FDA：医疗器械临床试验关于年龄、人种和种族的评价和报告

EvaluationandReportingofAge,Race,andEthnicityDatainMedicalDeviceClinicalStudies医疗器械临床试验关于年龄、人种和种族的评价和报告DraftGuidanceforIndustryandFoodandDrugAdministrationStaff企业和食药管理人员指导草案U.S.DepartmentofHealthandHumanServices美国健康和人类服务部FoodandDrugAdministration美国食品和药品监督管理局CenterforDevicesandRadiologicalHealth器械和放射健康中心CenterforBiologicsEvaluationandResearch生物制剂评价和研究中心Ⅰ.Introduction引言ThepurposeofthisguidanceistooutlinetheFDA’sexpectationsandproviderecommendationsfortheevaluationandreportingofage,raceandethnicitydatainmedicaldeviceclinicalstudies.Theprimaryintentoftheserecommendationsistoimprovethequality,consistencyandtransparencyofdataregardingtheperformanceofmedicaldeviceswithinspecificage,race,andethnicgroups.Properevaluationandreportingofthisdatacanbenefitpatients,clinicians,researchers,regulatorsandothers.Additionally,itisimportantthatclinicaltrialsincludediversepopulationsthatreflecttheintendedusepopulation.Ingeneral,toachieveanunbiasedestimateoftreatmenteffectinthegeneralpopulation,sponsorsshoulddevelopastrategytoenrolldiversepopulationsincludingrepresentativeproportionsofrelevantage,race,andethnicitysubgroups,whichareconsistentwiththeintendedusepopulationofthedevice.Thisdraftguidanceincludesrecommendationsandconsiderationstoassistsponsorsindevelopingsuchastrategy.该指导文件的目的是概述FDA的期望，为评价和报告医疗器械临床试验关于年龄、人种和种族方面提供建议。这些建议的主要意图是的提高关于医疗器械在特定年龄、人种和种族的性能实验数据的质量、稳定性和透明性。合理的评价和报告数据有益于病人、临床医生、研究人员和监管部门等等。另外，包含不同人群的临床试验是很重要的，影响到医疗器械的特定适用目标人群。一般来讲，为了验证治疗效果在普通人群中没有偏差，临床试验申请者应该制定一个方案，入组人员应包含代表相关年龄、人种和亚种族的不同比例人群，要与器械的目标人群相一致。该指导草案包含了辅助申办者制定试验方案的建议和注意事项。Whenfinalized,thisguidancewillextendthepolicysetforthintheFDA’sEvaluationofSex-SpecificDatainMedicalDeviceClinicalStudiesGuidance1toadditionaldemographicsubgroupsofage,race,andethnicity.FDAintendstointegratethefinalcontentintoonefinalguidancedocument.Whenfinalized,thisguidancewillalsoextendandcomplementFDA’sCollectionofRaceandEthnicityDatainClinicalTrialsGuidance,which,forcollectingandreportingraceandethnicityinformationinclinicaltrials,recommendedtheuseofthestandardizedapproachdevelopedbytheOfficeofManagementandBudget(OMB).完成指导文件能扩充FDA在《医疗器械临床试验性别差异数据评价》实施的政策，增加了年龄、人种和种族不同人群组成。FDA打算整合成最终的指导文件。完成指导文件也能扩展和补充FDA关于《收集临床试验人种和种族数据》的指导意见，在该指导意见是为了收集和报导临床试验人种和种族的信息，行政管理和预算局（OMB）建议使用了这个标准方法。Thespecificobjectivesofthisguidanceareto:1)encouragethecollectionandconsiderationduringthestudydesignstageofrelevantage,race,ethnicityandassociatedcovariates(e.g.,bodysize,biomarkers,bonedensity,etc.),fordevicesforwhichsafety,effectiveness(probablebenefit,forHDEs),orbenefit-riskprofileisexpectedtovaryacrossthesegroups;2)outlinerecommendedanalysesofstudysubgroupdata,withaframeworkforconsideringdemographicdatawheninterpretingoverallstudyoutcomes;and3)specifyFDA’sexpectationsforreportingage,race,andethnicity-specificinformationinsummariesandlabelingforapprovedorclearedmedicaldevices.该指导文件的具体实施目标如下：鼓励在试验启动阶段收集和考虑医疗器械在年龄、人种、种族和相关变量（如身体大小、生物标记、骨骼密度等）时的安全性、有效性，效益风险分析在这些族群中是不一样的。