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EMA/CHMP/QWP/104223/2015（草案）：
在评价化学物质是否新活性物质（NAS）
时考虑的化学结构和特性标准
2015-05-10
26March 2015
EMA/CHMP/QWP/104223/2015
Committeefor Medicinal Products for Human Use (CHMP)
Reflection paper on thechemical structure and properties criteria to be considered for the evaluationof New Active Substance (NAS) status of chemical substances
在评价化学物质是否新活性物质（NAS）时
考虑的化学结构和特性标准
Draft 草案
Draft agreed by the QWP
由QWP同意草案
Draft adopted by the CHMP release for consultation
由CHMP采纳并公开征求意见
Draft endorsed by CMD(h)
草案由CMD(h)采纳
Start of public consultation
开始公开征求意见
End of consultation (deadline for comments)
公开征求意见截止
Comments should be provided using this template. The completed comments form should be sent to qwp@ema.europa.eu
Keywords New Active Substances, NAS, salts, complexes, isomers, mixtures of isomers, derivative, esters and ethers
关键词 新活性物质，NAS，盐，复合物，异构体，异构体混合物，衍生物，酯和醚
Table of contents 目录
ExecutiveSummary 摘要
1.Introduction 概述
1.1.Scope 范围
1.2.Legal basis and relevant guidelines 法律依据和相关指南
2.Discussion and guidance 讨论和指南
2.1.Isomers 异构体
2.2.Mixtures of isomers 异构体混合物
2.3.Complexes 复合物
2.4.Derivative 衍生物
2.5.Esters and ethers 酯和醚
2.6.Salts 盐
2.7.Solid state forms and NAS status 固体状态和NAS状态
2.8.Documentation 文件记录
3.References 参考文献
ExecutiveSummary 摘要
Thisreflection paper is intended to reflect the current Experience of the QualityWorking Party (QWP), of the Committee for Medicinal Products for Human Use(CHMP) and the Co-ordination Group for Mutual Recognition and DecentralisedProcedures-Human (CMDh) concerning the definition of a New Active Substance(NAS) in the context of preparation of dossiers and submissions of applicationsfor Marketing Authorisation (MAA) in the Centralised Procedure (CP), the MutualRecognition Procedure (MRP)/Decentralised Procedure (DCP) and purely nationalprocedures for chemical medicinal products for human use.
本思考文意在反映目前质量工作组（QWP）和人药委员会（CHMP）及互认和人药非集中审评程序（CMDh）协调组关于新活性物质（NAS）在准备申报文件时，和采用集中审评程序（CP）、互认程序（MRP）/非集中审评程序（DCP）以及单个国家审评程序提交人用化学药品上市许可（MAA）申报时的经验。
Thepaper describes the chemical structure and properties criteria to be taken intoaccount by the CHMP to qualify a chemical active substance as NAS, as well asthe required elements to be submitted by applicants to substantiate theirclaims.
本文描述了CHMP认可一个化学活性物质为NAS时所考虑的化学结构和特性标准，以及申报人所需提交证明其观念的要素。
1.Introduction 概述
Thisreflection paper intends to provide clarifications for applicants on theelements to qualify an active substance as NAS in the light of Article 10.2b ofDirective 2001/83/EC and the Chapter I -Volume 2A of Notice to Applicants, aswell as the evidence required. However it cannot cover every scenario, andtherefore applicants are invited to obtain scientific advice for scenarios notcovered in this reflection paper.
本文意在为申报人根据指令2001/83/EC第10.2b条提供关于确认一个活性物质为NAS时的要素的说明。但是，它无法覆盖所有的情形，因此欢迎申报人向相关机构获取本思考文中未覆盖的情形的科学建议。
Theabove assessment is without prejudice to any assumption at the time ofeligibility to the CP, MRP/DCP procedures, or to the grant of an InternationalNon-proprietary Name (INN) by the WHO.
上述评估在对根据CP、MRP/DCP程序或是认可WHO给定的国际通用名时所用的假设没有偏见。
Eligibilityto the CP based on the claim that the medicinal product for human use containsa new active substance must be dissociated from the assessment of thescientific data submitted in support of the NAS claim during evaluation of themarketing authorisation application. Agreement on designation as a NAS can onlybe made after a detailed assessment of the application.
