{"id":77767,"date":"2018-12-10T00:00:50","date_gmt":"2019-02-01T06:09:27","guid":{"rendered":"http:\/\/www.05921.net\/index.php\/77767\/"},"modified":"2019-02-01T14:09:53","modified_gmt":"2019-02-01T06:09:53","slug":"508f8bbe9c","status":"publish","type":"post","link":"https:\/\/www.05921.net\/index.php\/77767\/","title":{"rendered":"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)"},"content":{"rendered":"
\n

\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"<\/p>\n

25 October 2018<\/span>
EMA\/572054\/2016<\/span>
<\/span><\/p>\n


<\/span><\/strong>Product- or Population-Specific Considerations IV: Paediatric <\/span><\/span>population<\/span><\/p>\n

\u4ea7\u54c1\u6216\u4eba\u7fa4\u7279\u5f02\u6027\u8003\u8651\u56e0\u7d20<\/span>IV<\/span>\uff1a\u513f\u79d1\u4eba\u7fa4<\/span><\/p>\n

\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"<\/p>\n

P.IV.A. Introduction<\/span><\/strong><\/p>\n

P.IV.A. <\/span><\/span><\/strong>\u4ecb\u7ecd<\/span><\/strong><\/p>\n

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:<\/span><\/p>\n

\u6b27\u6d32\u8054\u76df<\/span>(EU)<\/span>\u5c06\u513f\u79d1\u4eba\u7fa4\u5b9a\u4e49\u4e3a\u51fa\u751f\u81f3<\/span>18<\/span>\u5c81\u4e4b\u95f4\u7684\u4eba\u7fa4\u3002\u513f\u79d1\u4eba\u7fa4\u5305\u62ec\u51e0\u4e2a\u4e9a\u96c6\u3002\u6839\u636e\u73b0\u884c\u6307\u5357\uff0c\u513f\u79d1\u60a3\u8005\u7684\u5e94\u7528\u5e74\u9f84\u5206\u7c7b\u4e3a\uff1a<\/span><\/strong><\/p>\n


<\/p>\n

\u2022 <\/span><\/span>preterm newborn neonates: from day of birth through the expected date of delivery plus 27 days;<\/span><\/p>\n

\u2022<\/span>\u65e9\u4ea7\u65b0\u751f\u513f\uff1a\u4ece\u51fa\u751f\u65e5\u5230\u9884\u8ba1\u5206\u5a29\u65e5\u671f\u52a0<\/span>27<\/span>\u5929<\/span>\uff1b<\/span><\/strong><\/p>\n

\u2022 <\/span><\/span>term and post-term neonates: from day of birth plus 27 days;
<\/span>\u2022<\/span>\u8db3\u6708\u548c\u8db3\u6708\u65b0\u751f\u513f\uff1a\u4ece\u51fa\u751f\u65e5\u8d77\u52a0<\/span>27<\/span>\u5929<\/span>\uff1b<\/span><\/strong><\/p>\n

\u2022 <\/span><\/span>infants (or toddlers): from 1 month (28 days) to 23 months;
<\/span>\u2022<\/span>\u5a74\u513f<\/span>(<\/span>\u6216\u5e7c\u513f<\/span>)<\/span>\uff1a\u4ece<\/span>1<\/span>\u4e2a\u6708<\/span>(28<\/span>\u5929<\/span>)<\/span>\u5230<\/span>23<\/span>\u4e2a\u6708<\/span>\uff1b<\/span><\/strong><\/p>\n

\u2022 <\/span><\/span>children: from 2 years to 11 years; and
<\/span>\u2022<\/span>\u513f\u7ae5\uff1a<\/span>2<\/span>\u5c81\u81f3<\/span>11<\/span>\u5c81<\/span>\uff1b<\/span>\u548c<\/span><\/strong><\/p>\n

\u2022 <\/span><\/span>adolescents: from 12 years to less than 18 years.<\/span><\/p>\n

\u2022<\/span>\u9752\u5c11\u5e74\uff1a\u4ece<\/span>12<\/span>\u5c81\u5230\u4e0d\u5230<\/span>18<\/span>\u5c81\u3002<\/span><\/strong><\/p>\n


<\/p>\n

Adverse reactions 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<\/span> <\/span>P.IV.A.1.<\/span><\/span>). 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.<\/span><\/p>\n

\u513f\u79d1\u4eba\u7fa4\u5bf9\u836f\u54c1\u7684\u4e0d\u826f\u53cd\u5e94\u9700\u5177\u4f53\u8bc4\u4f30\uff0c\u56e0\u4e3a\u513f\u79d1\u4eba\u7fa4\u75be\u75c5\u5728\u53d1\u75c5\u9891\u7387\uff0c\u6027\u8d28\uff0c\u4e25\u91cd\u7a0b\u5ea6\u548c\u4e34\u5e8a\u8868\u73b0\u7b49\u65b9\u9762\u53ef\u80fd\u4e0e\u6210\u4eba\u4eba\u7fa4\u4e2d\u7684\u53d1\u751f\u60c5\u51b5\u4e0d\u540c<\/span>(<\/span>\u89c1<\/span>P.IV.A.1<\/span>.<\/span>)<\/span>\u3002<\/span> <\/span>\u5df2\u7ecf\u8ba4\u8bc6\u5230\u5e76\u5efa\u7acb\u4e86\u5728\u513f\u79d1\u4eba\u7fa4\u4e2d\u8fdb\u884c\u5b9a\u5236\u7684\u836f\u7269\u8b66\u6212\u7814\u7a76\u7684\u91cd\u8981\u6027\u3002\u836f\u7269\u8b66\u6212\u6570\u636e\u7684\u6536\u96c6\u5e94\u8003\u8651\u5230\u5728\u513f\u79d1\u4eba\u7fa4\u4e2d\u836f\u7269\u5177\u6709\u4e0d\u540c\u7684\u4f7f\u7528\u6a21\u5f0f\u5e76\u4e14\u7ecf\u5e38\u5728\u6807\u7b7e\u5916\u4f7f\u7528\uff0c\u5373\u6545\u610f\u7528\u4e8e\u4e0d\u7b26\u5408\u4e0a\u5e02\u8bb8\u53ef\u6761\u6b3e\u7684\u533b\u5b66\u76ee\u7684\u3002<\/span><\/strong><\/p>\n


<\/p>\n

Regulation (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 \u2018Paediatric Regulation\u2019, 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 \u2018Agency\u2019) 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.<\/span><\/p>\n

\u6b27\u6d32\u8bae\u4f1a\u548c\u7406\u4e8b\u4f1a\u7b2c<\/span>1901\/2006<\/span>\u53f7\u6761\u4f8b\uff0c\u5173\u4e8e\u513f\u79d1\u7528\u836f\u548c\u4fee\u8ba2\u6cd5\u89c4<\/span>(EEC)No 1768\/92<\/span>\uff0c\u6307\u4ee4<\/span>2001\/20\/EC<\/span>\u548c\u6cd5\u89c4<\/span>(EC)No 726\/2004<\/span>\uff0c\u8f6c\u4ecb\u4f5c\u4e3a<\/span>\u201c<\/span>\u513f\u79d1\u76d1\u7ba1<\/span>\u201d<\/span>\uff0c\u7279\u522b\u5f3a\u8c03\u6536\u96c6\u513f\u79d1\u4eba\u7fa4\u7684\u5b89\u5168\u6027\u6570\u636e\uff0c\u5305\u62ec\u53ef\u80fd\u7684\u957f\u671f\u4e0d\u826f\u53cd\u5e94\u6570\u636e\u3002\u6839\u636e\u8be5\u6cd5\u89c4\u7684\u8981\u6c42\uff0c\u6b27\u6d32\u836f\u54c1\u7ba1\u7406\u5c40<\/span>(\u201c<\/span>\u836f\u54c1\u7ba1\u7406\u5c40<\/span>\u201d)<\/span>\u9881\u5e03\u4e86<\/span>\u201c<\/span>\u513f\u79d1\u4eba\u7fa4\u836f\u7269\u836f\u7269\u8b66\u6212\u884c\u4e3a\u6307\u5357<\/span>\u201d(EMEA \/ CHMP \/ PhVWP \/ 235910\/2005 rev 1)<\/span>\uff0c\u8be5\u6307\u5357\u4e8e<\/span> <\/span>2007<\/span>\u5e74\u5b9e\u65bd\u4e86\u513f\u79d1\u76d1\u7ba1\u3002<\/span><\/strong><\/p>\n


<\/p>\n

Since the Paediatric Regulation came into force, a number of changes in the scientific and regulatory environment have had direct consequences for the conduct of pharmacovigilance in the paediatric population, in particular the following:<\/span><\/p>\n

\u81ea<\/span>\u201c<\/span>\u513f\u79d1\u6761\u4f8b<\/span>\u201d<\/span>\u751f\u6548\u4ee5\u6765\uff0c\u79d1\u5b66\u548c\u76d1\u7ba1\u73af\u5883\u7684\u4e00\u4e9b\u53d8\u5316\u5bf9\u513f\u79d1\u4eba\u7fa4\u7684\u836f\u7269\u8b66\u6212\u884c\u4e3a\u4ea7\u751f\u4e86\u76f4\u63a5\u5f71\u54cd\uff0c\u7279\u522b\u662f\u4ee5\u4e0b\u65b9\u9762\uff1a<\/span><\/strong><\/p>\n