2)概述亚组群研究数据的建议分析，组建综合考虑人口统计数据实验结果的框架。3)规定FDA的期望，总体报告年龄、人种和种族信息，标记医疗器械同意或批准。FDA'sguidancedocuments,includingthisdraftguidance,donotestablishlegallyenforceableresponsibilities.Instead,guidancesdescribetheAgency’scurrentthinkingonatopicandshouldbeviewedonlyasrecommendations,unlessspecificregulatoryorstatutoryrequirementsarecited.TheuseofthewordshouldinAgencyguidancemeansthatsomethingissuggestedorrecommended,butnotrequired.FDA包括该草案的指导文件不是建立在法律强制手段上的。相反，指导文件叙述的是机构现在的主题想法，应该只是被当成建议，除非是具体标准或法定要求。用于机构的指导文件意味着只是建议，不做要求。II.Scope范围Thisguidanceisintendedfordevicesthatincludeclinicalinformationinsupportofamarketingsubmission,whetherapremarketnotification(510(k)),premarketapproval(PMA)application,185evaluationofAutomaticClassIIIDesignation(denovorequest),orhumanitariandeviceexemption(HDE)application.Therecommendationscontainedhereinalsoapplytopost-approvalstudysubmissionsandpostmarketsurveillancestudies,wherenoted.该指导文件适用于设备上市前提交的临床试验信息，无论是上市前通知（510（k））、上市前批准（PMA）要求从头开始),还是人道用途器材的免除申请（HDE）。这里提出的建议也适用于批准后研究提交和上市后监督。Age,race,andethnicityarenottheonlydemographicvariablesthatmayaffectdeviceperformance.Whilethisguidancefocusesontheimpactofage,race,andethnicity,someoftherecommendationsmayalsobeusedtopromotestudyenrollmentanddataanalysisadequatelyaccountingforotherdemographicvariables,suchassexandgeographiclocation(e.g.,rural).Otherpatientcharacteristicssuchasemotional,physical,sensory,andcognitivecapabilitiescanoftenbeimportantvariableswhenevaluatingmedicaldevicesafetyandeffectiveness(orprobablebenefitforHDEs);however,thesewillnotbeaddressedwithinthisguidance.ForfurtherinformationrelatedtotheseuserconsiderationspleaseseetheDesignConsiderationsforDevicesIntendedforHomeUseGuidancedocument.一些建议也可用于提高其它统计变量如性别和地理位置（如乡村）的入组研究和数据分析。其它的病人特点，如情绪、身体、感官和认知能力往往是重要的评估医疗器械安全性和有效性的变量（或者有益于HDEs）;然而，这些将不会被本指导意见中解决。关于这些考虑使用者需要方面的更多信息请参考用于家庭使用设备的设计注意事项的指导文档Theimpactofdemographicvariablesondevicesafety,effectiveness(probablebenefit,forHDEs),orbenefit-riskprofilemayapplymoretocertaintypesofproductsordiseasesthanothers.Forexample,certaindermatologydevicesmayhavedifferentconsiderationsforuseinaspecificraceorethnicpopulation.Similarly,certainorthopedicdevicesmayhavedifferentconsiderationsforuseinspecificagegroups.Studiesofdevicesintendedonlyforcertaingroups(e.g.,pediatrics)wouldnotbeexpectedtoaddressthepotentialdifferencesinoutcomeforgroupsoutsidetheintendedusepopulation.Additionally,someinvitrodiagnostic(IVD)deviceclinicalstudiesareconductedonde-identifiedleftoverspecimens,soitmaynotbepossibletoobtaindemographicinformation,suchasage,raceorethnicity.Asaresult,evaluationofage,race,andethnicitydatawouldnotbepossibleinthesecases.Ingeneral,whenclinicallyrelevantdifferencesintreatmenteffectareanticipatedacrossage,race,orethnicgroups,theseeffectsshouldbeconsideredinthestudydesignandappropriatelyreportedinthedevicelabeling.人口统计学变量对某些设备的安全性、有效性（可能有利于HDEs申请）或利益风险状况的影响可能更适用。例如，某些治疗皮肤病的设备用于在一个特定的人种或种族应该不同的考虑。同样，某些骨科器械对特定的年龄组使用应有不同考虑。仅用于某些特定组群（例如，儿科）医疗设备的研究，除对潜在使用对象研究外，不要求对各个组群进行潜在的结果研究。