InternationalBiopharmaIndustryInternationalBiopharmaIndustryOrganization國際生物制藥產(chǎn)業(yè)組織ConsiderationsfortheDevelopmentofChimericAntigenReceConsiderationsfortheDevelopmentofChimericAntigenReceptor(CAR)TCellProducts開發(fā)嵌合抗原受體(CAR)T細(xì)胞產(chǎn)品的考量DraftGuidanceforIndustry行業(yè)指南草案ConsiderationsfortheDevelopmentofChimericAntigenReceThisguidancedocumentisforcomSubmitonesetofeitherelectroprovidedintheFederalRegisternoticeannouncingtheavailabilityofthedraftguidance.Submitelectroniccommentsto.ManagementStaff(HFAnoticeofavailabilitythatpublishesintheFederalRegister.在《聯(lián)邦公報(bào)》公布指南草案通知中提供的日期之前，可提交關(guān)于本指南草案的電子或書面評論。電子評論可向提交。書面意見可提交給食品和藥物管您應(yīng)該使用聯(lián)邦公報(bào)中發(fā)布通知中列出的案卷編號來標(biāo)識AdditionalcopiesofthisguidanceareavailablefromtheOfficeofCommunication,Outreachand20993-0002,orbycalling1-800-835-4709or240-40theInternetat/vaccines-blood-biologics/guidance-compliance-regulatory-本指南的其他副本可從通訊、外展和發(fā)展辦公室(OCOD)獲取，地址為10903NewHampshireAve.,Bld/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics。U.S.DepartmentofHealthandHumanServicesFoodandDrugAdministCenterforBiologicsEvaluationaiTableofContents目錄 2 3 5 5 6 7 8 9A.VectorManufacturingandTesting載體生產(chǎn)和檢測 B.Collection,Handling,andTestingof 1.CARTcellmanufact 2.CARTcellanalytica 17 D.ManagingManufacturingChangesandAssessingCompara 252.Comparabilitystudydesign可比 27E.Single-SiteorMultisiteManufactur 28 29 30A.GeneralPreclinicalConsi B.PreclinicalConsiderationsfortheVectorComp 30C.PreclinicalConsiderations 33E.CARTCellswithAdditionalModific 34 35A.StudyPopulation研究人群 1.Advancedvs.earlyd 2.Tissue-agnosticapproach組織不可 3.Targetidentificat 4.Pediatricsubjects兒科受 1.Doseselection,starting 39 4.Considerationformanufacturingdelayorfailure生產(chǎn)延遲或失 C.ClinicalPharmacologyConside 42 442.Toxicitygrading 453.Dose-limitingtoxicities(DLTs) 48 1ConsiderationsfortheDevelopmentofChimericAntigenReceptor(CAR)TCellProducts開發(fā)嵌合抗原受體(CAR)T細(xì)胞產(chǎn)品的考量DraftGuidanceforIndustry行業(yè)指南草案Thisdraftguidance,whenfinalized,willrepresentthecuAdministration(FDAorAgency)onthistopic.ItdoesnotestabisnotbindingonFDAortherequirementsoftheapplicablestatutesandregulations.TodiscussanalternativeapproacontacttheFDAstaffresponsibleforthisguidanceaslistedonthetitlepage.它不為任何人確立任何權(quán)利，也不對FDA或公眾具有約束力。如果滿足適用法規(guī)和法規(guī)的要求，您可以使用替代方法。要討論替代方法，請聯(lián)系標(biāo)題頁上列出的負(fù)責(zé)本指南的2I.INTRODUCTION介紹Chimericantigenreceptor(CAR)Tcellproductsarehumangenetherapy1productTcellspecificityisgenetictherapeuticpurposes.Thisguidanceisintendedtoassistsponacademicsponsors,developingCARTcellproducts.Inthisguidance,wecell-specificrecommendationsregardingchemistry,manufacturing,andcontrol(CMC),pharmacologyandtoxicology,andclinicalstudydesign.RecommendatiprovidesrecommendatthisguidancespecificallyfocusesonCARTcellproducts,muchoftheinfrecommendationsprovidedwillalsobeapplicabletoothergeneproducts,suchasCARNaturalKiller(NK)cellsorrelatedproducttypescanbehighlyspecialized,andinrecommendedinthisguprocess.TodiscussconsiderationssponsorscommunicatewiththeOfficeofTInvestigationalNewDrugApplication(IND)(e.g.,byrequestingapre-INDmeeting(Ref.