<\/p>\n

\u2022 <\/span><\/span>the development of new paediatric medicines – as well as the \u2018paediatric\u2019 development of medicines that were already marketed – have both increased; this is reflected by a growing number of paediatric indications for innovative medicines, newly authorised paediatric age-specific formulations and new paediatric indications for medicines with an existing marketing authorisation for adults4;
<\/span>\u2022<\/span>\u5f00\u53d1\u65b0\u7684\u513f\u79d1\u836f\u7269<\/span> <\/span>– <\/span><\/span>\u4ee5\u53ca\u5df2\u7ecf\u4e0a\u5e02\u7684\u836f\u7269\u7684<\/span>‘<\/span>\u513f\u79d1<\/span>‘<\/span>\u5f00\u53d1<\/span> <\/span>– <\/span><\/span>\u90fd\u589e\u52a0\u4e86<\/span>\uff1b<\/span>\u8fd9\u53cd\u6620\u5728\u8d8a\u6765\u8d8a\u591a\u7684\u521b\u65b0\u836f\u7269\u7684\u513f\u79d1\u9002\u5e94\u75c7\uff0c\u65b0\u6388\u6743\u7684\u513f\u79d1\u5e74\u9f84\u7279\u5f02\u6027\u914d\u65b9\u548c\u65b0\u7684\u513f\u79d1\u9002\u5e94\u75c7\u836f\u7269\u4e0a\uff0c\u73b0\u5df2\u83b7\u5f97\u6210\u4eba\u4e0a\u5e02\u8bb8\u53ef<\/span>\uff1b<\/span><\/strong><\/p>\n


<\/p>\n

\u2022 <\/span><\/span>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).<\/span><\/span><\/p>\n

\u2022<\/span><\/strong>\u65b0\u7684\u836f\u7269\u8b66\u6212\u7acb\u6cd5<\/span><\/strong>\uff0c<\/span>\u5373\u6307\u4ee4<\/span>2010\/84 \/ EU<\/span>\uff0c\u4fee\u8ba2\u6307\u4ee4<\/span>2001\/83 \/ EC(<\/span>\u540e\u8005\u5728\u672c\u6307\u5357\u4e2d\u79f0\u4e3a<\/span>DIR)<\/span>\u548c\u6cd5\u89c4<\/span>(EU)No 1235\/2010<\/span>\uff0c\u4fee\u8ba2\u6cd5\u89c4<\/span>(EC)No 726\/2004(<\/span>\u540e\u8005\u88ab\u79f0\u4e3a<\/span>REG)<\/span>\uff0c\u4e8e<\/span>2012<\/span>\u5e74<\/span>7<\/span>\u6708\u751f\u6548\uff0c\u4e3a\u6240\u6709\u836f\u7269\u63d0\u4f9b\u52a0\u5f3a\u7684\u836f\u7269\u8b66\u6212\u7a0b\u5e8f\uff0c\u4e0d\u8bba\u5176\u662f\u4ec0\u4e48\u9002\u5e94\u75c7\u548c\u4eba\u7fa4\u3002<\/span><\/strong><\/p>\n


<\/p>\n

This pharmacovigilance legislation introduced changes that are relevant for the paediatric population. In particular the extended definition of adverse reaction now acknowledges that adverse reactions 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.).<\/span><\/p>\n

\u8be5\u836f\u7269\u8b66\u6212\u7acb\u6cd5\u5f15\u5165\u4e86\u4e0e\u513f\u79d1\u4eba\u7fa4\u76f8\u5173\u7684\u53d8\u5316\u3002\u7279\u522b\u662f\u4e0d\u826f\u53cd\u5e94\u7684\u6269\u5c55\u5b9a\u4e49\u73b0\u5728\u627f\u8ba4\uff0c\u5728\u4e0a\u5e02\u8bb8\u53ef\u6761\u6b3e\u6216\u804c\u4e1a\u66b4\u9732\u6761\u6b3e\u4e4b\u5185\u6216\u4e4b\u5916\u4f7f\u7528\u8be5\u4ea7\u54c1\u53ef\u80fd\u4ea7\u751f\u4e0d\u826f\u53cd\u5e94<\/span>[DIR Art 101(1)]<\/span>\u3002\u5728\u8425\u9500\u8bb8\u53ef\u4e4b\u5916\u4f7f\u7528\u5305\u62ec\u6807\u7b7e\u5916\u4f7f\u7528\u3001\u8fc7\u91cf\u4f7f\u7528\u3001\u9519\u7528\u3001\u6ee5\u7528\u548c\u836f\u7269\u9519\u8bef<\/span>(<\/span>\u53c2\u89c1<\/span>GVP<\/span>\u9644\u4ef6<\/span>I<\/span>)<\/span>\uff0c\u8fd9\u4e9b\u90fd\u662f\u4e0e\u513f\u79d1\u4eba\u7fa4\u4e2d\u836f\u7269\u5229\u7528\u6a21\u5f0f\u76f8\u5173\u7684\u91cd\u8981\u65b9\u9762<\/span>(<\/span>\u53c2\u89c1<\/span>P.IV.A.1.4<\/span>.<\/span>)<\/span><\/strong>
<\/p>\n


<\/p>\n

Consequent 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 Considerations 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.<\/span><\/p>\n

\u7531\u4e8e\u8fd9\u4e9b\u53d8\u5316\uff0c\u4e4b\u524d\u7684\u6307\u5357<\/span>EMEA \/ CHMP \/ PhVWP \/ 235910\/2005 rev 1<\/span>\u9700\u8981\u66f4\u65b0\uff0c\u73b0\u5728\u5728\u672c\u4ea7\u54c1\u7279\u5b9a\u6ce8\u610f\u4e8b\u9879\u7b2c<\/span>IV<\/span>\u7ae0<\/span>\u201c<\/span>\u826f\u597d\u836f\u7269\u8b66\u6212\u5b9e\u8df5<\/span>(GVP)\u201d<\/span>\u4e2d\u63d0\u4f9b\u4e86\u4fee\u8ba2\u6307\u5357\u3002\u672c\u6307\u5357\u5e94\u7ed3\u5408\u513f\u79d1\u76d1\u7ba1\u6807\u9898<\/span>IV<\/span>\u53ca\u5176\u7b2c<\/span>34<\/span>\u6761\uff0c\u6cd5\u89c4<\/span>(EC)No 726\/2004<\/span>\u548c\u6307\u4ee4<\/span>2001\/83\/EC<\/span>\u4e00\u5e76\u9605\u8bfb\u3002<\/span><\/strong><\/p>\n


<\/p>\n

The creation of this guidance as a GVP Considerations 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.<\/span><\/p>\n

\u4f5c\u4e3a<\/span>GVP<\/span>\u6ce8\u610f\u4e8b\u9879\u7ae0\u8282\u521b\u5efa\u672c\u6307\u5357\u65e8\u5728\u6574\u5408\u513f\u79d1\u6574\u4f53\u4e0a\u836f\u7269\u8b66\u6212\u7684\u7ed3\u6784\u548c\u8fc7\u7a0b\u4e2d\u7684\u836f\u7269\u8b66\u6212\u3002\u56e0\u6b64\uff0c<\/span>P.IV<\/span>\u4e0e<\/span>GVP<\/span>\u6a21\u5757<\/span>I<\/span>\u81f3<\/span>XVI<\/span>\u4e00\u8d77\u5e94\u7528\u4e8e\u6b27\u76df\u7684\u836f\u7269\u8b66\u6212\u8fc7\u7a0b\uff0c\u9664\u4e86\u73b0\u6709\u6a21\u5757\u4e2d\u5df2\u6db5\u76d6\u7684\u90a3\u4e9b\u4e4b\u5916\uff0c\u4e0d\u4f1a\u53d6\u4ee3\u8fd9\u4e9b<\/span>GVP<\/span>\u6a21\u5757\u6216\u5f15\u5165\u6cd5\u89c4\u8981\u6c42\u3002\u672c\u7ae0\u63d0\u4f9b\u4e86\u5982\u4f55\u5145\u5206\u5229\u7528\u836f\u7269\u8b66\u6212\u5de5\u5177\u548c\u6d41\u7a0b\u6765\u89e3\u51b3\u513f\u79d1\u4eba\u7fa4\u7684\u9700\u6c42\u548c\u5177\u4f53\u6307\u5bfc\uff0c\u5e76\u652f\u6301\u89e3\u91ca\u5982\u4f55\u8c03\u6574\u76d1\u7ba1\u8981\u6c42\u4ee5\u9488\u5bf9\u7279\u5b9a\u4eba\u7fa4\u3002<\/span><\/strong><\/p>\n


<\/p>\n

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\/consumer organisations, healthcare professional organisations, organisations of national healthcare systems in Member States as well as sponsors of clinical studies.<\/span><\/p>\n

\u672c\u7ae0\u4e2d\u5305\u542b\u7684\u6307\u5357\u9002\u7528\u4e8e\u4e0a\u5e02\u8bb8\u53ef\u7533\u8bf7\u4eba\u548c\u6301\u6709\u4eba\uff0c\u4ee5\u53ca\u6210\u5458\u56fd\u548c\u673a\u6784\u7684\u4e3b\u7ba1\u5f53\u5c40\u3002<\/span> <\/span>\u6b64\u5916\uff0c\u7236\u6bcd<\/span>\/<\/span>\u62a4\u7406\u4eba\u5458\uff0c\u533b\u7597\u4fdd\u5065\u4e13\u4e1a\u4eba\u5458\uff0c\u60a3\u8005<\/span>\/<\/span>\u6d88\u8d39\u8005\u7ec4\u7ec7\uff0c\u533b\u7597\u4fdd\u5065\u4e13\u4e1a\u7ec4\u7ec7\uff0c\u6210\u5458\u56fd\u7684\u56fd\u5bb6\u533b\u7597\u4fdd\u5065\u7cfb\u7edf\u7ec4\u7ec7\u4ee5\u53ca\u4e34\u5e8a\u7814\u7a76\u7684\u8d5e\u52a9\u5546\u90fd\u4f1a\u5bf9\u6b64\u611f\u5174\u8da3\u3002<\/span><\/strong><\/p>\n