此外，一些体外诊断（IVD）设备临床研究是通过识别剩余的标本进行的，因此它可能无法获得人口统计信息，诸如年龄、人种或种族。其结果是，在这些情况下不能评估年龄、人种和种族的数据。在一般情况下，当相关临床治疗效果的差异跨越年龄、种族或族群预期的，在研究设计时应考虑这些影响，在设备标识时应进行合适的报告。FDArecommendstheuseofthisguidancedocumentasasupplementtootherFDAguidancewhereapplicable,inparticular,anyrelevantdevice-specificguidance,aswellasFDA’sCollectionofRaceandEthnicityDatainClinicalTrialsguidance.ConsultationwiththeFDAprimaryreviewingDivisionorBranchisadvised.FDA建议使用本指导文件用以补充其他适用的FDA指南，特别是任何特定相关设备的指南，以及FDA收集人种和种族临床试验数据的指南。建议咨询FDA主审部门或分部。Ⅲ.Background背景CertainelementsdescribedinthisguidancehavebeenemphasizedinAgencyregulationsand/orpolicyinthepast.OverrecentdecadestheAgency’sviews,aswellasthoseofthemedicalcommunityingeneral,haveevolvedregardingage,race,andethnicityinclinicalstudies.在本指南中强调的某些影响元素，以往在机构规定和政策里都有描述。近几十年来监管机构的观点，以及医学界普遍观念，已经演变为有关年龄、人种和种族在临床试验的研究。Priortodevelopingthepolicysetforthinthisguidance,FDApubliclysoughtinputfromavarietyofexpertsandstakeholdersregardingthestudyandevaluationofage,race,andethnicityinclinicalstudiesformedicaldevices.OnApril9,2015,theInstituteofMedicineconvenedapublicworkshopofvariousgovernmentagencies,physicianprofessionalsocieties,andpatientadvocacygroupsparticipatedinapublicworkshoptodiscussstrategiesforensuringdiversity,inclusion,andmeaningfulparticipationinclinicaltrials.Thisguidancedocumentreflectstherecommendationsgeneratedinthisandotherpublicfora.Itisintendedtoprovideguidanceonthedesign,conduct,andreportingofclinicalstudiestoimproveage,race,andethnicityinformationaboutthesafetyandeffectiveness(orprobablebenefitforHDEs)ofapprovedandclearednewmedicaldevices.本指南列出的以前制定的政策，FDA公开从各种专家和利益相关者征求关于年龄、人种和种族在对医疗器械临床研究中的研究和评估。在2015年4月9日，美国医学研究所召集各级政府机构、医师专业协会和病人权益团体公召开了一场公开研讨会，确保临床试验的多样性、包容性和有意义性。这个指导文件反映了本文章和其它公共论坛的建议。它的目的是为通过或批准新的医疗器械提供指导，在临床试验设计、实施和临床试验报告中提高和改善年龄、人种和种族有关安全性和有效性信息。A.Section907oftheFoodandDrugAdministrationSafetyandInnovationActof2012(FDASIA)2012食品药品监督管理局安全和创新法案（FDASIA）第907令Section907oftheFoodandDrugAdministrationSafetyandInnovationActof2012(FDASIA)directedtheAgencytopublishandprovidetoCongressaReportfollowedbyanActionPlanoutlining“recommendationsforimprovingthecompletenessandqualityofanalysesofdataondemographicsubgroups[includingsex,age,race,andethnicity]insummariesofproductsafetyandeffectivenessdata[orprobablebenefitforHDEs]andinlabeling;ontheinclusionofsuchdata,orthelackofavailabilityofsuchdata,inlabeling;andonimprovingthepublicavailabilityofsuchdatatopatients,healthcareproviders,andresearchers.”InthatActionPlan,CDRHcommittedtodevelopthisdraftguidance,asanactiontoimprovethecompleteness,quality,andpublicavailabilityofdemographicsubgroupdatafrommedicaldeviceclinicalstudies.2012食品药品监督管理局安全和创新法案（FDASIA）第907令指导机构依据行动计划大纲发表和提交报告给国会，提高完整性和提高设备产品对人口子群（包括性别、年龄、人种和种族）等统计数据安全性和有效性的分析质量。要标明有这样的数据，或缺乏这样的数据，提高这些数据的可用性，给病人、医疗服务提供者和研究人员。“在该行动计划中，CDRH致力于完善这一指导意见草案，提高医疗器械临床试验人口统计子群数据的完整性、质量和公众可用性。