中英对照最新FDA发布的仿制药一致性最终指导原则

TheUSFoodandDrugAdministration's(FDA)finalguidanceoncontrolledcorrespondencebetweentheagencyandthegenericdrugindustryreleasedMondayincludessomechangesthataddressindustryquestionsandcomments.FDA发布：仿制药生产商书面咨询最终指南，解决企业关心的问题BackgroundInitiallyreleasedinAugust2014,thedraftguidancewasthefourthguidancedocumentunderthe2012GenericDrugUserFeeAct,andwasintendedtoaddressformalquestionsposedtoFDApriortothegenericdrugreviewprocessandtoclarifyquestionscapableofaffectingaproduct'sreview.背景：该指南草案发布于2014年8月，是2012年《仿制药申报者付费法案》(GenericDrugUserFeeAct，GDUFA)下的第四份指导文件，旨在解答仿制药评审前企业向FDA提出的正式问题，对会影响药品评审的问题做澄清。Thisguidanceprovidesadditionaldetailandrecommendationsforindustryon:whatinquiriesFDAconsiderstobecontrolledcorrespondenceforthepurposesofmeetingitsGDUFAcommitmentwhatinformationrequestorscanincludeinacontrolledcorrespondencewhatinformationFDAwillprovideinitscommunicationstorequestorsthathavesubmittedcontrolledcorrespondence该指导原则为企业提供了附加明细和建议:什么样的咨询FDA认为是符合其GDUFA承诺的书面咨询什么样的信息可以包含在书面咨询中FDA在与递交书面咨询人交流时会提供什么样的信息Theagency'sdefinitionofcontrolledcorrespondenceencompassesarangeofissuesthatcanimpactgenericmanufacturersandrelatedindustry(e.g.,contractresearchorganizationsconductingbioanalyticalorbioequivalence(BE)clinicaltrials,activepharmaceuticalingredientmanufacturers,andexcipientmanufacturers).FDA对“controlledcorrespondence”,即本文中的“书面咨询”的定义涵括了一系列可影响仿制药生产商和相关产业的问题(例如进行生物分析或生物等效性(BE)临床试验的CRO，API生产商，还有辅料生产商)MinorChangestoDraftRevisionstothedraftguidanceincludeexplanatoryinformationthatwillassistgenericmanufacturersastheysubmitcontrolledcorrespondencetoFDA.ThefinalguidancealsoaddedadescriptionofhowtosubmitinformationtoFDA’sInactiveIngredientDatabase,andadescriptionofenhancedcommunicationtorequestorsregardingthestatusoftheircontrolledcorrespondence.草案细小改动：指南草案的修订包含了对解释性信息进行了修订，这些解释性信息将帮助仿制药生产商向FDA提交书面咨询。最终指南增加了“如何向FDA的非活性成分数据库提交信息”的描述，以及根据申请者书面咨询的状态，加强沟与申请者的沟通。ExclusionsFDAnotesinthefinalguidancethreetypesofinquiriesthatfallwithinthedefinitionofcontrolledcorrespondencebutwhichtheagencyhasandwillcontinuetotreatdifferentlyfromotherinquiriesongenericdrugs,including(1)requestsforrecommendationsontheappropriatedesignofBEstudiesforaspecificdrugproduct;(2)requestsforreviewofBEclinicalprotocols;and(3)requestsformeetingstodiscussgenericdrugdevelopmentpriortoAbbreviatedNewDrugApplication(ANDA)submission.FDAsaysitwillexcludetheseinquiriesfromthegoaldatesintheGDUFACommitmentLetter.Underthatletter,FDAactiononcontrolledcorrespondencelettersissettosteadilyrampupfrom:FDAwillrespondto70percentofcontrolledcorrespondencein4monthsfromdateofsubmissioninfiscalyear(FY)2015.FDAwillrespondto70percentofcontrolledcorrespondencein2monthsfromdateofsubmissioninFY2016.FDAwillrespondto90percentofcontrolledcorrespondencein2monthsfromdateofsubmissioninFY2017.例外情况：FDA在最终指南中指出三种咨询方式，这三种咨询方式都属于书面咨询的范畴，但FDA仍认为这三种咨询方式与其他仿制药咨询不同。包括:(1)申请对特定药品的BE研究设计提供建议;(2)申请对BE临床方案审核;(3)在简明新药申请(ANDA)提交之前申请会议讨论仿制药开发FDA表示，这些咨询不包含在GDUFA承诺函的目标时间之内。在这份承诺函中，FDA对书面咨询的回复时间将逐步加快:2015财年，70%咨询会在自提交日起4个月内得到FDA回复。2016财年，70%咨询会在自提交日起2个月内得到FDA回复。2017财年，90%咨询会在自提交日起2个月内得到FDA回复。IndustryCommentInitscommentsonthedraftguidance,industrygroupGenericPharmaceuticalAssociation(GPhA)tookparticularissuewiththeseexclusions,callingthemunacceptableandinconsistentwiththestatedGDUFAcommitments.TheGDUFACommitmentLetterinnowaycontemplatedexcludingcategoriescriticalforinformationexchangefromthecontrolledcorrespondencemetrics,GPhAsays.Infact,itisbecauseFDAresponsestothesecorrespondenceshavebeenhistoricallyslow,duetoresourceconstraints,industryclearlyaddressedtheseconcernsinitsagreementrelatedtocontrolledcorrespondence.Inaddition,GPhAtakesissuewiththeguidance'sproposaltoendcommunicationswithrequestorswhenasubjectisunderconsiderationbutdeemedcomplex.ThisproposalcontradictsthefundamentalaspectsofGDUFAwhichwasdesignedtoenhancetheFDA’sscientificknowledge-baseandembracedthegoalsofimprovingcommunicationsandincreasedtransparency,GPhAsays.GPhArespectfullyrequestsFDAtoestablishaprocedurethatwillassuretimelyresponsestocontrolledcorrespondenceincludingthosethatrepresentcomplexissues.行业意见：在对草案的意见中，仿制药协会（GenericPharmaceuticalAssociation，GPhA）就这些例外情况提出异议，称它们“不可接受且不符合规定的GDUFA承诺。”此外，GPhA还提出异议，质疑指南建议终止与申请人沟通在研究中的、被认为复杂的问题。“这个建议违背GDUFA的基础：旨在加强FDA的科学知识库，改善沟通，增加透明度，”GPhA说。“GPhA敬请FDA建立制度，确保及时回复书面咨询，包括那些含有复杂问题的咨询。FDAResponseThoughitdidnotdirectlyaddressGPhAanditsconcernsabouttheexclusions,FDAnotedthatitreceivedmultiplecommentsrequestingthatitrefrainfromexcludingrequestsforproduct-specificguidanceondemonstratingbioequivalence.Buttheagencysaysithasdeclinedtorevisetheguidanceinthatfashion.Amongotherthings,FDAsaysthattheshorttimeframecontemplatedforthecontrolledcorrespondenceresponsesisinconsistentwiththewell-establishedprocessforissuingproduct-specificrecommendationsdescribedintheguidanceforindustryon'BioequivalenceRecommendationsforSpecificProducts(June2010),'aswellaswiththeprinciplesintheGDUFACommitmentLetter.FDAalsosaiditreceivedanumberofcommentsonitsproposaltorespondtorequestsrelatedtoissuesforwhichithasnotyetdeterminedapolicy.Uponreviewofthecomments,