<\/p>\n

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.<\/span><\/p>\n

\u8be5\u6307\u5357\u4e3b\u8981\u9488\u5bf9\u5177\u6709\u513f\u79d1\u9002\u5e94\u75c7\u7684\u836f\u7269\u6216\u5177\u6709\u6210\u4eba\u9002\u5e94\u75c7\u548c\u6b63\u5728\u8fdb\u884c\u7684\u513f\u79d1\u53d1\u80b2\u7684\u836f\u7269\uff0c\u4ee5\u53ca\u5177\u6709\u6210\u4eba\u9002\u5e94\u75c7\u7684\u836f\u7269\uff0c\u5176\u4e2d\u6709\u8bc1\u636e\u8868\u660e\u5728\u513f\u79d1\u60a3\u8005\u4e2d\u4f7f\u7528\u3002<\/span><\/strong><\/p>\n


<\/p>\n

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.<\/span><\/p>\n

\u5c0f\u513f\u4f7f\u7528\u75ab\u82d7\u548c\u5728\u5b50\u5bab\u5185\u63a5\u89e6\u836f\u7269\u540e\u5bf9\u5c0f\u513f\u7684\u5b89\u5168\u76d1\u6d4b\u8d85\u51fa\u4e86<\/span>P.IV.<\/span>\u7684\u8303\u56f4\uff0c\u56e0\u4e3a<\/span>GVP P.I<\/span>\u548c<\/span>GVP P.III<\/span>\u6db5\u76d6\u4e86\u8fd9\u79cd\u6307\u5bfc\u3002<\/span><\/strong><\/p>\n


<\/p>\n

P.IV.A.1. Pharmacovigilance aspects specific to the paediatric population
P.IV.A.1.<\/span><\/em><\/strong>\u513f\u79d1\u4eba\u7fa4\u7279\u6709\u7684\u836f\u7269\u8b66\u6212\u65b9\u9762<\/span><\/em><\/strong><\/p>\n

P.IV.A.1.1. Susceptibility to adverse reactions<\/span><\/em><\/strong><\/p>\n

P.IV.A.1.1.<\/span><\/em><\/strong>\u6613\u611f\u4e0d\u826f\u53cd\u5e94<\/span><\/em><\/strong><\/p>\n


<\/p>\n

Due to growth and maturation, the susceptibility of paediatric patients to adverse reactions may substantially differ from adults. Various factors account for this difference and include, but are not limited to:<\/span><\/p>\n

\u7531\u4e8e\u751f\u957f\u548c\u6210\u719f\uff0c\u513f\u79d1\u60a3\u8005\u5bf9\u4e0d\u826f\u53cd\u5e94\u7684\u6613\u611f\u6027\u53ef\u80fd\u4e0e\u6210\u4eba\u663e\u7740\u4e0d\u540c\u3002\u5404\u79cd\u56e0\u7d20\u89e3\u91ca\u4e86\u8fd9\u79cd\u5dee\u5f02\uff0c\u5305\u62ec\u4f46\u4e0d\u9650\u4e8e\uff1a<\/span><\/strong><\/p>\n


<\/p>\n

\u2022 <\/span><\/span>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;<\/span><\/p>\n

\u2022<\/span>\u751f\u957f\u548c\u53d1\u80b2\u8fc7\u7a0b\u4e2d\u7684\u751f\u7406\u53d8\u5316<\/span>(<\/span>\u4e2a\u4f53\u53d1\u80b2<\/span>)<\/span>\uff0c\u4e0e\u53ef\u80fd\u5f71\u54cd\u836f\u7269\u5b89\u5168\u6027\u7684\u6210\u5e74\u4eba\u76f8\u6bd4\uff0c\u53ef\u80fd\u5bfc\u81f4\u513f\u79d1\u60a3\u8005\u7684\u836f\u6548\u5b66\u548c\u836f\u4ee3\u52a8\u529b\u5b66\u53c2\u6570\u4e0d\u540c<\/span>\uff1b<\/span><\/strong><\/p>\n


<\/p>\n

\u2022 <\/span><\/span>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 reactions and their sequelae;<\/span><\/p>\n

\u2022<\/span>\u67d0\u4e9b\u5668\u5b98\u7cfb\u7edf<\/span>(<\/span>\u5982\u76ae\u80a4\u3001\u6c14\u9053\u3001\u80be\u810f\u3001\u809d\u810f\u3001\u80c3\u80a0\u7cfb\u7edf\u3001\u8111\u548c\u8840\u8111\u5c4f\u969c\u3001\u514d\u75ab\u7cfb\u7edf\u3001\u9aa8\u9abc\u3001\u836f\u7269\u8f6c\u8fd0\u4f53<\/span>)<\/span>\u7684\u4e0d\u6210\u719f\uff0c\u53ef\u80fd\u589e\u52a0\u4e0d\u826f\u53cd\u5e94\u53ca\u5176\u540e\u9057\u75c7\u7684\u6613\u611f\u6027<\/span>\uff1b<\/span><\/strong><\/p>\n


<\/p>\n

\u2022 <\/span><\/span>changes in body mass and composition that may lead to a narrowing of the therapeutic window and an increased susceptibility to dose-related adverse reactions;<\/span><\/p>\n

\u2022<\/span>\u4f53\u91cd\u548c\u7ec4\u6210\u7684\u53d8\u5316\u53ef\u80fd\u5bfc\u81f4\u6cbb\u7597\u7a97\u53e3\u7f29\u5c0f\uff0c\u5e76\u589e\u52a0\u5bf9\u5242\u91cf\u76f8\u5173\u4e0d\u826f\u53cd\u5e94\u7684\u6613\u611f\u6027<\/span>\uff1b<\/span><\/strong><\/p>\n


<\/p>\n

\u2022 <\/span><\/span>increased sensitivity to pharmacologically active excipients5 that may lead to an increased risk of adverse reactions.<\/span><\/p>\n

\u2022<\/span>\u5bf9\u836f\u7406\u6d3b\u6027\u8f85\u6599\u7684\u654f\u611f\u6027\u589e\u52a0\uff0c\u53ef\u80fd\u5bfc\u81f4\u4e0d\u826f\u53cd\u5e94\u98ce\u9669\u589e\u52a0\u3002<\/span><\/strong><\/p>\n


<\/p>\n

Within the paediatric population itself, the different maturation milestones might alter the susceptibility to specific adverse reactions across the various paediatric sub-populations (e.g. (pre)term neonates to toddlers or pre-\/post-pubertal children).<\/span><\/p>\n

\u5728\u513f\u79d1\u4eba\u7fa4\u4e2d\uff0c\u4e0d\u540c\u7684\u6210\u719f\u91cc\u7a0b\u7891\u53ef\u80fd\u6539\u53d8\u5bf9\u5404\u79cd\u513f\u79d1\u4e9a\u7fa4<\/span>[<\/span>\u4f8b\u5982<\/span>(<\/span>\u524d<\/span>)<\/span>\u8db3\u6708\u65b0\u751f\u513f\u5230\u5e7c\u513f\u6216\u9752\u6625\u671f\u524d<\/span>\/<\/span>\u540e\u513f\u7ae5\u7684\u7279\u5b9a\u4e0d\u826f\u53cd\u5e94\u7684\u6613\u611f\u6027<\/span>]<\/span>\u3002<\/span><\/strong><\/p>\n


<\/p>\n

Moreover, effects on developing organs and organ systems – e.g. on skeletal growth, sexual 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).<\/span><\/p>\n

\u6b64\u5916\uff0c\u5bf9\u53d1\u80b2\u5668\u5b98\u548c\u5668\u5b98\u7cfb\u7edf\u7684\u5f71\u54cd<\/span>– <\/span><\/span>\u4f8b\u5982\u5173\u4e8e\u9aa8\u9abc\u751f\u957f\uff0c\u6027\u6210\u719f\uff0c\u795e\u7ecf\u884c\u4e3a\u53d1\u80b2<\/span>– <\/span><\/span>\u53ef\u80fd\u4ec5\u5728\u66b4\u9732\u6216\u957f\u671f\u4f7f\u7528\u540e<\/span>(<\/span>\u5373\u5728\u9752\u6625\u671f\u6216\u6210\u5e74\u671f<\/span>)<\/span>\u663e\u7740\u5ef6\u8fdf\uff0c\u53ef\u89c1\u6216\u53ef\u8bc6\u522b\u3002<\/span><\/strong><\/p>\n


<\/p>\n

These considerations 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. Considerations for long-term follow-up should carefully take these factors into account.<\/span><\/p>\n

\u8fd9\u4e9b\u8003\u8651\u7a81\u51fa\u4e86\u5728\u8ba1\u5212\u65f6\u8003\u8651\u4e0e\u5668\u5b98\u6210\u719f\uff0c\u53d1\u80b2\u751f\u7406\u5b66\u548c\u53d1\u80b2\u836f\u7406\u5b66\u76f8\u5173\u7684\u65b9\u9762\u7684\u91cd\u8981\u6027<\/span><\/strong><\/p>\n

\u9488\u5bf9\u513f\u79d1\u4eba\u7fa4\u7684\u836f\u7269\u8b66\u6212\u6d3b\u52a8\u3002\u957f\u671f\u968f\u8bbf\u7684\u8003\u8651\u56e0\u7d20\u5e94\u4ed4\u7ec6\u8003\u8651\u8fd9\u4e9b\u56e0\u7d20\u3002<\/span><\/strong><\/p>\n


<\/p>\n

P.IV.A.1.2. Limited numbers of subjects in paediatric clinical trials<\/span><\/strong><\/p>\n

P.IV.A.1.2.<\/span><\/strong>\u513f\u79d1\u4e34\u5e8a\u8bd5\u9a8c\u4e2d\u53d7\u8bd5\u8005\u6570\u91cf\u6709\u9650<\/span><\/strong><\/p>\n


<\/p>\n

Clinical trials conducted in adults have known limitations in generating safety data. Trials often are limited in size and in duration, might exclude high-risk populations and have limited statistical power to detect rare, but potentially serious, adverse reaction that will only be detected in the real-world setting. These limitations are even more relevant for paediatric clinical trials.<\/span><\/p>\n