B、Terminology术语（1）Age年龄Whenevaluatingage-specificdata,clinicalstudiesshouldplantogroupsubjectsbyagegroupsasappropriateforthediseasecondition.Standardizingagecategoriesmaynotbeappropriateforalldevices;however,morediscreteagegroupingsshouldbeconsidered.Forexample,youmaygroupolderpatientsforanalysisat65-74yearsold,and75-84yearsold,ratherthansimplyolder/youngerthan65.当评估年龄数据时，临床试验应按病情依据受试者的年龄进行合适的分组。按年龄标准化分组可能不适合所有的设备，可以进行分散式年龄分组。例如，你可以把老年患者按65-74岁和75-84岁分组，而不是简单年龄大于或/小于65。FDAdoesnotdefineaspecificageforthegeriatricpopulationduetothedifferentconsiderationsforthewidevarietyofmedicaldevicesanddiagnostics.However,werecommendstratifyingagebasedonrelevantdiseasecharacteristics(e.g.65-74,≥75years).FDA没有为老年人界定一个特定的年龄段，考虑到医疗设备和诊断的广泛性。然而，我们可以在相关疾病特征的基础上进行年龄分组（如65-74，≥75年）。Deviceregulationsdefinethepediatricpopulationasanypatientlessthan22yearsofage.9Itshouldbenotedthatthismaydifferfromthedrugandbiologicregulationsbutforpurposesofthisguidance,thedefinitionofpediatricpatientin21CFR814.3(s)shouldbeused.Thispopulationisfurthersubdividedintoseveralagegroupsasdescribedinguidanceorbydevelopmentalmilestonesasappropriate.设备法规规定儿科病人为任何小于22周岁的病人。这可能有别于药物和生物学上的规定，但在本次指导方案中，21CFR814.3(s)里界定的儿科病人在这里适用。（2）RaceandEthnicity人种和种族InaccordancewithFDA’sguidanceCollectionofRaceandEthnicityDatainClinicalTrials11,patientsmayself-identifyinbothanethnicandracialcategory(e.g.,Hispanic-White,Hispanic-Black).Thisguidancespecifiedthat“theOfficeofManagementandBudget(OMB)statedthatitsraceandethnicitycategorieswerenotanthropologicorscientificallybaseddesignations,butinsteadwerecategoriesthatdescribedthesocioculturalconstructofoursociety.TheDepartmentofHealthandHumanServices(HHS)chosetoadoptthesestandardizedcategoriesforitsagenciesthatreportstatisticsbecausethecategoriesarerelevanttoassessingvarioushealthrelateddata,includingpublichealthsurveillanceandresearch.”FDAacceptsapplicationscontainingclinicalstudydatawithethnicandracialdemographicdatacapturedasonecategoryorseparately,althoughthegenerallypreferredmethodistocollectethnicityandraceseparately.根据FDA收集人种和种族临床试验数据的指导原则，要自动确认病人的人种和种族（如西班牙裔白人，西班牙裔黑人）。被指南规定：“管理和预算办公室（OMB）所说的种和种族的分类不是人类学的或是科学上的分类，而是描述社会文化构成的分类。美国卫生和人类服务部所属机构采用的标准化的分类来统计是因为这些类别影响各类健康相关数据的评估，包括公共卫生监测和研究。”FDA可以单独或整体性的接受人种和种族的临床研究数据的申请，首选方法是分开申请。Moregranularracedatamaybeimportantdependingonthediseaseorcondition(e.g.,iftheconditionissubstantiallymoreprevalentorvariedincourseforAshkenaziJewishorHanChinese).Additionally,FDAacknowledgesthatotherethnicandracialcategoriesmaybeappropriatedependingonthestudypopulation,e.g.,inglobalstudiesinvolvingsitesandpatientsoutsidetheUnitedStates(OUS).Thecategoriesandidentificationmethodshouldbedefinedinthestudyprotocol.更多单独的依据病情或条件的（如在德系犹太人或汉族普遍存在或变化的）人种数据是必要的。另外FDA承认其它的根据研究人群确定的人种和种族的分类，如全球性的和美国以外的（OUS）。分类和确认方法应该在研究协议了表明。CollectionandpoolingofdatafromOUSstudysitesmayresultinconfoundingissuesofethnicityandstandardofcare.OUSsitesmaynotcategorizeraceandethnicityinthesamemannerasUSsitesormaydefinecertainraceorethnicitygroupsdifferentlythandoUSsites(e.g.,“Caucasian”vs“white”inEuropeanvsUSdata).Additionally,thestandardofcareatOUSsitesmaynotbeequivalent.ThesedifferencesmaymakeitdifficulttopoolraceandethnicitysubgroupdatafromOUSsites.