认可人用药品中含有一种新的活性物质从而适用CP程序，必须与上市许可申请评审过程中对所提交的NAS声明支持性科学数据的评估分开。只有在对申报文件做出详细的评审后，才能认可其中活性物质为NAS。
Applicantsare invited to consult the ‘pre-submission guidance’ on the EMA website forfurther details on the eligibility to the CP.
欢迎申报人在EMA网站上的“申报前指南”中寻找更多CP程序资格认可的详细信息。
1.1.Scope 范围
Thisreflection paper describes the chemical structure and properties criteria to betaken into account to qualify a chemical active substance as NAS, as well asthe required elements to be submitted by applicants. It applies to marketingauthorisation applications including solely chemical active substance(s)eligible to the centralised and MPR/DCP and purely national procedures.
本思考文描述了认可一个化学活性物质为NAS时所考虑的化学结构和特性标准，以及申报人所需提交证明其观念的要素。它适用于上市许可申报，包括适用集中审评程序和MPR/DCP和单个国家审评程序的单个化学活性物质。
Biologicaland biotechnological active substances and active substances to be included inradiopharmaceutical medicinal products are excluded from the scope of thisreflection paper.
生物制品和生物活性物质以及要包括在辐射药品中的活性物质不在此思考文章的范围之内。
1.2.Legal basis and relevant guidelines 法律依据和相关指南
Directive2001/83/EC
指令2001/83/EC
Article10.2.b of Directive 2001/83/EC states:
指令2001/83/EC的第10.2b条规定：
“[...]The different salts, esters, ethers, isomers, mixture of isomers, complexes orderivatives of an active substance shall be considered to be the same activesubstance unless they differ significantly in properties with regard to safety and/or efficacy. In such cases,additional information providing proof of the safety and/or efficacy of thevarious salts, esters or derivatives of an authorised active substance must besupplied by the applicant [...].”
“……一个活性物质不同的盐、、酯、异构体、异构混合物、复合物或衍生物应被认为是相同的活性物质，除非它们在安全性和/或有效性的特性上有显著差异。在这种情形下，申报者必须提交更多资料来证明已批准活性物质的不同的盐、酯或衍生物的安全性和/或有效性……”
Furtherinformation can be found in the Annex 1, Volume 2A, Chapter 1 of the Notice toApplicants (NtA).
更多信息可以在申报者须知（NTA）卷2A第1章附录1中找到。
2.Discussion and guidance 讨论和指南
Achemical active substance that is not previously authorized in a medicinalproduct for human use in the European Union and that is from a chemicalstructure point of view not related to any other authorised substances shouldbe considered as a NAS. Such substance is considered to be new in itself, whenthe structure of the therapeutic moiety is different from any other authorisedso far as a medicinal product for human use.
一种之前在欧盟未批准为人药成份，并且从化学结构的角度来说与其它任何已批准的物质不相关的化学活性物质应被视为是一个NAS。如果治疗片断的结构区别于任何其它已批准的人药成分，则该物质被认为是新的。
Ifthe chemical active substance is structurally related as a salt, ester, ether,isomer, mixture of isomers, complex or derivative of an already approved activesubstance(s) in the European Union, it should be assessed whether it shares thesame therapeutic moiety at the site of the biological activity as the alreadyapproved active substance and if so whether it differs significantly inproperties with regard to safety and /or efficacy.
如果一种化学活性物质在结构上是欧盟已批准的活性物质的盐、酯、异构体、异构混合物、复合物或衍生物，则需要评估其是否与已批准的活性物质在相同的生物活性位置具有相同的治疗片断，如果是的，它在安全性和/或有效性方面是否具有显著的差异。
Guidanceis provided below to define the elements taken into account to qualify anactive substance as salt, ester, ether, isomer, mixture of isomers, complex orderivative of another one in the context of the NAS status claim.
以下给出了根据 NAS状态声明来定义在确认一种活性物质是另一种活性物质的盐、酯、异构体、异构混合物、复合物或衍生物时需要考虑的要素。
2.1.Isomers 异构体
Isomersshould in this context be understood as enantiomers. Other types of isomers arepresumed not to share the same therapeutic moiety unless they are able toisomerise in vivo. Stereoisomers related to each other as enantiomers have thesame connectivity but are non-superimposable mirror images of each other. Thisimplies that enantiomers Have the same chemical and physical properties (excepttheir ability to rotate plane polarized light), i.e. act in exactly the samemanner, except when they interact with other chiral structures.