\u6210\u4eba\u8fdb\u884c\u7684\u4e34\u5e8a\u8bd5\u9a8c\u5df2\u77e5\u5728\u751f\u6210\u5b89\u5168\u6027\u6570\u636e\u65b9\u9762\u5b58\u5728\u5c40\u9650\u6027\u8bd5\u9a8c\u7684\u89c4\u6a21\u548c\u6301\u7eed\u65f6\u95f4\u901a\u5e38\u6709\u9650\uff0c\u53ef\u80fd\u6392\u9664\u9ad8\u98ce\u9669\u4eba\u7fa4\uff0c\u6709\u9650\u7684\u7edf\u8ba1\u80fd\u529b\u6765\u68c0\u6d4b\u7f55\u89c1\u4f46\u53ef\u80fd\u4e25\u91cd\u7684\u4e0d\u826f\u53cd\u5e94\uff0c\u8fd9\u79cd\u53cd\u5e94\u53ea\u80fd\u5728\u73b0\u5b9e\u73af\u5883\u4e2d\u68c0\u6d4b\u5230\uff0c\u8fd9\u4e9b\u9650\u5236\u4e0e\u513f\u79d1\u4e34\u5e8a\u8bd5\u9a8c\u66f4\u4e3a\u76f8\u5173\u3002<\/span><\/strong><\/p>\n


<\/p>\n

Due 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 demonstration of efficacy and cannot gather a sufficient number of participants for collecting precise information on the incidence of adverse reactions, particularly in some paediatric age sub-groups. Adverse reactions that are rarer than \u2018common\u2019, 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 reactions that have a long latency between exposure and onset might not be adequately captured.<\/span><\/p>\n

\u7531\u4e8e\u901a\u5e38\u53ef\u4ee5\u62db\u52df\u7684\u60a3\u8005\u4eba\u6570\u8f83\u5c11\uff0c\u56e0\u6b64\u513f\u79d1\u4e34\u5e8a\u8bd5\u9a8c\u7684\u6837\u672c\u91cf\u901a\u5e38\u4e0d\u5177\u6709\u9759\u6001\u529f\u6548\u4ee5\u8bc1\u660e\u7597\u6548\uff0c\u5e76\u4e14\u65e0\u6cd5\u6536\u96c6\u8db3\u591f\u6570\u91cf\u7684\u53c2\u4e0e\u8005\u6765\u6536\u96c6\u5173\u4e8e\u4e0d\u826f\u53cd\u5e94\u53d1\u751f\u7387\u7684\u51c6\u786e\u4fe1\u606f\u3002\u7279\u522b\u662f\u5728\u4e00\u4e9b\u513f\u79d1\u5e74\u9f84\u5206\u7ec4\u3002\u5728\u4e34\u5e8a\u8bd5\u9a8c\u4e2d\u53ef\u80fd\u68c0\u6d4b\u4e0d\u5230\u6bd4<\/span>\u201c<\/span>\u5e38\u89c1<\/span>\u201d<\/span>\u66f4\u7f55\u89c1\u7684\u4e0d\u826f\u53cd\u5e94\uff0c\u5373\u4ee5\u5c0f\u4e8e<\/span>1\/1008<\/span>\u7684\u9891\u7387\u53d1\u751f\u7684\u4e0d\u826f\u53cd\u5e94\u3002\u6b64\u5916\uff0c\u8fd9\u4e9b\u8bd5\u9a8c\u7684\u6301\u7eed\u65f6\u95f4\u901a\u5e38\u662f\u6709\u9650\u7684\uff0c\u5e76\u4e14\u53ef\u80fd\u65e0\u6cd5\u5145\u5206\u6355\u83b7\u5728\u66b4\u9732\u548c\u53d1\u4f5c\u4e4b\u95f4\u5177\u6709\u957f\u6f5c\u4f0f\u671f\u7684\u4e0d\u826f\u53cd\u5e94\u3002<\/span><\/strong><\/p>\n


<\/p>\n

Overall, 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.<\/span><\/p>\n

\u603b\u7684\u6765\u8bf4\uff0c\u8fd9\u610f\u5473\u7740\u4e0e\u7ed9\u4e88\u4e0a\u5e02\u8bb8\u53ef\u65f6\u6210\u4eba\u901a\u5e38\u53ef\u83b7\u5f97\u7684\u5b89\u5168\u6027\u6570\u636e\u76f8\u6bd4\uff0c\u9488\u5bf9\u7ed9\u5b9a\u836f\u7269\u7684\u65b0\u751f\u513f\u3001\u5a74\u513f\u3001\u513f\u7ae5\u548c\u9752\u5c11\u5e74\u6536\u96c6\u7684\u5b89\u5168\u6027\u6570\u636e\u53ef\u80fd\u7279\u522b\u6709\u9650\u3002<\/span><\/strong><\/p>\n


<\/p>\n

P.IV.A.1.3. Medication errors<\/span><\/strong><\/p>\n

P.IV.A.1.3.<\/span><\/strong>\u7528\u836f\u9519\u8bef<\/span><\/strong>
<\/span><\/strong><\/p>\n

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 <\/span><\/span>GVP Annex I<\/span>). Medication errors can occur at the time of prescribing, storing, dispensing, preparing as well as administering a medicine.<\/span><\/p>\n

\u836f\u7269\u9519\u8bef\u662f\u836f\u7269\u6cbb\u7597\u8fc7\u7a0b\u4e2d\u7684\u610f\u5916\u5931\u8d25\uff0c\u5bfc\u81f4\u6216\u6709\u53ef\u80fd\u5bfc\u81f4\u5bf9\u60a3\u8005\u7684\u4f24\u5bb3<\/span>(<\/span>\u53c2\u89c1<\/span>GVP<\/span>\u9644\u5f55<\/span>I)<\/span>\u3002\u5728\u5904\u65b9\u3001\u50a8\u5b58\u3001\u5206\u914d\u3001\u51c6\u5907\u4ee5\u53ca\u65bd\u7528\u836f\u7269\u65f6\u53ef\u80fd\u53d1\u751f\u836f\u7269\u9519\u8bef\u3002<\/span><\/strong><\/p>\n


<\/p>\n

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 presentations. 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 considerations, 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 reactions than adults9,10.<\/span><\/span><\/p>\n

\u4ece\u5386\u53f2\u4e0a\u770b\uff0c\u513f\u79d1\u60a3\u8005\u7684\u836f\u7269\u5f00\u53d1\u6709\u9650\uff0c\u5bfc\u81f4\u4ea7\u54c1\u4fe1\u606f\u4e2d\u7f3a\u4e4f\u7279\u5b9a\u7684\u513f\u79d1\u5242\u91cf\u6307\u5bfc\uff0c\u4ee5\u53ca\u5e74\u9f84\u9002\u5f53\u7684\u836f\u7269\u5f62\u5f0f\u6216\u8868\u73b0\u5f62\u5f0f\u7684\u7f3a\u4e4f\u3002<\/span> <\/span>\u7531\u4e8e\u5177\u6709\u6388\u6743\u513f\u79d1\u9002\u5e94\u75c7\u548c<\/span>\/<\/span>\u6216\u9002\u5408\u5e74\u9f84\u7684\u836f\u7269\u5f62\u5f0f\u7684\u836f\u7269\u4f9b\u5e94\u6709\u9650\uff0c\u513f\u7ae5\u60a3\u8005\u53ef\u4ee5\u4ece\u6210\u4eba\u60a3\u8005\u63a8\u65ad\u7684\u5242\u91cf\u8fdb\u884c\u6cbb\u7597\uff0c\u4ec5\u57fa\u4e8e\u4f53\u91cd\u8003\u8651\uff0c\u6216\u4f7f\u7528\u4e0d\u9002\u5f53\u7684\u836f\u7269\u5f62\u5f0f<\/span>(<\/span>\u4f8b\u5982<\/span> <\/span>\u7247\u5242\u4ee3\u66ff\u7cd6\u6d46\u6216\u6ef4\u5242<\/span>)<\/span>\u3002\u8fd9\u79cd\u6807\u7b7e\u5916\u4f7f\u7528\u7684\u666e\u904d\u505a\u6cd5<\/span>(<\/span>\u53c2\u89c1<\/span>P.IV.A.1.4<\/span>)<\/span>\u8fc7\u53bb\u548c\u73b0\u5728\u4ecd\u7136\u5b58\u5728\u836f\u7269\u9519\u8bef\u7684\u98ce\u9669\u3002\u7531\u4e8e\u8fd9\u4e9b\u7528\u836f\u9519\u8bef\u53ef\u80fd\u4f1a\u5bfc\u81f4\u7ed9\u836f\u5242\u91cf\u4e0d\u5408\u9002<\/span>(<\/span>\u5982\u8fc7\u91cf\u6216\u4e9a\u6cbb\u7597\u5242\u91cf<\/span>)<\/span>\uff0c\u56e0\u6b64\u513f\u79d1\u60a3\u8005\u53d1\u751f\u4e0d\u826f\u53cd\u5e94\u7684\u98ce\u9669\u9ad8\u4e8e\u6210\u4eba\u3002<\/span><\/strong><\/p>\n


<\/p>\n

Furthermore, the consequences of such medication errors in can also be much more serious particularly in the most vulnerable paediatric age sub-groups such as neonates.<\/span><\/p>\n

\u6b64\u5916\uff0c\u8fd9\u79cd\u7528\u836f\u9519\u8bef\u7684\u540e\u679c\u4e5f\u53ef\u80fd\u66f4\u52a0\u4e25\u91cd\uff0c\u7279\u522b\u662f\u5728\u6700\u8106\u5f31\u7684\u513f\u79d1\u5e74\u9f84\u4e9a\u7ec4\u5982\u65b0\u751f\u513f\u3002<\/span><\/strong><\/p>\n