从美国以外的试验结构搜集和集中数据可能导致种族分组标准混乱。美国以外的试验机构可能没有像美国一样分组人种和种族、界定特定人种或种族分组不同（欧洲“白种人”和美国“白种人”）。此外美国以外的试验机构的护理标准可能是不平衡的。这些差异导致汇集人种和种族子集数据的困难。C、WhyConsiderAge,Race,andEthnicityDifferences为什么考虑年龄、人种和种族的差异（1）Age年龄Considerationofdifferentagepopulations,particularlypediatricandolderpatients,whichareoftenunderrepresentedinclinicaltrials,canbeimportantforpropercharacterizationofadevice’ssafetyandeffectiveness(orprobablebenefitforHDEs)inthepatientpopulation.Inthe2013FDASIA907Report12,oftheapprovedPMAsevaluatedforthereport,only40%publiclyreportedanagebasedanalysisofoutcomesdata.Theamountofageinformationavailablewasinconsistentandoftennotdetailedenoughtoanalyzedeviceperformancerelatedtoage.Themannerinwhichtheagedescriptivestatisticsarepresented(e.g.,mean,median,standarddeviation,distribution)inasubmissionmayaffectdatainterpretation.Properstudyofdeviceuseinbotholderandpediatricpopulationsisimportantwhenthedeviceislikelytobeusedforthesesubgroups.考虑不同年龄的人群，特别是未成年人和老年人可以适当表征设备安全性和有效性，往往在临床试验中代表数量不足。2013FDASIA907批准的上市前申请报告，只有40%的报告公开了基于年龄的数据分析结果。可用的年龄信息往往不一致并且不够详细，不能分析设备有关年龄方面的性能。递交的申请里关于年龄描述性的统计分析（如平均值、中位数、标准偏差、分布）可能影响数据的理解。当设备适用于儿童和老年人时，关于这些人群的合理研究是非常必要的。Olderpatientsandpediatricpatientsoftenhaveco-morbidities,concomitanttherapies,ordevelopmentconsiderationsthatcouldinteractwiththeinvestigationaldeviceeffectsandimpactdeviceperformance.Olderpatientsmayhaveage-relatedcovariatessuchascharacteristicsofbonedensity,metabolism,digestion,synovialfluid,etc.thatcouldaffecttheperformanceofmedicaldevices.Meanwhile,medicaldevicesmayhavedifferentpositiveoradverseeffects,orotherwiseimpactthedevelopmentofapediatricpatient,whereitwouldhavenoeffectonanadult.Forexample,theuseofcochlearimplantsincertainpediatricsubgroupsmaynotbeadvisableduetothesizeoftheimplant,ormaybeinappropriateduetothestageoftheneurologicaldevelopmentofthechild.13Inthecaseofintraocularlensesusedtotreatvisionloss,deviceusemayalsoimprovefuturevisualdevelopmentinayoungchild.Forthesereasons,itisimportanttoconsistentlyconsiderthepotentialimpactofageondeviceeffects,andtoplanstudiesandanalysesaccordingly.老年人和未成年病人常有并发症、伴随治疗或者发育考虑，这可能影响设备研究的性能。老年人身体会发生与年龄相关的变化如骨骼密度、代谢、消化、滑膜液等，这可能影响医疗设备的性能。同时医疗设备可能对儿童的发育有积极或消极的影响，而对成年人没有影响。例如人工耳蜗植入不建议用于一些儿童人群，出于移植物体积和儿童神经发育阶段的考虑。使用人工晶体治疗失明，器械可能也会提高儿童将来的视力。出于这些原因，始终考虑医疗器械在年龄方面的潜在影响并进行研究和分析是非常重要的。FDAprovidesguidanceondevelopingmedicaldevicesforpediatricpopulationsubgroups(e.g.,neonates,infants,children,andadolescents).13FDAcurrentlyhasseveraldevice-relatedinitiativesunderwaythataimtoaddresschallengesinthepediatricsubpopulation.In2007,CongressenactedthePediatricMedicalDeviceSafetyandImprovementAct(PMDSIA)aspartoftheFoodandDrugAdministrationAmendmentsAct(FDAAA)whichprovidesthatFDAmayextrapolateadultdatawhenappropriate.FDA为未成年人亚群（如新生儿、婴儿、儿童和青少年）医疗设备的发展提供了指导文件。FDA正在进行几项医疗器械相关的举措旨在解决未成年人亚群的问题。2007年，国会颁布了儿科医疗设备安全和改进法案（PMDSIA），作为食品和药品监督管理局修正法案的一部分，在合适的时候可以推断成人的数据。