以識別治療目的所需的靶抗原。本指南旨在幫助發(fā)起人（包括行業(yè)和學(xué)術(shù)發(fā)起人）開發(fā)CART細(xì)胞產(chǎn)品。在本指南中，就化學(xué)、生產(chǎn)和控制(CMC)、藥理學(xué)和毒理學(xué)以及臨床研究設(shè)計(jì)，我們FDA提供針對CART細(xì)胞的建議。本指南中注明了針對自體或同種異體1Humangenetherapyseekstomodifyormanipulatetheexpressionofageneortoalterthebiologicalpropertiesoflivingcellsfortherapeuticuse.FDAgenerallyconsidershumangenetherapyproductstoincludeallproductsthatmediatetheireffectsbytranscriptionortranslationoftransferredgeneticmaterial,orbyspecificallyalteringhost(human)geneticsequences.Someexamplesofgenetherapyproductsincludenucleicacids,geneticallymodifiedmicroorganisms(e.g.,viruses,bacteria,fungi),engineeredsite-specificnucleasesusedforhumangenomeediting,andexvivogeneticallymodifiedhumancells.Genetherapyproductsmeetthedefinitionof“biologicalproduct”insection351(i)ofthePublicHealthService(PHS)Act(42U.S.C.262(i))whensuchproductsareapplicabletotheprevention,treatment,orcureofadiseaseorconditionofhumanbeings(seeFederalRegisterNotice:ApplicationofCurrentStatutoryAuthoritiestoHumanSomaticCellTherapyProductsandGeneTherapyProducts(58FR53248,October14,1993),/media/76647/download).人類基因療法尋求修改或操縱基因的表達(dá)、或改變活細(xì)胞的生物學(xué)特性，以用于治療用途。FDA通常認(rèn)為人類基因治療產(chǎn)品包括所有通過轉(zhuǎn)錄或翻譯轉(zhuǎn)移的遺傳物質(zhì)、或通過特異性改變宿主（人類）基因序列來介導(dǎo)其作用的產(chǎn)品?；蛑委煯a(chǎn)品的一些例子包括：核酸、基因改造的微生物（例如病毒、細(xì)菌、真菌）、用于人類基因組編輯的工程化位點(diǎn)特異性核酸酶，以及離體基因改造的人類細(xì)胞。當(dāng)此類產(chǎn)品適用于人類疾病的預(yù)防、治療或治愈時(shí)，基因治療產(chǎn)品符合公共衛(wèi)生服務(wù)(PHS)法案第351(i)節(jié)(42U.S.C.262(i))中對“生物制品”的定義（參見聯(lián)邦公報(bào)通知：現(xiàn)行法定機(jī)構(gòu)對人體細(xì)胞治療產(chǎn)品和基因治療產(chǎn)品的應(yīng)用（58FR53248，1993年10月14日），/media/76647/download)。CART細(xì)胞產(chǎn)品的建議。本指南還為CART細(xì)胞產(chǎn)品的分析可比性研究提供了建議。雖然本指南特別關(guān)注CART細(xì)胞產(chǎn)品，但提供的大部分信息和建議也適用于其他轉(zhuǎn)基因淋巴細(xì)胞產(chǎn)品，例如CAR自然殺傷(NK)細(xì)胞或T細(xì)胞受體(TCR)修飾的T細(xì)胞。這些相將取決于特定的產(chǎn)品和生產(chǎn)工藝。為了討論這些相關(guān)產(chǎn)品的具體考量，我們建議，發(fā)起人在提交研究性新藥申請(IND)之前與生物制品審評與研究中心(CBER)的組織和先進(jìn)療法辦公室(OTAT)溝通（例如，通過請求IND前考量將取決于具體的產(chǎn)品和生產(chǎn)工藝。為了討論這些相關(guān)產(chǎn)品的具體考量，我們建議，在提交研究性新藥申請(IND)之前，發(fā)起人與生物制品審評與研究中心(CBER)的組織和先Thecontentsofthisdocumentdonothavetheforceandeffectoflawandarenotthepublicinanyway,unlessspecificallyincorporatedintonlytoprovideclaritytothepublicregardingexistingrequirementsunderthelaw.FDAguidancedocuments,includingthisguidanregulatoryorstatutoryreqmeansthatsomethingissuggestedorrecommended,butnotrequire本文件的內(nèi)容不具有法律效力，也不以任何方式約束公眾，除非特別納入合同。本文件僅旨在向公眾說明法律的現(xiàn)有要求。除非引用了特定的法規(guī)或法定要求，否則包括本指南在內(nèi)的FDA指南應(yīng)僅被視為建議。在FII.BACKGROUND背景CARTcells2areregulatedasagenetherapy(GTbiologicalproducts.Werecognizethatthedevelopment,manufacture,testing,andclinicalassessmentofCARTcellsischallenging.Carefuldesigtransgene3anddeliveryvectorarecriticaltoproductsafety,specmanufacturinginvolvesmultiplebiologicalmaterialsandcomplexmarepotentialsourcesofvariabilityamongproductlots.Thus,controlofthemanufacturingprocessandappropriatein-processandlotreleasquality,andlot-to-lotconsistency.Inaddition,changestothemanufacturingprocessduringproductdevelopment.Itisessentialtounderstandtheefquality.Comprehensiveproductcharacterizationstudiesarevaluablcriticalqualityattributes(CQAs)thestablishedthroughprocessqualificationtoensurethatmanufacCQAs(Ref.2).FDA’sguidanceentitled2CARTcellproductswillbereferredtoasCARTcellsthroughoutthisguidance.