<\/p>\n

It is expected that increased availability of new products with specific paediatric indications and ageappropriate form and presentations (see P.IV.A.1.) will reduce adverse reactions deriving from medication errors in the future.<\/span><\/p>\n

\u9884\u8ba1\u5177\u6709\u7279\u5b9a\u513f\u79d1\u9002\u5e94\u75c7\u548c\u5e74\u9f84\u9002\u5f53\u7684\u5f62\u5f0f\u548c\u8868\u73b0\u7684\u65b0\u4ea7\u54c1\u7684\u53ef\u7528\u6027\u589e\u52a0<\/span>(<\/span>\u53c2\u89c1<\/span>P.IV.A.1<\/span>.<\/span>)<\/span>\u5c06\u51cf\u5c11\u672a\u6765\u836f\u7269\u9519\u8bef\u5f15\u8d77\u7684\u4e0d\u826f\u53cd\u5e94\u3002<\/span><\/strong>
<\/span><\/p>\n

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 considerations applicable to paediatric patients. These include calculation tables in educational material, appropriate dispensing devices and presentations and recommendations 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 considered when developing paediatric medicines or risk management plans.<\/span><\/span><\/p>\n

\u836f\u7269\u8b66\u6212\u98ce\u9669\u8bc4\u4f30\u59d4\u5458\u4f1a<\/span>(PRAC)<\/span>\u5173\u4e8e\u98ce\u9669\u6700\u5c0f\u5316\u548c\u9884\u9632\u836f\u7269\u9519\u8bef\u7684\u826f\u597d\u5b9e\u8df5\u6307\u5357\u63d0\u4f9b\u4e86\u6709\u5173\u5728\u6574\u4e2a\u4ea7\u54c1\u751f\u547d\u5468\u671f\u4e2d\u7cfb\u7edf\u8bc4\u4f30\u548c\u9884\u9632\u7528\u836f\u9519\u8bef\u7684\u6307\u5bfc<\/span>\uff0c\u5e76\u5305\u542b\u9002\u7528\u4e8e\u513f\u79d1\u60a3\u8005\u7684\u5176\u4ed6\u6ce8\u610f\u4e8b\u9879\u3002\u8fd9\u4e9b\u5305\u62ec\u6559\u80b2\u6750\u6599\u4e2d\u7684\u8ba1\u7b97\u8868\uff0c\u9002\u5f53\u7684\u5206\u914d\u8bbe\u5907\u548c\u6f14\u793a\u4ee5\u53ca\u589e\u5f3a\u533b\u7597\u4fdd\u5065\u4e13\u4e1a\u4eba\u5458\uff0c\u60a3\u8005\u53ca\u5176\u7236\u6bcd<\/span>\/<\/span>\u62a4\u7406\u4eba\u5458\u4e4b\u95f4\u7684\u6c9f\u901a\u7684\u5efa\u8bae\u3002\u8fd8\u63d0\u4f9b\u4e86\u5173\u4e8e\u836f\u7269\u7684\u9002\u5f53\u5904\u65b9\u3001\u50a8\u5b58\u3001\u5206\u914d\u3001\u51c6\u5907\u548c\u7ba1\u7406\u4ee5\u53ca\u60a3\u8005\u76d1\u6d4b\u7684\u5efa\u8bae\u3002\u5e94\u91c7\u53d6\u6b64\u7c7b\u98ce\u9669\u6700\u5c0f\u5316\u548c\u9884\u9632\u7528\u836f\u9519\u8bef\u7684\u7b56\u7565\u548c\u63aa\u65bd\u5728\u5236\u5b9a\u513f\u79d1\u836f\u7269\u6216\u98ce\u9669\u7ba1\u7406\u8ba1\u5212\u65f6\u8003\u8651\u3002<\/span><\/strong><\/p>\n


<\/p>\n

P.IV.A.1.4. Off-label use<\/span><\/strong><\/p>\n

P.IV.A.1.4.<\/span><\/strong>\u6807\u7b7e\u5916\u4f7f\u7528<\/span><\/strong><\/p>\n


<\/p>\n

Off-label use indicates situations where a medicinal product is intentionally used for a medical purpose not in accordance with the terms and conditions 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).<\/span><\/p>\n

\u6807\u7b7e\u5916\u4f7f\u7528\u8868\u793a\u533b\u7597\u4ea7\u54c1\u6545\u610f\u7528\u4e8e\u533b\u7597\u76ee\u7684\u800c\u4e0d\u7b26\u5408\u4e0a\u5e02\u8bb8\u53ef\u7684\u6761\u6b3e\u548c\u6761\u4ef6\u7684\u60c5\u51b5\u3002\u76f8\u5173\u75c5\u4f8b\u662f\u4ec5\u9488\u5bf9\u6210\u4eba\u4f7f\u7528\u836f\u7269\u7684\u60c5\u51b5\uff0c\u4f46\u4ecd\u7136\u7528\u4e8e\u513f\u79d1\u53d7\u8bd5\u8005<\/span>(<\/span>\u53ef\u80fd\u5177\u6709\u4e0d\u540c\u7684\u5242\u91cf\uff0c\u4e0d\u540c\u7684\u7ed9\u836f\u9014\u5f84\u548c<\/span>\/<\/span>\u6216\u6cbb\u7597\u7279\u5b9a\u7684\u513f\u79d1\u75be\u75c5<\/span>)(<\/span>\u89c1<\/span>GVP<\/span>\u9644\u4ef6<\/span>I<\/span>)<\/span>\uff0c\u6216\u8005\u5f53\u5b58\u5728\u4ec5\u9650\u4e8e\u67d0\u4e9b\u513f\u79d1\u5e74\u9f84\u4e9a\u7ec4\u7684\u513f\u79d1\u9002\u5e94\u75c7\u65f6\uff0c\u8be5\u4ea7\u54c1\u4e5f\u7528\u4e8e\u5176\u4ed6\u5e74\u9f84\u4e9a\u7ec4<\/span>(<\/span>\u4f8b\u5982\uff0c\u836f\u7269\u4ec5\u5728\u9752\u5c11\u5e74\u4e2d\u6307\u793a\uff0c\u4f46\u4e5f\u5728\u513f\u7ae5\u4e2d\u4f7f\u7528<\/span>)<\/span>\u3002<\/span>
<\/span><\/strong><\/p>\n

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 conditions where the need for specific paediatric medicines is not met and off-label use continues.<\/span><\/p>\n

\u7531\u4e8e\u6ca1\u6709\u513f\u79d1\u4e13\u7528\u836f\u54c1\u8fd9\u4e00\u4e8b\u5b9e\uff0c\u513f\u79d1\u60a3\u8005\u7684\u6807\u7b7e\u5916\u836f\u7269\u4f7f\u7528\u5df2\u6210\u4e3a\u5e38\u89c1\u505a\u6cd5\uff0c\u4f46\u4e0d\u80fd\u62d2\u7edd\u5fc5\u8981\u7684\u6cbb\u7597\u3002\u968f\u7740<\/span>P.IV.A.<\/span>\u4e2d\u63cf\u8ff0\u7684\u53d1\u5c55\uff0c\u73b0\u5728\u7684\u60c5\u51b5\u6709\u6240\u6539\u5584\uff0c\u4f46\u662f\u4ecd\u7136\u5b58\u5728\u8bb8\u591a\u533b\u7597\u6761\u4ef6\uff0c\u5176\u4e2d\u4e0d\u6ee1\u8db3\u5bf9\u7279\u5b9a\u513f\u79d1\u836f\u7269\u7684\u9700\u6c42\u5e76\u4e14\u6807\u7b7e\u5916\u4f7f\u7528\u4ecd\u5728\u7ee7\u7eed\u3002<\/span><\/strong>

<\/span><\/p>\n

Such off-label use, as discussed above, might expose paediatric patients to an increased risk of medication errors and of adverse reactions. Therefore, it is relevant that important risks arising from off-label use in paediatric patients are addressed appropriately (see P.IV.B.1.).<\/span><\/p>\n

\u5982\u4e0a\u6240\u8ff0\uff0c\u8fd9\u79cd\u6807\u7b7e\u5916\u4f7f\u7528\u53ef\u80fd\u4f7f\u513f\u79d1\u60a3\u8005\u66b4\u9732\u4e8e\u836f\u7269\u9519\u8bef\u548c\u4e0d\u826f\u53cd\u5e94\u7684\u98ce\u9669\u589e\u52a0\u3002\u56e0\u6b64\uff0c\u9002\u5f53\u5730\u89e3\u51b3\u513f\u79d1\u60a3\u8005\u6807\u7b7e\u5916\u4f7f\u7528\u4ea7\u751f\u7684\u91cd\u8981\u98ce\u9669<\/span>(<\/span>\u89c1<\/span>P.IV.B.1<\/span>.<\/span>)<\/span><\/strong><\/p>\n


<\/p>\n

P.IV.A.1.5. Clinical presentation of adverse reactions<\/span><\/strong><\/p>\n

P.IV.A.1.5<\/span><\/strong>.<\/span><\/strong>\u4e34\u5e8a\u8868\u73b0\u4e0d\u826f\u53cd\u5e94<\/span><\/strong>
<\/span><\/strong><\/p>\n

Signs and symptoms of adverse reactions and their clinical course may be different in paediatric patients compared to adults. This is also true among the various paediatric age sub-groups. Nonspecific symptoms, such as vomiting and diarrhoea as well as sleepiness or variation in the intensity and pattern of crying, can be the only manifestations of some adverse reaction observed in neonates, infants and toddlers. Moreover, symptoms that are dependent on patient communication ability (e.g.nausea, pain, mood alterations) in younger or mentally disabled children12 might be under- or misreported.<\/span><\/p>\n