PMDSIAalsorequirescertainmedicaldeviceapplicationstoinclude,ifreadilyavailable,adescriptionofanypediatricsubpopulationsthatsufferfromthediseaseorconditionthatthedeviceisintendedtotreat,diagnose,orcureandthenumberofaffectedpediatricpatients.16FDAissuedaguidancedocumentoutliningtheimplementationofthisprovision.PMDSIA也需要一些特定医疗器械的申请，如果现成的，一份医疗设备治疗、诊断和治愈儿科病人病情和条件的详细说明，受影响未成年人的数量。FDA发布一个指导文件概述了这一规定的进展情况。（2）RaceandEthnicity人种和种族WhiletheU.S.populationdemographicischanging,diverserepresentationinclinicaltrialsremainsachallenge,andinconsistentanalysisandreportingcontributestoapersistentlackofpubliclyavailabledataondeviceperformanceindiverseethnicandracialgroups.The2013FDASIA907Reportshowedadistinctlackofpubliclyreportedraceandethnicitydataformedicaldevices.18Only27%ofthestudiesreviewedcontainedaraceorethnicitysubgroupanalysis,andonly16%hadpublicstatementsregardingaraceorethnicityanalysis.由于美国人口分布一直在发生变化，不同代表性的临床试验仍然是一个挑战，不一致性的分析和报告导致了医疗设备性能在不同人种和种族上的公众可用数据的缺少。2013FDASIA907报告明显表现出医疗设备在人种和种族方面公众报道数据的缺乏。评审的研究只有27%包含人种或种族亚群的分析，只有16%有关于人种或种族分析的公开声明。Thereareseveraldeviceswheredifferencesineffectwereobservedthatwerecorrelatedwithraceandethnicity.Forexample,differencesinskinstructureandphysiologycanaffectresponsetodermatologicandtopicallyappliedproducts.19Mortalityratesofpatientsondialysishavebeenshowntodifferacrossraceandethnicitygroups.20FDAencouragessponsorstocollectraceandethnicitydataaccordingtotherecommendationsinthe2005CollectionofRaceandEthnicityGuidanceDocument.观察到有几种设备效能上与使用者人种和种族有关。例如不同的皮肤机构和生理机能影响皮肤病外用产品的功效。结果表明不同人种和种族透析病人的死亡率不同。FDA鼓励发起人依据2005人种和种族收集指导文件进行人种和种族数据的收集。D、ParticipationofAge,Race,andEthnicitySubgroupsinClinicalTrials临床试验中参与者的年龄、人种和种族Itisimportantthatclinicaltrialsincludediversepopulationsthatreflecttheintendedpopulation,especiallywhenclinicallymeaningfuldifferencesinsafety,effectiveness,(probablebenefit,forHDEs),orbenefit-riskprofileareexpectedacrossthesegroups.Ingeneral,toachieveanunbiasedestimateoftreatmenteffectinthegeneralpopulation,sponsorsshoulddevelopastrategytoenrolldiversepopulationsincludingrelevantage,race,andethnicgroups.在临床试验中包括不同的目标人群是很重要的，尤其是在具有安全性、有效性和风险预计方面的临床统计意义上的差异时。一般要在普通人群中完成公正的治疗效果评估时，申办者应该制定一个包括年龄、种族和人种等不同组群的试验方针。Wherepossible,itisalsoimportanttoenrolldiversepopulationsthroughouttheenrollingsites,particularlyinstudieswheresurgicaloroperatorskillmaybeofkeyimportance.Ifpatientsenrolledatonesitearepredominantlyofonedemographicsubgroup,itmaybepossibletoincorrectlyattributedifferencesindeviceperformanceorsurgicalskilltodemographicsubgroups;thisshouldbeconsideredwhenplanningandanalyzingtrials.必要时，在所有的入组机构都要入组不同的人群，特别是外科手术和操作技能是重要关键时。如果一个实验单位只入组了一类人群，可能造成器械性能的误判或对人群子组手术技能的差异。当计划和分析试验时应该考虑到这点。Ingeneral,studyprotocolsshouldincludepre-specifiedstatisticalplansforaddressingtheseandotherissuesoutlinedinthisguidance.Unplannedsubgroupanalysesorthosewithinadequatesamplesizearegenerallynotconsideredtobeadequatetosupportstatementsinthelabelingregardingthesafetyoreffectivenessofthedevice.However,theoverallbenefit-riskprofileofthedevicewillbeconsidered.