在本指南中，CART細(xì)胞產(chǎn)品將被稱為CART細(xì)胞。3Forthepurposesofthisguidance,transgenemeansanexogenousgenethatisintroducedintoa為本指南的目的，轉(zhuǎn)基因是指引入宿主細(xì)胞的外源基因。另見（參考文獻(xiàn)10）。a4InformationforHumanGeneTherapyInvestigationalNforIndustry,”January2020(Ref.3)(hereinadescribesthegeneralconsiderationsforGTproductmanufacturingand在FDA現(xiàn)有的生物制品框架下，CART細(xì)胞被監(jiān)管為基因治療(GT)產(chǎn)品。我們認(rèn)識到能，CAR轉(zhuǎn)基因和傳遞載體的精心設(shè)計(jì)和適當(dāng)檢測至關(guān)重要。CART細(xì)胞生產(chǎn)涉及多種生物材料和復(fù)雜的多步驟程序，這些是產(chǎn)品批次間差異的潛在來源。因此，對于確保CART細(xì)胞的安全性、質(zhì)量和批次間的一致性，生產(chǎn)工藝中評估的相關(guān)關(guān)鍵質(zhì)量屬性(CQA)，全面的產(chǎn)品表征研究很有價(jià)值（參考文獻(xiàn)2）。然后可以通過工藝確認(rèn)確定關(guān)鍵工藝參數(shù)(CPP)，以確保生產(chǎn)的批次始終符合CQA（2）。FDA的指南，題為“人類基因治療研究性新藥申請(INDs)的化學(xué)、生產(chǎn)和控制(CMC)信息：行業(yè)指南”，2020年1月（參考文獻(xiàn)3以下簡稱“GTCMC指南”）描述PreclinicalevaluationofCAsafetoadministertheproductinaclinicalinvestigation(Title21oftheCodeofFederalRegulations312.23(a)(8)(21CFR312.23(a)(8)).PreclinicaltestingofCARTcellscanchallengingduetotheinherentbiologicalcomplexityandvariabilityofthisproducttypeandthelimitedavailabilityofsuitableanimalmodelstotepreclinicaltestingstrategyshouldbeappliedusinginvivo,invitro,andinsilicotestingstrategies,asappropriate,inconjunctionwithavailableclinicalandpreclinicaldatafromrelasupportuseofCARTcellsinaproposedclinicaltrial.對于支持在臨床研究中使用該產(chǎn)品是合理安全的結(jié)論，CART細(xì)胞的臨床前評估是必要的（聯(lián)邦法規(guī)312.23(a)(8)(21CFR312.23(a)(8)第21條）)。由于該產(chǎn)品類型固有的生物學(xué)的臨床前測試可能具有挑戰(zhàn)性。應(yīng)采用逐例臨床前測試策略，可應(yīng)測試策略，酌情結(jié)合相關(guān)產(chǎn)品的可用臨床和臨床前數(shù)據(jù)，以支持在擬議的臨床試驗(yàn)中使用Well-designedearly-phaseclinicalstudiesarecriticaltoestablish:safetyoftheproduct,toriskmitigationmeasures,dose-respodifferencesinindication,andpreliminaryevidenceofefficacyandfeasibtaketomaketheproductandwhetherbridgingtherapcontroltheactivediseasewhilesubjectswaitforthcells,early-phasestudiescanalsoinformwithregar(GVHD).Informationgacellsinlater-phaseclinicalstudiesandmayexpeditetheclinicalde對于確定產(chǎn)品的安全性、對風(fēng)險(xiǎn)緩解措施的反應(yīng)、劑量-反應(yīng)關(guān)系、基于適應(yīng)癥差異的最佳劑量差異，以及有效性和生產(chǎn)可行性的初步證據(jù)，精心設(shè)計(jì)的早期臨床研究至關(guān)對于自體CART細(xì)胞，早期研究還提供了有關(guān)的信息，如生產(chǎn)該產(chǎn)品需要多長時(shí)間、以及在受試者等待CART細(xì)胞治療時(shí)是否將橋接療法用作控制活動性疾病的嘗試。對于同種異體CART細(xì)胞，早期研究還可以告知移植物抗宿主病(GVHD)的風(fēng)險(xiǎn)。從這些早期研究中獲得的信息支持CART細(xì)胞在后期臨床研究中的開發(fā)，并可能加快CART細(xì)胞的III.GENERALCONSIDERATIONSFORCARTCELLDESIGNANDDEVELOPMENTCART細(xì)胞設(shè)計(jì)和開發(fā)的一般考量CARTcellsarecomplexproductsthatmayincorporatemultiplefuncfthesefunctionalelements,howthefunctionalelementsareintroducedintothecells(i.e.,vercelldesignanddevelopmenCARsgenerallycontaintwotypesofdomains:antigenrecognitionandsignaling.AntigenrecognitiondomainsallowCARTcellstobindtooneormoretargetantigen(s).Werecommendsponsorsassesstheabilityofeachdomaintospecificallybindtoitstargetantigen,asdescribedinsectionV.Bofthisguidance.Manyantigenrecognitiondomainsarederivedfrommurinemonoclonalantibodiesthatmaybeimmunogenicinhumans,leadingtorejectionoftheCARTcellsorothersafetyrisks(e.g.,anaphylaxis).Ifapproachestoreduceimmunogenicity(e.g.,“humanization”byComplementarity-DeterminingRegiongrafting)areused,werecommendtheINDdescribethesechangesandtheirimpactontargetbindingandbiologicalactivity(Refs.4,5,6).CAR通常包含兩種類型的結(jié)構(gòu)域：抗原識別和信號傳導(dǎo)?？