\u4e0e\u6210\u4eba\u76f8\u6bd4\uff0c\u513f\u79d1\u60a3\u8005\u7684\u4e0d\u826f\u53cd\u5e94\u7684\u75c7\u72b6\u548c\u4f53\u5f81\u53ca\u5176\u4e34\u5e8a\u8fc7\u7a0b\u53ef\u80fd\u4e0d\u540c\u3002\u5728\u5404\u79cd\u513f\u79d1\u5e74\u9f84\u7ec4\u4e2d\u4e5f\u662f\u5982\u6b64\u3002\u975e\u7279\u5f02\u6027\u75c7\u72b6\uff0c\u4f8b\u5982\u5455\u5410\u548c\u8179\u6cfb\u4ee5\u53ca\u55dc\u7761\u6216\u5f3a\u5ea6\u548c\u54ed\u6ce3\u6a21\u5f0f\u7684\u53d8\u5316\uff0c\u53ef\u80fd\u662f\u5728\u65b0\u751f\u513f\uff0c\u5a74\u513f\u548c\u5e7c\u513f\u4e2d\u89c2\u5bdf\u5230\u7684\u4e00\u4e9b\u4e0d\u826f\u53cd\u5e94\u7684\u552f\u4e00\u8868\u73b0\u3002\u6b64\u5916\uff0c\u4f9d\u8d56\u4e8e\u5e74\u8f7b\u6216\u667a\u969c\u513f\u7ae5\u60a3\u8005\u6c9f\u901a\u80fd\u529b<\/span>(<\/span>\u4f8b\u5982\u6076\u5fc3\u3001\u75bc\u75db\u3001\u60c5\u7eea\u6539\u53d8<\/span>)<\/span>\u7684\u75c7\u72b6\u53ef\u80fd\u4f1a\u88ab\u4f4e\u4f30\u6216\u8bef\u62a5\u3002<\/span><\/strong><\/p>\n


<\/p>\n

This means that the clinical presentation of adverse reactions can be non-specific and be misinterpreted as the manifestation of a pre-existing condition. As such these reactions will be less likely to be suspected and reported.<\/span><\/p>\n

\u8fd9\u610f\u5473\u7740\u4e0d\u826f\u53cd\u5e94\u7684\u4e34\u5e8a\u8868\u73b0\u53ef\u80fd\u662f\u975e\u7279\u5f02\u6027\u7684\u88ab\u8bef\u89e3\u4e3a\u5148\u524d\u5b58\u5728\u7684\u6761\u4ef6\u7684\u8868\u73b0\u3002\u56e0\u6b64\uff0c\u8fd9\u4e9b\u53cd\u5e94\u4e0d\u592a\u53ef\u80fd\u88ab\u6000\u7591\u548c\u62a5\u544a\u3002<\/span><\/strong><\/p>\n


<\/p>\n

Aspects relating to the modalities of presentation of adverse reactions 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).<\/span><\/p>\n

\u5728\u9009\u62e9\u6700\u9002\u5408\u6267\u884c\u4fe1\u53f7\u68c0\u6d4b\u7684\u641c\u7d22\u672f\u8bed\u65f6\uff0c\u9700\u8981\u8003\u8651\u4e0e\u513f\u79d1\u4eba\u7fa4\u4e2d\u4e0d\u826f\u53cd\u5e94\u5448\u73b0\u65b9\u5f0f\u6709\u5173\u7684\u65b9\u9762<\/span>(<\/span>\u53c2\u89c1<\/span>P.IV.B.5<\/span>.<\/span>)(<\/span>\u4f8b\u5982\u6700\u4f4e\u7ea7\u522b\u672f\u8bed\u548c\u9996\u9009\u672f\u8bed<\/span>)<\/span>\u6267\u884c\u6807\u51c6\u5316<\/span>MedDRA<\/span>\u67e5\u8be2<\/span>(SMQ)<\/span>\u65f6\u3002\u5728\u89c4\u5212\u53ef\u80fd\u6d89\u53ca\u513f\u79d1\u533b\u751f\u548c\u7236\u6bcd<\/span>\/<\/span>\u7167\u987e\u8005\u7684\u79ef\u6781\u4f5c\u7528\u7684\u836f\u7269\u8b66\u6212\u6d3b\u52a8\u65f6\uff0c\u8fd9\u4e5f\u5f88\u91cd\u8981\uff0c\u56e0\u4e3a\u4ed6\u4eec\u5e94\u8be5\u80fd\u591f\u89e3\u91ca\u7279\u5b9a\u7684\u4f53\u5f81\u548c\u75c7\u72b6<\/span>(<\/span>\u4f8b\u5982\u54ed\u6ce3\u548c\u75bc\u75db<\/span>)<\/span>\u3002<\/span><\/strong><\/p>\n


<\/p>\n

P.IV.B. Structures and processes<\/span><\/strong><\/p>\n

P.IV.B.<\/span><\/strong>\u7ed3\u6784\u548c\u8fc7\u7a0b<\/span><\/strong><\/p>\n

P.IV.B.1. Risk management plan (RMP)<\/span><\/em><\/strong><\/p>\n

P.IV.B.1<\/span><\/em><\/strong>.<\/span><\/em><\/strong>\u98ce\u9669\u7ba1\u7406\u8ba1\u5212<\/span><\/em><\/strong>(RMP)<\/span><\/em><\/strong>
<\/span><\/em><\/strong><\/p>\n

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 \u2013 in integrated format13 includes considerations for the paediatric population. Methods used to minimise risk of adverse reactions 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.).<\/span><\/p>\n

GVP<\/span>\u6a21\u5757<\/span>V<\/span>\u4e2d\u7684\u98ce\u9669\u7ba1\u7406\u8ba1\u5212<\/span><\/span>(RMP)<\/span>\u7684\u5f53\u524d\u8981\u6c42\u548c\u6b27\u76df\u98ce\u9669\u7ba1\u7406\u8ba1\u5212<\/span>(RMP)<\/span>\u683c\u5f0f\u7684\u6307\u5357<\/span>–<\/span>\u4ee5\u7efc\u5408\u683c\u5f0f<\/span>\u5305\u62ec\u5bf9\u513f\u79d1\u4eba\u7fa4\u7684\u8003\u8651\u3002\u8003\u8651\u5230\u513f\u79d1\u60a3\u8005\u7279\u6709\u7684\u65b9\u9762<\/span>(P.IV.A.1<\/span><\/span>.<\/span>)<\/span>\uff0c\u5e94\u8bc4\u4f30\u5e76\u9002\u5e94\u513f\u79d1\u60a3\u8005\u7684\u65b9\u6cd5\uff0c\u4ee5\u5c3d\u91cf\u51cf\u5c11\u6210\u4eba\u4eba\u7fa4\u4e2d\u4e0d\u826f\u53cd\u5e94\u7684\u98ce\u9669\u3002<\/span><\/strong><\/p>\n


<\/p>\n

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 questions (e.g. accumulation of active substance in some organs of the animals tested, impairment in some behavioural tests).<\/span><\/p>\n

\u5c31\u4e34\u5e8a\u524d\u8bc1\u636e\u800c\u8a00\uff0c\u5e7c\u5e74\u52a8\u7269\u6bd2\u7406\u5b66\u7814\u7a76\u7684\u7ed3\u679c\u53ef\u4ee5\u5bf9\u513f\u79d1\u4eba\u7fa4\u7684\u5f71\u54cd\u5177\u6709\u9884\u6d4b\u4ef7\u503c\uff0c\u5e76\u4e14\u53ef\u4ee5\u652f\u6301\u4f18\u5148\u8003\u8651\u836f\u7269\u8b66\u6212\u7814\u7a76\u95ee\u9898<\/span>(<\/span>\u4f8b\u5982\uff0c\u5728\u6d4b\u8bd5\u52a8\u7269\u7684\u67d0\u4e9b\u5668\u5b98\u4e2d\u6d3b\u6027\u7269\u8d28\u7684\u79ef\u7d2f\uff0c\u4e00\u4e9b\u884c\u4e3a\u6d4b\u8bd5<\/span>)<\/span>\u3002<\/span><\/strong><\/p>\n


<\/p>\n

Regarding 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.<\/span><\/p>\n

\u5173\u4e8e\u73b0\u6709\u7684\u4e34\u5e8a\u6570\u636e\uff0c\u4ece\u6210\u4eba\u4eba\u7fa4\u7684\u7814\u7a76\u4e2d\u83b7\u5f97\u7684\u77e5\u8bc6\u5e94\u8be5\u6709\u52a9\u4e8e\u8bc6\u522b\u91cd\u8981\u7684\u6f5c\u5728\u98ce\u9669\uff0c\u786e\u5b9a\u5b89\u5168\u6982\u51b5\u7684\u7279\u5f81\u4ee5\u53ca\u964d\u4f4e\u4e0e\u4f7f\u7528\u4ea7\u54c1\u6709\u5173\u7684\u98ce\u9669\u7684\u5de5\u5177\u7684\u63cf\u8ff0\u513f\u79d1\u4eba\u7fa4\u3002<\/span><\/strong><\/p>\n


<\/p>\n

Sometimes 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.<\/span><\/p>\n

\u6709\u65f6\uff0c\u4e0d\u5b58\u5728\u6765\u81ea\u6210\u4eba\u7684\u5148\u524d\u4e34\u5e8a\u6216\u771f\u5b9e\u6570\u636e\uff1a\u5f53\u4e13\u95e8\u4e3a\u513f\u79d1\u60a3\u8005\u6388\u6743\u836f\u7269\u6216\u540c\u65f6\u6388\u6743\u6210\u4eba\u548c\u513f\u79d1\u60a3\u8005\u65f6\uff0c\u53ef\u80fd\u4f1a\u53d1\u751f\u8fd9\u79cd\u60c5\u51b5\u3002<\/span><\/strong>

<\/span><\/p>\n

Conversely, a paediatric indication might be added after considerable post-marketing experience has been gained in adults. Therefore, the amount of available evidence can vary greatly.<\/span><\/p>\n

