人可以咨询欧盟儿童及其家人，以及机构和成员国主管当局通过已建立的年轻人咨询小组，为其他RMM准备和修订安全通信和教育材料(参见EMA(欧洲药物管理局)关于青年患者和消费者参与的原则)。Enpr-EMA青年咨询小组工作组(YPAG)目前致力于资源和建立互动框架，该框架将可供机构和欧盟监管网络以及欧盟的上市许可持有人使用。
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