乖R別結(jié)構(gòu)域允許CART細(xì)胞與一種或多種靶抗原結(jié)合。我們建議，發(fā)起人評估每個(gè)結(jié)構(gòu)域與其靶抗原特異性結(jié)合的能力，如本指南第VB部分所述。許多抗原識別結(jié)構(gòu)域來源于鼠單克隆抗體，這些抗體可能對人類具有免疫原性，導(dǎo)致對CART細(xì)胞的排斥或其他如果使用降低免疫原性的方法（例如，通過互補(bǔ)決定區(qū)移植的“人源化”我們建議，Signalingdomainsinitiadomainsbethoroughlydemonstrated,asdescribedinsectionV.6thecontributionoftransmembranedomain,hinge,andlinkfunctionalregionsoftheconstructshouldbeevaluated,asthesemayaffe信號域啟動T細(xì)胞激活。我們建議，全面闡明信令域例如，應(yīng)評估用于分離構(gòu)建體不同功能區(qū)域的跨膜結(jié)構(gòu)域、鉸鏈和接頭區(qū)域delivergeneticmaterial.Examplesofvectorsincludeplasmids,viruses,andbacteriatcomponentthatfurnishesapharmacologicalactivityforthetreatmentofdisease(sectionIV.Bofvectorsortransposons)canprovidelongtermtransgeneexpressvectors.Longtermfollowupisrecommendedforprodbecauseintegratingvectorsmayipredictedriskofdelayedadverseeventsisthougenerallylongtermfollowupwouldnotbeneeded.修飾以轉(zhuǎn)移遺傳物質(zhì)的質(zhì)粒、病毒和細(xì)菌（參考文獻(xiàn)10）。對于CART細(xì)胞，載體是提供治療疾病的藥理活性的關(guān)鍵成分（GTCMC指南（參考文獻(xiàn)3）的IV.B部分）。與非整合載體相比，整合到細(xì)胞DNA中的載體（例如，基于逆轉(zhuǎn)錄病毒的載體或轉(zhuǎn)座子）可以提供長期的轉(zhuǎn)基因表達(dá)。建議對包含整合載體的產(chǎn)品進(jìn)行長期隨訪，因?yàn)檎螴nadditiontotheCAR,vectorsmayexpressadditionalfunctionalelement除了CAR，載體還可以表達(dá)其他功能要素。例如，載體可以表達(dá)額外的功能要素，允許在生產(chǎn)工藝中選擇或富集細(xì)胞亞群（參考文獻(xiàn)11）；改變T細(xì)胞的持久性和/或活性（參effectiveness.Werecommendsponsorsprovidejustificationandreincorporationofadditionalelements.Thejustificationshouldincludeanassessmentofanyimpactthattheseadditionimmunogenicity,orsafety(seesectionV.Eofthisguidance).Transgenesunnecessaryforthebiologicalfunctionofapr7unanticipatedeffectsonproductpersistenceoractivity.Asageneralguidingprincirecommendthatunnecessarytransgenesshouldnotbeincludedinthevecto需要注意的是，每一個(gè)額外的功能要素都可能影響CART細(xì)胞的安全性和有效性。我們建議，發(fā)起人提供論證和相關(guān)數(shù)據(jù)，以支持納入其他要素。論證應(yīng)包括評估這些額外元素將對CART細(xì)胞特異性、功能、免疫原性或安全性產(chǎn)生的任何影響（參見本指南的第VE部分）。對產(chǎn)品的生物學(xué)功能而言不必要的轉(zhuǎn)基因序列，其可能在體內(nèi)具有免疫原性或?qū)Ξa(chǎn)品持久性或活性具有其他意料之外的影響。作為一般指導(dǎo)原則，我們建議，載體中不應(yīng)C.CellularStartingMatforCARTfpatients(forautologousproducts)orhealthydonors(forallogeneicproIV.Bofthisguidance.4通常通過患者（對于自體產(chǎn)品）或健康供體（對于同種異體產(chǎn)品）的白細(xì)胞分離，來獲得生產(chǎn)CART細(xì)胞的起始物料。如本指南第IV.B節(jié)所述，自體和同種異體產(chǎn)品的安全性和clinicalstudiesduetolackofresponsetothepreviouslyadministeredCARTcells,relapseofthestartingmaterial(e.g.,leukapheresis)fmaydifferfromthesampatientswhohavenot.PrevunexpectedeffectsonCARTcellmanufacturing(e.g.,expansionortransductionrates),invivoexpansion,safety,andefficacy.Therefore,evaluationofthepreviouslyadministeredCARTcelllevelsinthecelluassociatedwithincreasedvectorintegrationfrequencies,CARTcelltestievaluationofthevectorcopynumber(VCN)inthefiandpreviouslyadministeredCARTcells,ifthepreviouslyadministeredCARTcellsaredetectable.IfanautologousCARTcellCARTcellspreviouslyandpwhetheranygivenpatientwouldstitheadministrationofanadditionalCARTcellpreparativeregimen,suchaschemotherapyortotalbodyradiation,whichmayposelife-threateningriskofmyeloablationtopatientswhohavebeenpreviouslyextensivelytreated.Werecommendsponsorsdiscusstheseconside4SeealsoFDA’sdraftguidanceentitled“HumanGeneTherapyProductsIncorporatingHumanGenomeEditing:DraftGuidanceforIndustry,”March2022(GEDraftGuidance)(Ref.15).Whenfinalized,thisguidancewillrepresentFDA’scurrentthinkingontheseissues.另見FDA的指南草案，題為“包含人類基因組編輯的人類基因治療產(chǎn)品：行業(yè)指南草案”，2022年3月（GE草案指南參考文獻(xiàn)15）。最終確定后，該指南將代表FDA目前對這些問題的看法。8andclinicalstudydesig之前接受過CART細(xì)胞的患者可能會考慮進(jìn)行不同的CART細(xì)胞臨床研究，因?yàn)閷χ敖o予的CART細(xì)胞缺乏反應(yīng)、相同疾病的復(fù)發(fā)或不同惡性腫瘤的治療。對于使用來自先前接受過CART細(xì)胞的患者的細(xì)胞起始物料（例如，白細(xì)胞分離術(shù)）產(chǎn)生的CART細(xì)胞，其可能不同于使用來自未接受過CART細(xì)胞的患者的細(xì)胞起始材料產(chǎn)生的相同類型的CART細(xì)胞。對于CART細(xì)胞生產(chǎn)（例如擴(kuò)增或轉(zhuǎn)導(dǎo)率）、效力、體內(nèi)擴(kuò)增、安全性和功效而言，先前在起始物料中施用的CART細(xì)胞可能具有意想不到的影響。因此，評估細(xì)胞起始物料中先前施用的CART細(xì)胞水平可能是適當(dāng)?shù)摹４送?，基于與增加的載體整合頻率相關(guān)的風(fēng)險(xiǎn)，如果先前施用的CART細(xì)胞是可檢測的，CART細(xì)胞檢測應(yīng)包括評估成品中新引入的和先前施用的CART細(xì)胞的載體拷貝數(shù)(VCN)。如果一項(xiàng)自體CART細(xì)胞臨床研究將招募兩種類型的患者：既往接受過CART細(xì)胞的和未接受過CART細(xì)胞的，則應(yīng)在臨床研究設(shè)計(jì)中評估和考慮CART細(xì)胞的潛在差異。發(fā)起人還應(yīng)考慮任何特定患者是否仍有資格接受額外的CART細(xì)胞治療所需的輔助治療，包括另一種非清髓準(zhǔn)備方案，如化療或全身放療，這可能對先前接受過廣泛治療的患者造成危及生命的清髓風(fēng)險(xiǎn)。我們建議，發(fā)起人在IND提交之前，與OTAT討論產(chǎn)品表征、檢測、給藥和臨床研D.FreshorCryopreservedFinalProducts新鮮或冷凍保存choiceofformulationdependsontheproductdevelopmentstrategyandpracticalconstrainCART細(xì)胞可配制用于新鮮輸注或冷凍保存以備后FreshCARTcellshavealimitedshelflifebeforeproductqualitydegrades.Werecommendtthemaximumtimebetweenformulationandinfusionbedefinedandstudies.Additionally,thetimeframeinwhichreleasetestscanbeperformedislimited.Therefore,Assurance(QA)reviewforlotreleasofthefreshproductattheclinicalsite.新鮮的CART細(xì)胞在產(chǎn)品質(zhì)量下降之前的保質(zhì)期有限。我們建議，確定制劑和輸注之間開發(fā)和實(shí)施精心設(shè)計(jì)的流程至關(guān)重要，其中可能包括：取樣時(shí)間和批次放行檢測；報(bào)告質(zhì)Ontheotherhand,cryopreservationallowssufficienttimefschedulingpatientsforiaremanufacturedatacentrallocatiocryopreservedCARTcells,therisksassociassessed,andcontrolledthawingoftheproductattheclinproductquality.Regardlessoftheformulation,thereshouldbeappradequatecontroloftheCARTcellsduringshippingtotheclinicalsite.ThesbedescribedintheIND,inplacebeforeinitiatingclinicalstudies,andvalidatedp另一方面，冷凍保存為完全放行檢測和安排患者輸注的靈活性提供了足夠的時(shí)間。當(dāng)CART細(xì)胞在中心位置生產(chǎn)并運(yùn)送到臨床場所進(jìn)行給藥時(shí)，對于冷凍保存的CART細(xì)胞，應(yīng)評估與輸注冷凍保護(hù)劑相關(guān)的風(fēng)險(xiǎn)，并且臨床現(xiàn)場受控下解凍產(chǎn)品可能對保持產(chǎn)品質(zhì)量至關(guān)重要。無論配方如何，都應(yīng)該有適當(dāng)?shù)某绦騺泶_保在運(yùn)送到臨床場所期間對CART細(xì)胞進(jìn)行充分控制。