\u76f8\u53cd\uff0c\u5728\u6210\u4eba\u83b7\u5f97\u76f8\u5f53\u5927\u7684\u4e0a\u5e02\u540e\u7ecf\u9a8c\u540e\uff0c\u53ef\u80fd\u4f1a\u589e\u52a0\u513f\u79d1\u9002\u5e94\u75c7\u3002\u56e0\u6b64\uff0c\u73b0\u6709\u8bc1\u636e\u7684\u6570\u91cf\u53ef\u80fd\u5dee\u522b\u5f88\u5927\u3002<\/span><\/strong><\/p>\n


<\/p>\n

Particularly important aspects to be considered for paediatric patients for the purpose of risk identification and characterisation include:<\/span><\/p>\n

\u4e3a\u4e86\u98ce\u9669\u76ee\u7684\uff0c\u513f\u79d1\u60a3\u8005\u9700\u8981\u8003\u8651\u7684\u7279\u522b\u91cd\u8981\u7684\u65b9\u9762\u8bc6\u522b\u548c\u8868\u5f81\u5305\u62ec\uff1a<\/span><\/strong>
<\/span><\/p>\n

\u2022 <\/span><\/span>age-related shifts in the interaction of the medicinal product with its target organs or tissues;<\/span><\/p>\n

\u2022<\/span>\u836f\u7269\u4e0e\u5176\u9776\u5668\u5b98\u6216\u7ec4\u7ec7\u76f8\u4e92\u4f5c\u7528\u7684\u5e74\u9f84\u76f8\u5173\u53d8\u5316<\/span>\uff1b<\/span><\/strong><\/p>\n


<\/p>\n

\u2022<\/span>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;<\/span><\/p>\n

\u2022<\/span>\u5438\u6536\u3001\u5206\u5e03\u3001\u4ee3\u8c22\u548c\u6392\u6cc4<\/span>(ADME)<\/span>\u7684\u4e2a\u4f53\u53d1\u751f\uff0c\u5305\u62ec\u6d3b\u6027\u7269\u8d28\u5728\u4e2a\u4f53\u5185\u7ed3\u6784<\/span>(<\/span>\u4f8b\u5982\u8840\u8111\u5c4f\u969c<\/span>)<\/span>\u4e2d\u7684\u5904\u7f6e<\/span>\uff1b<\/span><\/strong>
<\/span><\/p>\n

\u2022 <\/span><\/span>potential adverse reactions due to different exposure to (different) metabolites as opposed to the adult age;<\/span><\/p>\n

\u2022<\/span>\u4e0e\u6210\u5e74\u4eba\u76f8\u6bd4\uff0c\u7531\u4e8e\u4e0d\u540c\u7684<\/span>(<\/span>\u4e0d\u540c<\/span>)<\/span>\u4ee3\u8c22\u7269\u63a5\u89e6\u800c\u4ea7\u751f\u7684\u6f5c\u5728\u4e0d\u826f\u53cd\u5e94<\/span><\/strong>\uff1b<\/span><\/p>\n


<\/p>\n

\u2022 <\/span><\/span>long-term effect on developing reproductive and neurodevelopmental systems;<\/span><\/p>\n

\u2022<\/span>\u5bf9\u53d1\u5c55\u751f\u6b96\u548c\u795e\u7ecf\u53d1\u80b2\u7cfb\u7edf\u7684\u957f\u671f\u5f71\u54cd<\/span>\uff1b<\/span>
<\/span><\/strong><\/p>\n

\u2022 <\/span><\/span>effects on bone and cartilage during active growth phase;<\/span><\/p>\n

\u2022<\/span>\u5728\u6d3b\u8dc3\u751f\u957f\u9636\u6bb5\u5bf9\u9aa8\u9abc\u548c\u8f6f\u9aa8\u7684\u5f71\u54cd<\/span>\uff1b<\/span><\/strong>
<\/span><\/p>\n

\u2022 <\/span><\/span>impact on maturation of the immune system in the pathogenesis of known adverse reactions and effect of transition from passive maternal immunity to maturing immune systems in infants.<\/span><\/p>\n

\u2022<\/span>\u5728\u5df2\u77e5\u4e0d\u826f\u53cd\u5e94\u7684\u53d1\u75c5\u673a\u5236\u4e2d\u5bf9\u514d\u75ab\u7cfb\u7edf\u6210\u719f\u7684\u5f71\u54cd\u4ee5\u53ca\u5a74\u513f\u4ece\u88ab\u52a8\u6bcd\u4f53\u514d\u75ab\u5411\u6210\u719f\u514d\u75ab\u7cfb\u7edf\u8fc7\u6e21\u7684\u5f71\u54cd\u3002<\/span><\/strong><\/p>\n


<\/p>\n

Evaluation of these aspects can help in assessing whether a risk of adverse reactions for a given medicine might differ from the adult population and whether its pharmacological properties suggest any possibility of developmental risk.<\/span><\/p>\n

\u5bf9\u8fd9\u4e9b\u65b9\u9762\u7684\u8bc4\u4f30\u6709\u52a9\u4e8e\u8bc4\u4f30\u7ed9\u5b9a\u836f\u7269\u7684\u4e0d\u826f\u53cd\u5e94\u98ce\u9669\u662f\u5426\u53ef\u80fd\u4e0e\u6210\u5e74\u4eba\u7fa4\u4e0d\u540c\uff0c\u4ee5\u53ca\u5176\u836f\u7406\u5b66\u7279\u6027\u662f\u5426\u8868\u660e\u5b58\u5728\u53d1\u80b2\u98ce\u9669\u7684\u53ef\u80fd\u6027\u3002<\/span><\/strong><\/p>\n


<\/p>\n

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.<\/span><\/p>\n

\u540c\u6837\uff0c\u5f53\u9884\u8ba1\u513f\u79d1\u4eba\u7fa4\u7684\u4e00\u4e2a\u4e9a\u7ec4\u53ef\u80fd\u4e0e\u6210\u5e74\u4eba\u7fa4\u4e0d\u540c\u65f6<\/span>(<\/span>\u4f8b\u5982\uff0c\u9752\u6625\u671f\u540e\u7684\u513f\u7ae5\uff0c\u8d85\u8fc7\u4e00\u5b9a\u5e74\u9f84\u548c<\/span>\/<\/span>\u6216\u4f53\u91cd\u7684\u513f\u7ae5<\/span>)<\/span>\uff0c\u8fd9\u5e94\u5f97\u5230\u8bc1\u636e\u7684\u652f\u6301\uff0c\u5e76\u5728\u521d\u59cb\u4e0a\u5e02\u6388\u6743\u7533\u8bf7\u7684\u65f6\u95f4\u3002<\/span><\/strong>
<\/span><\/p>\n

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 – consideration 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.<\/span><\/span><\/p>\n

\u5982\u679c\u7a81\u51fa\u663e\u793a\u7279\u5b9a\u7684\u513f\u79d1\u98ce\u9669\u5e76\u5c06\u5176\u5217\u4e3a<\/span>RMP<\/span>\u4e2d\u7684\u5b89\u5168\u95ee\u9898<\/span>–<\/span>\u6839\u636e<\/span>GVP<\/span>\u6a21\u5757<\/span>V<\/span>\u4e2d\u63d0\u4f9b\u7684\u6307\u5bfc<\/span>–<\/span>\u5e94\u8003\u8651\u662f\u5426\u8fdb\u884c\u513f\u79d1\u6388\u6743\u540e\u5b89\u5168\u6027\u7814\u7a76<\/span>(PASS)(<\/span>\u53c2\u89c1<\/span>P. IV.B.4<\/span>.<\/span>)<\/span>\u9002\u5408\u8fdb\u4e00\u6b65\u8868\u5f81\u8fd9\u79cd\u98ce\u9669\u3002<\/span><\/strong><\/p>\n

\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"<\/p>\n

\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"\"\u6cd5\u89c4\u901f\u9012\uff5c\uff08\u6b27\u76df\uff09\u826f\u597d\u7684\u836f\u7269\u8b66\u6212\u5b9e\u8df5\u6307\u5357(GVP)\"<\/p>\n

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 considered by the marketing authorisation holder to enable the conduction of appropriate PASS to follow-up and appropriately document long-term safety.<\/span><\/p>\n

\u5728\u5f00\u53d1\u6cbb\u7597\u513f\u7ae5\u60a3\u8005\u7f55\u89c1\u75be\u75c5\u7684\u836f\u7269\u7684\u60c5\u51b5\u4e0b\uff0c\u513f\u7ae5\u6570\u636e\u7f3a\u4e4f\u6216\u975e\u5e38\u6709\u9650\uff0c\u4e0a\u5e02\u8bb8\u53ef\u6301\u6709\u4eba\u53ef\u4ee5\u8003\u8651\u767b\u8bb0\u6216\u5176\u4ed6\u957f\u671f\u6570\u636e\u6536\u96c6\u624b\u6bb5\uff0c\u4ee5\u4fbf\u9002\u5f53\u7684<\/span>PASS(<\/span>\u4e0a\u5e02\u540e\u836f\u54c1\u7684\u5b89\u5168\u4e60\u6027\u7814\u7a76<\/span>)<\/span>\u8ddf\u8fdb\u5e76\u9002\u5f53\u8bb0\u5f55\u957f\u671f\u5b89\u5168\u6027\u3002<\/span><\/strong><\/span><\/p>\n


<\/p>\n

In these cases, high level planning of paediatric registries and related PASS should already be considered 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.).<\/span><\/p>\n