一般试验方案应当包括预先明确的统计学计划，解决本指导文件中概述的这些和其它问题。无计划的子组分析或没有足够样本量就不能提供足够标识设备安全性和有效性的声明。因而将会考虑设备的整体受益风险。（1）BarrierstoEnrollment招募入组障碍Recruitingparticipantstoclinicalstudieswhorepresenttherangeofage,race,andethnicgroupsconsistentwiththeintendedusepopulationofthedevicemaypresentadditionalchallenges.Therearenumeroussuspectedreasonsforlowminorityparticipationandlowparticipationofolderandpediatricpatients.22In2009,FDApublishedaReporttoCongressonidentifiedbarrierstoenrollmentinclinicaldrugtrialsandrecommendationsonhowtoaddressthedisproportionatelylowenrollmentofcertainpopulationsinclinicaltrials,especiallythosetrialsinwhichthesepopulationsarehighlyaffectedbyorarelikelytosufferworseoutcomesfromthediseasebeingevaluated.23FDAbelievesmuchofthisinformationisrelevanttomedicaldeviceclinicaltrialsaswell.临床试验招募设备目标人群，代表不同年龄、人种和种族的受试者存在额外的困难。受试者参与人少和未成年人和老人参与人少是因为存在诸多的怀疑。2009年，FDA向国会提交报告，确认了药物临床试验的障碍和提出一些建议用于解决一些特定人群入组率低、有失平衡问题，尤其是那些有高度影响或有严重后果的试验。FDA相信许多信息都与医疗器械临床有关。Thefollowinghavebeenidentifiedaspotentialbarrierstoenrollment:以下确认为招募入组潜在的障碍：˜lackofunderstandingaboutmainobstaclestoparticipationofdifferentage,缺乏临床试验关于不同年龄、人种和种族主要障碍的理解˜inclusion/exclusioncriteriawhichunintentionallyexcludedifferentage,race,orethnicgroups(e.g.,creatininelevelsforAfricanAmericans)纳入/排除标准无意中排出了不同的年龄、人种和种族组群（如非裔美国人的肌酐水平）˜lackofunderstandingaboutdifferencesindiseaseetiologyandpathophysiologymayleadtounder-diagnosisandunder-referralofspecificdemographicsubgroups缺乏疾病病因和生理上的差异的理解可能导致特定人口亚群的诊断和转诊˜patientconcernsrelatedtotreatmentgroup,randomization,possiblesideeffects,privacy,andhistoricalmistrustofclinicaltrialethics;病人关注相关治疗、随机、可能的副作用、隐私和历史性的临床试验伦理不信任˜language,cultural,andhealthliteracygapsbetweeninvestigatorsandpatients;研究者和病人之间语言、文化和健康素养的差异˜investigatorandsponsoravoidanceofspecificage,race,orethnicgroupsofpatientsduetotheperceptionthatitismoredifficultandpotentiallymoreexpensivetorecruitandmaintainparticipation研究者和申办者排除一些特定年龄、人种和种族的病人，预感到入组这些病人更困难和花费更高˜pressureoninvestigatorstoquicklyenrollpatientsregardlessofdemographiccharacteristics;迫于压力研究者不顾人群特征快速的入组病人˜perceivedethicalconcernsamonginvestigatorsregardingenrollmentofcertaindemographicgroupsinclinicaltrials;临床试验中研究者关于特定人群伦理上的考虑˜triallogistics(e.g.,transportation,childcare)maydisproportionatelyaffectspecificage,raceandethnicgroups’abilitytocompletestudyfollow-upvisits;试验的流动性（如流动、幼托）可能不成比例的影响特定年龄、人种和种族的人群来完成后续的研究回访。˜disproportionatedropoutandlost-to-follow-uprates;and不成比例的脱落率˜typeorlocationofstudysitesmaylimitparticipationofspecificage,race,orethnicgroups研究地点的类型和地点可能限制特定年龄、人种和种族组群的参与（2）EnrollmentResources招募入组资源Whereongoingenrollmentdatademonstrateanunderrepresentationofcertainsubgroupsenrollinginthestudy,sponsorsareencouragedtoinvestigatethereason(s)forlackofenrollmentandconsidertheapproachesinSectionIVtoenhanceenrollment.Itmaybeinformativetoevaluatewhetherthedemographicdistributionvariesatdifferentkeytimepoints(e.g.,atscreening,afterevaluationofstudyinclusion/exclusioncriteria,afterconsent,andatvariousfollow-uptimepoints).Informationregardingchangesindemographicdistributionatkeytimepointsinstudyscreening,enrollment,andfollow-upcanprovideinsightintorootcausesoflowerenrollmentratesinthesegroups.Thismayhelpidentifywaystosubstantiallylowerbarrierstoenrollmentofage,race,andethnicitysubgroupsthathavebeenshowntoimproveenrollmentratesandstudyretentionratesinothersubgroupsofstudyparticipants,(e.g.,flexibilityinfollow-upvisitschedulingwithconsiderationofchildcareoreldercareservicesduringappointments).ChangestoastudyprotocolandinformedconsentmaybemadebasedondemographicdistributioninformationwithappropriatenotificationtoandapprovalfromtheIRBandFDA,wherenecessary.在研究中入组的数据显示某特定组群代表性不足，鼓励申办者调查缺乏入组的原因，在IV部分考虑这个问题增加入组。可以提供信息来评估在不同关键时间点人口统计分布变化（如，筛选中，评估研究纳入/排除标准后，经同意后和后续的不同时间点）。在关键时间点临床研究的分布、入组和后续人口分布变化的信息能找出这些组群入组率低的根本原因。这有助于确定方法大幅度解决年龄、人种和种族入组的障碍，在其它研究子组里已经证明这可以提高入组率和研究保持率（如在后续随访过程中中灵活考虑儿童护养和老人护理服务问题）。必要时，可基于人口分布信息改变试验方案和知情协议，要通知IRB和FDA并得到批准。SponsorsmayalsowishtoconsiderresourcesdevelopedbytheNationalInstitutesofHealth,discussionwithacademicandcontractresearchorganizations,andpracticesofhigh-enrollingclinicalstudysites,indeterminingpracticesbestsuitedtoachieveappropriateenrollmentofdemographicgroups,andtoprovideinvestigatortrainingaboutthesetechniques.SomespecificexamplesofstrategiestoincreaseinclusionofdiversestudypopulationsarediscussedinSectionIVbelow.申办者还应考虑利用国家健康研究所的资源，和学术机构、CRO、高入组率临床试验机构进行讨论，确定最好最合适的人口组群入组方法，对研究者进行培训这些技能。一些具体提升不同研究人群纳入率策略在第四部分进行讨论。Ⅳ.RecommendationsforAchievingAppropriateEnrollment完成合适入组的建议Historically,manymedicaldeviceclinicalstudieshavenotenrolledproportionsofage,race,andethnicsubgroupsthatreflecttheunderlyingdiseasedistributionintheaffectedpopulation.Thiscanbeproblematicbecausetheabilitytodetectdifferencesinresponsetotreatmentismarkedlydiminishedifthereisnoorlimitedclinicalexperiencewiththeproductinthesubgroupofinterest.Thishascontributedtoasubstantiallackofavailabledataregardingtherisksandbenefitsofmedicaldeviceuseinage,race,andethnicsubgroups.Thus,itisimportantthatclinicaltrialsincludediversepopulationsthatreflecttheintendedpopulationwheneverpossibleandappropriate.以往很多临床研究没有入组年龄、人种和种族比例的子群，这些影响潜在的疾病分布。这是有问题的，因为如果没有这些子组的临床研究，检测治疗效果的能力会显著下降。这就会导致关于医疗器械在年龄、人种和种族子组缺乏风险效益可用数据的严重缺乏。因此临床试验考虑各类任何可能合适的目标人群是很重要的。Ingeneral,toachieveanunbiasedestimateoftreatmenteffectinthegeneralpopulation,sponsorsshouldideallyplantoenrollrepresentativeproportionsofage,race,andethnicitysubgroups,whichareconsistentwiththeintendedusepopulationofthedevice,orjustifyintheinvestigationalplanhowtheenrollmentcriteriawillprovidereasonablerepresentationofthe468intendedoraffectedpopulation.一般来说，为了完成在普通人群中治疗效果的一个合理估测，申办者应该进行合理的计划，入组具有年龄、人种和种族代表性特点的子组，保持与器械目标使用人群的一致性，合理解释研究计划入组标准代表目标人群的合理性。Incaseswhereknowndiseasescienceorpriorclinicalstudyresultssuggestaclinicallymeaningfuldifferenceinbenefitsorrisksinoneormoreage,racial,orethnicsubgroups,sponsorsshouldaimtoenrollsufficientnumbersof