异构体在本文中应被理解为对映异构体。其它类型的异构体被假定不会具有相同的治疗片断，除非可以在体内异构化。相互有关的立体异构体作为对映异构体具有相同的连通性，但相互是非重叠镜像。这表示该对映异构体具有相同的化学和物理特性（除非他们可能旋转平面偏振光），即以完全相同的方式起作用，除了其与其它手性结构相互作用时以外。
Inthe case one enantiomer is applied for where the other enantiomer is the activesubstance in a previously authorised medicinal product for human use within theEuropean Union it has to be assessed whether they differ significantly withrespect to safety and/or efficacy properties. This assessment will be based onthe data provided by the applicant.
如果申报的活性物质是一种对映异构体，而另一个对映异构体之前已在欧盟被批准为人用药的活性物质，则必须评估这两种对映异构体是否具有不同的安全性和/或有效性。该评估将根据申报人所提交的数据来展开。
Whenan isomer that is not the enantiomer of an already approved active substance(diastereoisomer, geometrical isomer, regioisomer, constitutional isomer etc.)is applied for it is presumed that it will not expose the patients to the sametherapeutic moiety, unless it is able to isomerise in vivo, and could beconsidered as NAS. In such cases, evidence that the substance is not able toisomerise in vivo may need to be provided.
如果所申报的异构体并非已批准的活性物质的手性异构体（非对映手性异构体、几何异构体、位置异构体、构造异构体等），则假定患者不会暴露于相同的治疗分子。除非在体内会异构化，并可以认为是NAS。在这种情形下，可能需要提交证据证明该物质在体内不会异构化。
2.2.Mixtures of isomers 异构体混合物
Wherea previously authorised medicinal product for human use in the European Unionincludes a racemate and a new application for only one of the two enantiomersof the racemate is submitted, this enantiomer would have been a substantialpart (50%) of the racemate and would therefore be considered as the same activesubstance as the racemic mixture, unless the applicant provides evidence thatthe two substances differ significantly in properties with regard to safetyand/or efficacy.
如果之前在欧盟已批准的人药包括了一个外消旋物，所提交的新申报是外消旋物里2种对映异构体中的一个，则该对映异构体是外消旋体的显著成分（50%），就要被认为与外消旋混合物是同一种活性物质。除非申报人提供证据证明2种物质具有显著不同的安全和/或有效性质。
This does also apply to other situations where mixtures ofdiastereoisomers or other isomers have been authorised as medicinal productsfor human use and a new application contains only one of the isomers of themixture.
这也适用于其它情形，即非对映异构体或其它对映异构体的混合物已被批准作为人药，或一个新的申报中只含有混合物中的对映异构体的一种。
2.3.Complexes 复合物
Theterm ‘complexes’ encompasses several types of structures. Two examples ofcomplexes used as medicinal products for human use can be found below.
术语复合物指示几种结构类型。用于人药的复合物的2个例子如下：
a) Complexes intended to releasean active substance that is entrapped by the complex in the blood circulationor elsewhere. Examples of such complexes are e.g. piroxicam betadex or nicotinebetadex.
用于释放活性物质的复合物，该复合物将活性物质限制在血液循环中或其它地方，这种复合物的例子如吡罗昔康倍他环糊精复合物或尼古丁倍他环糊精复合物。
b) Another type of complexes isthose that are intended to remain intact in the body. There are e.g. a numberof gadolinium complexes, with different complexing ligands, and with extremelylow dissociation constant. They exhibit their effect by distributing gadoliniumto places where it enhances the images obtained by NMR imaging. Due to thetoxicity of free gadolinium they are designed to remain intact (not dissociateand release the metal).
另一种类型的复合物是那些用来将活性物质完整地保持在体内的，例如大量的钆复合物，具有不同的复合配位体，离解常数很低。他们通过将钆分布在一些地方来增强获得NMR图像。由于游离钆的毒性，它们的设计是要保持其完整性（不会离解和释放金属）。
Complexesof the category a. above prepared from an already approved active substance aredesigned to release the original substance in vivo and will consequently not beconsidered as NAS in themselves. Therefore the NAS status will have to bejustified by significant differences with regard to safety and/or efficacy. Onthe contrary, complexes of the category b. exhibit their effect withoutdissociating, and different ligands may be used to complex the same metal.Because they do not dissociate the therapeutic moieties are presumed to bedifferent and could be considered as NAS. In such cases, evidence that thecomplex does not dissociate may need to be provided.