\u5728\u8fd9\u4e9b\u60c5\u51b5\u4e0b\uff0c\u5728\u63d0\u4ea4<\/span>PIP<\/span>\u65f6\u5e94\u8be5\u8003\u8651\u513f\u7ae5\u767b\u8bb0\u5904\u548c\u76f8\u5173<\/span>PASS(<\/span>\u4e0a\u5e02\u540e\u836f\u54c1\u7684\u5b89\u5168\u4e60\u6027\u7814\u7a76<\/span>)<\/span>\u7684\u9ad8\u7ea7\u522b\u89c4\u5212<\/span>(<\/span>\u89c1<\/span>P.IV.C.2<\/span>)<\/span>\uff0c\u4ee5\u4fc3\u8fdb\u9884\u5148\u751f\u6210\u5b89\u5168\u6570\u636e\u7684\u8fde\u7eed\u6027\u3002<\/span> <\/span>\u548c\u6388\u6743\u540e\u9636\u6bb5<\/span>(<\/span>\u5982<\/span>P.IV.B.4<\/span>\u4e2d\u5f3a\u8c03\u7684<\/span>)<\/span>\u3002<\/span><\/strong><\/span><\/p>\n


<\/p>\n

The consultation 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.<\/span><\/p>\n

\u4e13\u5bb6\u7f51\u7edc\u7684\u54a8\u8be2<\/span>(<\/span>\u4f8b\u5982\u6b27\u6d32\u836f\u7269\u6d41\u884c\u75c5\u5b66\u548c\u836f\u7269\u8b66\u6212\u4e2d\u5fc3\u7f51\u7edc<\/span>(ENCePP))<\/span>\u4ee5\u53ca\u9002\u5f53\u7684\u513f\u7ae5\u4e34\u5e8a\u8bd5\u9a8c\u7f51\u7edc<\/span>(<\/span>\u4f8b\u5982\u6b27\u6d32\u836f\u54c1\u7ba1\u7406\u5c40\u7684\u6b27\u6d32\u513f\u7ae5\u7814\u7a76\u7f51\u7edc<\/span>(Enpr-EMA))<\/span>\u53ef\u80fd\u6709\u52a9\u4e8e\u89e3\u51b3\u4e0e\u513f\u7ae5\u7684<\/span>PASS<\/span>\u8bbe\u8ba1\u548c\u5b9e\u65bd\u76f8\u5173\u7684\u5177\u4f53\u65b9\u9762\u3002\u8fd8\u9f13\u52b1\u6b27\u76df\u7684\u7533\u8bf7\u4eba<\/span>\/<\/span>\u4e0a\u5e02\u8bb8\u53ef\u6301\u6709\u4eba\u5411\u673a\u6784\u8bf7\u6c42\u5173\u4e8e<\/span>PASS<\/span>\u534f\u8bae\u7279\u5b9a\u65b9\u9762\u7684\u79d1\u5b66\u5efa\u8bae<\/span>(SA)<\/span>\uff0c\u7279\u522b\u662f\u9488\u5bf9\u590d\u6742\u6216\u6709\u4e89\u8bae\u7684\u95ee\u9898\u6216\u521b\u65b0\u65b9\u6cd5\u6216\u65b9\u6cd5\uff0c\u5305\u62ec\u513f\u7ae5\u7814\u7a76\u3002<\/span><\/strong><\/span><\/p>\n


<\/p>\n

P.IV.C.6. Signal management within the EU regulatory network<\/span><\/strong><\/span><\/p>\n

P.IV.C.6. <\/span><\/span>\u6b27\u76df\u76d1\u7ba1\u7f51\u7edc\u5185\u7684\u4fe1\u53f7\u7ba1\u7406<\/span><\/strong><\/span><\/p>\n

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).<\/span><\/p>\n

\u9664\u4e86<\/span>P.IV.B.5.<\/span>\u4e2d\u7684\u6307\u5bfc\uff0c\u513f\u7ae5\u60a3\u8005\u7684<\/span>ICSR(<\/span>\u4e2a\u4f8b\u5b89\u5168\u6027\u62a5\u544a<\/span>)<\/span>\u5e94\u901a\u8fc7\u6b27\u76df\u836f\u7269\u8b66\u6212\u76d1\u7ba1\u7cfb\u7edf\u63d0\u4f9b\u7684\u5de5\u5177\u4e0e\u6210\u4eba\u60a3\u8005\u7684<\/span>ICSR(<\/span>\u4e2a\u4f8b\u5b89\u5168\u6027\u62a5\u544a<\/span>)<\/span>\u5206\u5f00\u8fdb\u884c\u5206\u6790<\/span>(<\/span>\u4f8b\u5982\u7535\u5b50\u53cd\u5e94\u76d1\u6d4b\u62a5\u544a<\/span>(eRMR))<\/span>\u3002<\/span><\/strong><\/span><\/p>\n


<\/p>\n

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.<\/span><\/p>\n

\u5efa\u8bae\u4e0d\u4ec5\u4f7f\u7528\u6709\u5173\u513f\u7ae5\u60a3\u8005\u7684<\/span>ICSR(<\/span>\u4e2a\u4f8b\u5b89\u5168\u6027\u62a5\u544a<\/span>)<\/span>\u8ba1\u7b97\u4e0d\u6210\u6bd4\u4f8b\u62a5\u544a\u7684\u7edf\u8ba1\u6570\u636e<\/span>(<\/span>\u53c2\u89c1<\/span>GVP(<\/span>\u836f\u7269\u8b66\u6212\u7ba1\u7406\u89c4\u8303<\/span>)<\/span>\u6a21\u5757<\/span>IX<\/span>\u9644\u5f55<\/span>I<\/span>)<\/span>\uff0c\u4ee5\u63d0\u9ad8\u4ece\u9002\u5f53\u6570\u636e\u5e93<\/span>(<\/span>\u5373\u6b27\u76df\u836f\u7269\u8b66\u6212\u76d1\u7ba1\u7cfb\u7edf<\/span>)<\/span>\u53bb\u6bd4\u4f8b\u5316\u62a5\u544a\u7edf\u8ba1\u503c<\/span>(SDR)<\/span>\u7684\u513f\u7ae5\u4fe1\u53f7\u7684\u80fd\u529b\u3002\u6309\u5e74\u9f84\u8fdb\u884c\u5206\u6790\uff0c\u5e76\u6bd4\u8f83\u513f\u7ae5\u60a3\u8005\u4e0e\u6210\u4eba\u7684\u4e0d\u6210\u6bd4\u4f8b\u7edf\u8ba1\u6570\u636e<\/span>(<\/span>\u5982\u679c\u9002\u7528\uff0c\u53d6\u51b3\u4e8e\u6570\u636e\u96c6\u7684\u5927\u5c0f<\/span>)<\/span>\uff0c\u6709\u52a9\u4e8e\u786e\u5b9a\u513f\u7ae5\u60a3\u8005\u662f\u5426\u53ef\u80fd\u66f4\u9891\u7e41\u5730\u53d1\u751f\u7591\u4f3c\u4e0d\u826f\u53cd\u5e94\u3002<\/span><\/strong><\/span><\/p>\n


<\/p>\n

P.IV.C.7. Safety communication in the EU<\/span><\/em><\/strong><\/span><\/p>\n

P.IV.C.7. <\/span><\/span><\/em><\/strong>\u6b27\u76df\u7684\u5b89\u5168\u901a\u4fe1<\/span><\/em><\/strong><\/span><\/p>\n

Further to the guidance in P.IV.B.5., children and their families in the EU can be consulted 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 Consumers Within EMA Activities27). The Enpr-EMA Working Group on Young Persons 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.<\/span><\/p>\n

\u7ee7<\/span>P.IV.B.5.<\/span>\u4e2d\u7684\u6307\u5bfc\uff0c\u6b27\u76df\u7684\u4e0a\u5e02\u8bb8\u53ef\u6301\u6709\u4eba\u53ef\u4ee5\u54a8\u8be2\u6b27\u76df\u513f\u7ae5\u53ca\u5176\u5bb6\u4eba\uff0c\u4ee5\u53ca\u673a\u6784\u548c\u6210\u5458\u56fd\u4e3b\u7ba1\u5f53\u5c40\u901a\u8fc7\u5df2\u5efa\u7acb\u7684\u5e74\u8f7b\u4eba\u54a8\u8be2\u5c0f\u7ec4\uff0c\u4e3a\u5176\u4ed6<\/span>RMM<\/span>\u51c6\u5907\u548c\u4fee\u8ba2\u5b89\u5168\u901a\u4fe1\u548c\u6559\u80b2\u6750\u6599<\/span>(<\/span>\u53c2\u89c1<\/span>EMA(<\/span>\u6b27\u6d32\u836f\u7269\u7ba1\u7406\u5c40<\/span>)<\/span>\u5173\u4e8e\u9752\u5e74\u60a3\u8005\u548c\u6d88\u8d39\u8005\u53c2\u4e0e\u7684\u539f\u5219<\/span>)<\/span>\u3002<\/span>Enpr-EMA<\/span>\u9752\u5e74\u54a8\u8be2\u5c0f\u7ec4\u5de5\u4f5c\u7ec4<\/span>(YPAG)<\/span>\u76ee\u524d\u81f4\u529b\u4e8e\u8d44\u6e90\u548c\u5efa\u7acb\u4e92\u52a8\u6846\u67b6\uff0c\u8be5\u6846\u67b6\u5c06\u53ef\u4f9b\u673a\u6784\u548c\u6b27\u76df\u76d1\u7ba1\u7f51\u7edc\u4ee5\u53ca\u6b27\u76df\u7684\u4e0a\u5e02\u8bb8\u53ef\u6301\u6709\u4eba\u4f7f\u7528\u3002<\/span><\/strong><\/span><\/p>\n

\uff08\u5b8c\uff09
<\/p>\n<\/p><\/div>\n","protected":false},"excerpt":{"rendered":"

25 October 2018EMA\/572054\/2016 Product- or Population-S […]<\/p>\n","protected":false},"author":1,"featured_media":77768,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[2],"tags":[],"_links":{"self":[{"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/posts\/77767"}],"collection":[{"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/comments?post=77767"}],"version-history":[{"count":1,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/posts\/77767\/revisions"}],"predecessor-version":[{"id":77800,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/posts\/77767\/revisions\/77800"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/media\/77768"}],"wp:attachment":[{"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/media?parent=77767"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/categories?post=77767"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/tags?post=77767"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}