這些程序應(yīng)在IND中進(jìn)行描述，在開IV.CMCRECOMMENDATIONSCMC建議WerecommendsponsorsorganizeinformationintheCommonTechnformatwiththevectorCMCinformationdescrandtheCARTcellinformationorganizedintoaseparateDSsectionandasepara(DP)section,asdiscussedinsectionIV.BoftheGTCMCGuidance(Ref.3).WhenCARTcellsaremanufacturedusingacontinuousprocesswherethereisnocleardivisionbetweentheDSandDP,werecommendthatyouprovideanexplanationtosupportyourDS/DPdistinctsummaryinformationinModule2oftheCTDsubtheformatandnumberingschemerecommendedinModule3ofFDA’sGuidanc“M4Q:TheCTD–Quality,”AugusfromoneanotherbyincludingtheDSnameandmanufacturerintheheading3.2.S.1GeneralInformation[name,manufacturer]).我們建議，發(fā)起人以通用技術(shù)文件(CTD)格式組織信息，將載體CMC信息描述在完整的原料藥(DS)部分中，并將CART細(xì)胞信息組織到單獨(dú)的DS部分和單獨(dú)的藥品(DP)部分中，如GTCMC指南（參考文獻(xiàn)3）第IV.B節(jié)所述。如果CART細(xì)胞是使用連續(xù)工藝生產(chǎn)的，其中DS和DP之間沒有明確的區(qū)分，我們建議，您在CTD提交的模塊2的摘要信息中提供解釋以支持您的DS/DP區(qū)分。CTDDS部分應(yīng)遵循FDA行業(yè)指南模塊3中推薦標(biāo)題中包含DS名稱和生產(chǎn)商來區(qū)分各個(gè)部分（例如，第3.2.S.1節(jié)一般信息[名稱，生產(chǎn)TheemphasisforCMCinallphasesofdevelopmentisproductsafetyandmanufacWerecommendthatCARTcellsbedevelopedfollowingalifecmanner.TheamountofCMCinformationtobesubmittedinyourINDdependsonthephaseandthescopeoftheclinicalinvestigationpvectorsaretobemanufacturedunappropriateforthestageofCosmeticAct(FD&CActinformationmaybeneededtoalignproductdeveespeciallywhenthelatterisrapidlyprogressingunderanexpediteddevelopmentpCMC在所有開發(fā)階段的重點(diǎn)是產(chǎn)品安全和生產(chǎn)控制。我們建議，按照生命周期方法開發(fā)CART細(xì)胞，在產(chǎn)品開發(fā)過程中收集信息、并以適合階段的方式提交。要在您的IND中您可能不需要完成原始IND提交中的所有CTD部分。同樣，CART細(xì)胞和載體將在適合開發(fā)階段的GMP條件下制造（《聯(lián)邦食品(2)(B)節(jié)21U.S.C.351(a)(2)(B)另見參考文獻(xiàn)17）。可能需要額外的CMC信ForCARTcellsintheearlystagesofclinicaldevelopment,andsometestsmaystillbeunderdevelopment(secti3)).Cellularcharacterizationdatacollectedduringearlystudiesclaterdevelopmenttoensureprimaryobjectiveistogathermeaningfuldataaboutproductefficacy,werecommendthatacceptancecriteriaberefinedtoensurebatchesarewell-definedandconsistentlymanufactured.對于處于臨床開發(fā)早期階段的CART細(xì)胞，最終確定的質(zhì)量標(biāo)準(zhǔn)很少，一些檢測可能仍在開發(fā)中（GTCMC指南（參考文獻(xiàn)3）的VA4.a部分對于支持產(chǎn)品開發(fā)和可比性評估，特性研究至關(guān)重要。對于主要目標(biāo)是收集有關(guān)產(chǎn)品功效的有意義數(shù)據(jù)的研究，我們建議，改進(jìn)可接受標(biāo)準(zhǔn)，以確保批次定義明確并始終如一地生A.VectorManufacturingandTesting載體生產(chǎn)TheGTCMCGuidance(Ref.3)providesrecommendationsformanufacturingvector.Thevectorshouldbewell-characterizedpriortoinitiationofclinicalstudies.Forlicensure,thevectormustbemanufacturedaccordingtoCGMPstandards(2LicenseApplication(BLA)review,vectormanufacturingfacilitiesaresubjecttoinspectGTCMC指南（參考文獻(xiàn)3）為載體的生產(chǎn)和檢測提供了建議。在開始臨床研究之前，應(yīng)充分表征載體。為獲得許可，載體必須按照CGMP標(biāo)準(zhǔn)（21CFR第210和211部分）生產(chǎn)，并且分析方法必須經(jīng)過驗(yàn)證（21CFR211.165(e)，參考文獻(xiàn)18）。在CART細(xì)胞生VectorqualitydirectlycontributestothequalityandconsistencyoftheCARTrecommendthatsponsorsdescribethevectorstructure,characterizationandtestingoftheMasterandWorkingCellBanks,characterizationofreferencematerials,vectormanufactureandtesting,andvectorstability.Vectorlotreleasetestingshouldincludemeasuresofsafety,identity,purity,andpotency.Apotencyassaythatassessesthebiologicalactivityofthetransgemeasureofpotencymaybesufficienttosupportearly-pmeasuresofbiologicalpotencywilllikelyberequestedforcliprimaryevidenceofeffectivenesstosupportamarrecommendvectorlotreleasetestingincludecanbeusedtonormalizetheamountofvectorusedfortransductionduringCARTcellmanufacturing.Forexample,werecommendtestingviralvectorsfortransducingunitspermilliliter(mL)inasuitablecellthenbeoptimizedtodeterminetheamounpercentageofCAR-positivecellsintheCARTcellDP.