上述a类的复合物是从已批准的活性物质制备，其设计目的是在体内释放出原始物质，因而其自身不被认为是NAS。如果需要认可其NAS状态，则必须证明其与原始活性物质具有显著不同的安全性和/或有效性。相反，b类复合物的效果则不需要离解，不同的配位体可以用于复合相同的金属。由于其并不会离解，因此其治疗片断被认为是不同的，可以被认为是NAS。在这种情形下，可能需要提供该复合物不会离解的证据。
2.4.Derivative 衍生物
Theterm derivative, in the context of this reflection paper, includes relatedactive substances which expose the patient to the same therapeutic moiety.
术语衍生物在本思考文中包括患者暴露于相同治疗部分的相关的活性物质
Thisincludes notably situations: 特别包括以下情形
a) Where the original substance orits active metabolite(s) in vivo will be derived from the new applied substancein such a manner that the patients are exposed to the same therapeutic moietyof the original substance (the applied substance is a prodrug).
如果原始的物质或其体内活性代谢物不会从新的所用物质中衍生出，患者暴露于与原始物质同的治疗片断（使用的物质为药物前体）
b) Where the new applied activesubstance is the same substance as the therapeutic moiety that the patientswere exposed to when treated with the original active substance (the appliedsubstance is a metabolite).
如果新应用的活性物质是与治疗片断相同的物质，患者在治疗时暴露于原始的活性物质中（所采用的物质是一种代谢物）。
Inthese situations, substances related as a “derivative” to the active substanceof an already approved medicinal product for human use in the European Unionwill not be confirmed as NAS unless the applicant provides evidence that thesubstance being evaluated differs significantly in properties with regard tothe safety and/or efficacy from the substance already approved.
在这些情形下，如果所谓的衍生物是在欧盟已批准的人用活性物质的衍生物，将不会被确认为NAS，除非申报者提供证据证明该物质已经过评估具备与已批准物质显著不同的安全性和/或有效性。
Theabove mentioned situations also apply to stereoisomers which isomerise toauthorised active substances in vivo.
上述情形也适用于在体内异构化为批准的活性物质的立体异构体。
2.5. Esters and ethers 酯和醚
Convertingan active substance to certain esters or ethers is a well-established way ofpreparing so-called prodrugs. The purpose of a prodrug is to deliver the sametherapeutic moiety to the patient, possibly with some differences such as adifferent bioavailability, a different in vivo distribution pattern, etc. Suchesters or ethers of an already approved medicinal product in the European Unionthat are designed to be hydrolysed in vivo and expose the patient to the sametherap eutic moiety as the original active substance will not be considered asNAS unless the applicant provides evidence that the substance being evaluateddiffers significantly in properties with regard to safety and/or efficacy fromthe one already approved.
将活性物质转化为特定的酯或醚是一种成熟的制备药物前体的方法。药物前体的目的是将相同的治疗片断送达至患者，可能会有差异如不同的生物利用度，不同的体内分布模式等。这样在欧盟已批准的药物的酯或醚的设计使得其在体内水解，患者会暴露于原创活性物质相同的治疗片断下，不会被作为是NAS，除非申报者能提供证据证明该物质经过评估，与之前已批准的物质安全性和/或有效性具有显著差异。
Ifthe applicant provides evidence that an ester or ether of an already approvedmedicinal product in the European Union exerts its effect in an intact shape(is not hydrolysed in vivo), and the patients are not exposed to the sametherapeutic moiety as with the already approved medicine it could be consideredas NAS.
如果申报人能提交证据证明已在欧盟批准的药品的酯或醚会在以完整的形状（体内未水解）发挥其效果，患者不会暴露于与已批准药品相同的治疗片断，则可以认为是NAS。
Insuch cases, evidence that the substance exerts its effect in an intact shape(is not hydrolysed in vivo) may need to be provided.
在这种情形下，可能需要提交证据证明该物质会在以完整的形状（体内未水解）发挥其效果。
2.6.Salts 盐
Saltsusually dissociate in aqueous solution and the therapeutic moiety is no longerassociated with the counter ion but is rather surrounded by solvent moleculesand ions present in the solution.