載體質(zhì)量直接影響CART細(xì)胞的質(zhì)量和一致性。我們建議，發(fā)起人描述載體結(jié)構(gòu)、主細(xì)體批放行檢測應(yīng)包括安全性、鑒別、純度和效力的測量?？梢耘cCART細(xì)胞效力測定一起開發(fā)評估轉(zhuǎn)基因生物活性的效力測定。單獨(dú)的轉(zhuǎn)基因表達(dá)作為效力的衡量標(biāo)準(zhǔn)可能足以支持早期IND研究；然而，臨床研究可能需要額外的生物效力測量，旨在提供有效性的主要證據(jù)來支持上市申請。此外，我們建議，載體批放行檢測包括確定載體濃度的測定，該測定可用于標(biāo)準(zhǔn)化CART細(xì)胞生產(chǎn)工藝中用于轉(zhuǎn)導(dǎo)的載體量。例如，我們建議，在合適的細(xì)胞系或健康供體細(xì)胞中檢測病毒載體的每毫升(mL)轉(zhuǎn)導(dǎo)單位。隨后，可以優(yōu)化T細(xì)胞轉(zhuǎn)導(dǎo)以確定每個(gè)細(xì)胞添加的載體量，以實(shí)現(xiàn)CART細(xì)胞DP中CAR陽性細(xì)胞的目標(biāo)百分比。Vectorsafetytestingshouldincludemicrobiologicaltestingsuchassterility,AdditionaltestingmayberecommendeddependingonthetypeoftransgenevectForexample,thereareadditionalsafetyconcernsrelatedtotheuseofretroviral-basedvectorsandadditionaltestingexp19)).TherecommendationsforlonconcernsassociatedwiththevectorandthepropensityforthevectortointeCART細(xì)胞DP不受影響。根據(jù)所使用的轉(zhuǎn)基因載體的類型，可能會建議如，與使用基于逆轉(zhuǎn)錄病毒的載體和額外的檢測預(yù)期相關(guān)的其他安全問題（GTB.Collection,Handling,andTestingofCellularStartingunction.Duetopatientordonorvarsourceoflot-to-lotvariability.Here,wedescribeconsusingstartingmaterofcellularstartingmaterialaswell.用作起始物料的細(xì)胞的性質(zhì)可能對CART細(xì)胞的質(zhì)量和功能至關(guān)重要。由于患者或供體的變異性，細(xì)胞起始物料可能是批次間變異性的主要來源。在這里，我們以從白細(xì)胞分離本節(jié)中的建議也可能適用于其他類型的細(xì)胞起Werecommendthatproceduresusedforhandlingtheleukapheresisstartingmaterialfromcollectiontothestartofthemanufacturingprocessaredescribedasdiscussedinsectcryopreservationprocedures.Werecommendtheseproccollectionsitestoensurequalityoftheprocess,ithemanufacturingsite.Youshocontroloftheleukapheresisstartingmatemperaturecontrol),andinformatioshouldbeprovided.Validationoftheshippingprocesincludingassessmentofleukapheresisstartingmateriashouldbeincludedforlicens我們建議，按照GTCMC指南（參考文獻(xiàn)3）的VA2.c.ii部分中的討始生產(chǎn)工藝的用于處理白細(xì)胞分離起始物料的程序。該描述應(yīng)包括任何洗滌步驟或冷凍保存程序。我們建議，在所有白細(xì)胞分離采集點(diǎn)實(shí)施這些程序，以確保過程質(zhì)量，包細(xì)胞和運(yùn)送到生產(chǎn)場所。您應(yīng)該有適當(dāng)?shù)某绦?，來確保在運(yùn)輸?shù)缴a(chǎn)設(shè)施期間對白細(xì)胞分離起始物料進(jìn)行充分控制（例如，溫度控制并且應(yīng)該提供有關(guān)運(yùn)輸容器和溫度監(jiān)測的信息。運(yùn)輸過程和任何保留或冷凍保存步驟的驗(yàn)證，包括在預(yù)期條件下評估白細(xì)胞分離起Theprobabilityofmanufacturingsuccessmaybeincreasedbyestablishingacceptancecriteriaforspecifyaminimumcellnumber,viability,andpercentCD3+cells.Werecommtheleukapheresisstartingmaterialformicrobialcontamination(e.g.,stereventofaDPsterilitytestfailure.Additionalcharacterizationoftheleukapheresisstartingmaterial(e.g.,forpercentandabsolutenumberofCD4+andCD8+Tcells,NKcells,monocBcells)mayinformtheCARTcellmanufacturingprocessasthesecharacteristicTcellselectionandexpansionand通過建立用于CART細(xì)胞生產(chǎn)的白細(xì)胞分離起始物料的可接受標(biāo)準(zhǔn)，可以提高生產(chǎn)成功始CART細(xì)胞生產(chǎn)之前檢測白細(xì)胞分離起始物料的微生物污染（例如，無菌或生物負(fù)對數(shù)量）可能會為CART細(xì)胞生產(chǎn)工藝提供信息，因?yàn)檫@些特征可能會影響T細(xì)胞的選Autologousleukapheresisstarttheotherhand,doesrequiredonoreligibilitydeterminationandscreenicellbanksoriginatingfromallog自體白細(xì)胞分離術(shù)起始物料不需要確定供體資格（參考文獻(xiàn)23）、篩選或檢測（21CFR1271.90(a)(1)）。另一方面，同種異體白細(xì)胞分離術(shù)起始物料確實(shí)需要根據(jù)21CFR第1271部分的C子部分確定供體資格、以及對相關(guān)傳染病病原體進(jìn)行篩查和檢測。在GTCMC指南（參考文獻(xiàn)3）的V.A.2.c.ii.b部分中，討論了來自同種異體細(xì)胞或組織的細(xì)胞TomaintaintheChainofIdentity(COI),labelingandtrackingofmaterial,fromcollectionalltheAdditionally,werecommendlabelibuiltintothebatchrecordpriortoeachprocessingstep.TheCOIshouldalsoclinicalsitewithtwoIV.C.3ofthisguidanceforconsiderationsregardinglabelingfortheCARTcellDP.為了維護(hù)鑒別鏈(COI)，必須記錄從收集到CART細(xì)胞管理的材料標(biāo)簽和跟蹤（21CFR驟之前將標(biāo)簽檢查內(nèi)置到批記錄中。COI還應(yīng)在臨床現(xiàn)場進(jìn)行維護(hù)，并在床邊進(jìn)行兩名獨(dú)立的患者和標(biāo)簽檢查。有關(guān)CART細(xì)胞DP標(biāo)記的考量，請參閱本指南的第productprofile(Refs.24,25).Recommendationsforthemaearlyproductcharacterization(sectionIV.A);characterizationoandii);manufacturingprocessdevelopment(sectionsV.A.2.fanddetailsforCARTcellmanufacturingandtesting.CART細(xì)胞生產(chǎn)是一個(gè)復(fù)雜的過程，應(yīng)進(jìn)行定制以實(shí)現(xiàn)目標(biāo)產(chǎn)品配置（參考文獻(xiàn)24、的建議。我們建議，發(fā)起人考慮GTCMC指南（參考文獻(xiàn)3）中的建議（如適用）：早期產(chǎn)品表征（第IV.A節(jié)）；雜質(zhì)的表征（第VA3.bi和ii部分）；生產(chǎn)工藝開發(fā)（VA2.f和VB2.c部分和設(shè)施考慮（第VC1節(jié)）。本指南提供了有關(guān)CART細(xì)胞生產(chǎn)Coupledwithdonor-to-donorvariabilityinherenttothecellularstartingmaterial,multi-smanufacturingprocessescanbeasourceofvariability.TominconsistencybetweenCARTcelllots,werecommendthemanufacturingprocessbewell-controlled.Thiscanbeachievedviatheuseofqualitymaterials,in-processcprocesstesting,andtestingofintermediatesandthefinalproductforCQAs(Ref.26).再加上細(xì)胞起始物料固有的供體間變異性，多步驟生產(chǎn)工藝可能是變異性的來源。為了最大限度地減少變異性、并促進(jìn)CART細(xì)胞批次之間的一致性，我們建議，對生產(chǎn)工藝進(jìn)CARTcellmanufacturingoftenrequiresspecializedancilqualityofsuchmaterialexample,werecommendthathumanoranimal-derivedcomponentsarenotsogeographicalareasofconcernforpotentialviraland/ortransmissiblespon(TSE)agentcontaminaLot-to-lotvariabilityandstabilityofreagentscqualifyancillarymaterialsforquality,safety,andpotencythroughvendorqualificationprogramsandincomingmaterialqualificationprograms,includingquarantine,CertificateofAnalysis(COA)andCertificateofOrigin(COO)assessment,visualinspection,andtesting,asappro例如，我們建議，人源或動物源性成分不得來自可能受到病毒和/或傳染性海綿狀腦病(TSE)病原體污染的地理區(qū)域，并且建議對成分進(jìn)行適當(dāng)?shù)耐庠葱圆≡w檢測。試劑的批次間變異性和穩(wěn)定性也可能存在問題。我們建議，通過供應(yīng)商確認(rèn)計(jì)劃和進(jìn)料確認(rèn)計(jì)劃（包括檢疫、分析證書(COA)和原產(chǎn)地證Toassureproductsafety,Chowever,thefinalDPcannotbeterminallysterilizedascellsneedtfunctional.Therefore,manufacturingshouldbeconductedbundercurrentgoodmanufacturingpractice(CGMP)conditions(Ref.27supportedbytheuseofsterilitytestingChapter71oranappropriatelyqualifiedandvalidatedtestmethod.為確保產(chǎn)品安全，CART細(xì)胞應(yīng)不含活的污染微生物；然而，最終的DP不能最因?yàn)榧?xì)胞需要完全存活并發(fā)揮功能。因此，應(yīng)在cGMP條件下使用經(jīng)過驗(yàn)證的無菌工藝進(jìn)TheINDshouldcontaininformationdemonstratingtheabitotheproposedmanufacturingprocessthroughtheproductionofdevelopmentalorenginebatches.Tosupportprocessdevelopment,sponsorsmaycrossreferenceinformationfconstruct)atthesamefacility.Generally,startimanufacturingprocessdevelopmentalbatches.However,patient-derhaveintrinsicpropertiesthataffectCARTcellman