盐一般在水溶液里会分解，治疗片断不再与配对离子一起，而是被溶液中的溶剂分子和离子所围绕。
Adifferent salt of an active substance previously authorised as part of amedicinal product in the European Union would be considered as the same activesubstance, unless the applicant provides evidence that the substance beingevaluated differs significantly in properties with regard to safety and/orefficacy from the one already approved.
在欧盟已批准的作为药品一部分的活性物质的不同的盐会被认为是相同的活性物质，除非申报者能提供证据证明该物质经评估具有与已批准的物质显著不同的安全性和/或有效性。
2.7.Solid state forms and NAS status 固体状态形态和NAS状态
Sincecocrystals, hydrates and solvates are held together by weak interactions thatusually dissociate in a similar way as salts upon dissolution they will exposea patient to the same therapeutic moiety. As for salts, they will not beconsidered as NAS unless the applicant provides evidence that the substancebeing evaluated differs significantly in properties with regard to safetyand/or efficacy from the one already approved.
由于共晶、水合物和溶剂化物由弱键维持，其离解方式通常与盐相同，患者将会暴露于相同的治疗片断下，因此作为盐，这些物质不会被认为是NAS，除非申报人可以提交证据证明该物质经评估具有与已批准的物质显著不同的安全性和/或有效性。
Thisapplies also to morphologically different crystal forms of an active substance.The differences between such polymorphic forms will immediately disappear whendissolved and they will be considered as the same active substances.
这也适用于形态不同的活性物质晶型。这种晶型的差异会在溶解时立即消失，因此它们被认为是相同的活性物质。
2.8.Documentation 文件记录
Wherean applicant submits a claim of NAS in the light of Article 10.2b of Directive2001/83/EC, the applicant should demonstrate whether the active substance(s)subject of the application shares the same therapeutic moiety as the activesubstance(s) previously authorised in medicinal product(s) for human use. Thisshould include a demonstration that the administration of the applied activesubstance would not expose the patient to the same therapeutic moiety as analready authorised active substance in the European Union.
如果申报人根据指令2001/83/EC第10.2b条提交了一份NAS声明，则申报人应证明申报中的活性物质是否具有与之前已批准的人药中的活性物质相同的治疗片断。其中应包括证明资料可以证明摄入所申报的活性物质不会使患者暴露于在欧盟已批准的药用物质相同的治疗片断中。
Itis recommended that this is substantiated by comparison of structuralsubstance/features which can be obtained using established databases anddiscussion on the therapeutic moieties for any structurally related alreadyauthorised substances in relation to the therapeutic moiety of the claimed NAS.Results of such investigations should be provided within the dossier.
建议对使用可以获得的已知数据库来对结构/特征进行比较，讨论已批准物质和申请的NAS中所有与结构相关的治疗片断。该研究的结果应在申报资料中提交。
When a substance applied for exposes the patient to the sametherapeutic moiety as the previously active substance(s) as part of a medicinalproduct(s) authorised in the European Union, the applicant should provideevidence that the related active substances differ significantly in propertieswith regard to safety and/or efficacy. The documentation needed for such aclaim will be dependent on the particular case details; applicants are advisedto seek Scientific Advice accordingly.
如果申报的物质使得患者暴露于与欧盟之前已批准的药品中活性物质相同的治疗片断，则申报人应提交证据说明相关的活性物质具有显著不同的安全性和/或有效性。该声明所需的文件记录将取决于各案详细情况，建议申报人寻求相应的科学建议。
3.References 参考文献
Directive2001/83/EC of the European Parliament and of the Council of 6 November 2001 onthe Community Code relating to medicinal products for human use.
指令2001/83/EC，人药相关的共同体法规
Noticeto Applicants (NtA), Volume 2A –Procedures for marketing authorisation -Chapter1 marketing authorisation.
申报者须知（NTA）卷2A---上市许可批准程序---第1章—上市许可
Reflectionpaper on considerations given to designation of a single stereo isomeric form(enantiomer), a complex, a derivative, or a different salt or ester as newactive substance in relation to the relevant reference active substance (Doc.Ref.: EMA/651649/2010).
基于相关对照活性物质设计作为新的活性物质的单一立体异构体形态（对映异构体）、复合物、衍生物或不同的盐或酯时考量的思考
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