FDA：醫(yī)療器械臨床試驗關(guān)于年齡、人種和種族的評價和報告

EvaluationandReportingofAge,Race,andEthnicityDatainMedicalDeviceClinicalStudies醫(yī)療器械臨床試驗關(guān)于年齡、人種和種族的評價和報告DraftGuidanceforIndustryandFoodandDrugAdministrationStaff企業(yè)和食藥管理人員指導(dǎo)草案U.S.DepartmentofHealthandHumanServices美國健康和人類服務(wù)部FoodandDrugAdministration美國食品和藥品監(jiān)督管理局CenterforDevicesandRadiologicalHealth器械和放射健康中心CenterforBiologicsEvaluationandResearch生物制劑評價和研究中心Ⅰ.Introduction引言ThepurposeofthisguidanceistooutlinetheFDA’sexpectationsandproviderecommendationsfortheevaluationandreportingofage,raceandethnicitydatainmedicaldeviceclinicalstudies.Theprimaryintentoftheserecommendationsistoimprovethequality,consistencyandtransparencyofdataregardingtheperformanceofmedicaldeviceswithinspecificage,race,andethnicgroups.Properevaluationandreportingofthisdatacanbenefitpatients,clinicians,researchers,regulatorsandothers.Additionally,itisimportantthatclinicaltrialsincludediversepopulationsthatreflecttheintendedusepopulation.Ingeneral,toachieveanunbiasedestimateoftreatmenteffectinthegeneralpopulation,sponsorsshoulddevelopastrategytoenrolldiversepopulationsincludingrepresentativeproportionsofrelevantage,race,andethnicitysubgroups,whichareconsistentwiththeintendedusepopulationofthedevice.Thisdraftguidanceincludesrecommendationsandconsiderationstoassistsponsorsindevelopingsuchastrategy.該指導(dǎo)文件的目的是概述FDA的期望，為評價和報告醫(yī)療器械臨床試驗關(guān)于年齡、人種和種族方面提供建議。這些建議的主要意圖是的提高關(guān)于醫(yī)療器械在特定年齡、人種和種族的性能實驗數(shù)據(jù)的質(zhì)量、穩(wěn)定性和透明性。合理的評價和報告數(shù)據(jù)有益于病人、臨床醫(yī)生、研究人員和監(jiān)管部門等等。另外，包含不同人群的臨床試驗是很重要的，影響到醫(yī)療器械的特定適用目標人群。一般來講，為了驗證治療效果在普通人群中沒有偏差，臨床試驗申請者應(yīng)該制定一個方案，入組人員應(yīng)包含代表相關(guān)年齡、人種和亞種族的不同比例人群，要與器械的目標人群相一致。該指導(dǎo)草案包含了輔助申辦者制定試驗方案的建議和注意事項。Whenfinalized,thisguidancewillextendthepolicysetforthintheFDA’sEvaluationofSex-SpecificDatainMedicalDeviceClinicalStudiesGuidance1toadditionaldemographicsubgroupsofage,race,andethnicity.FDAintendstointegratethefinalcontentintoonefinalguidancedocument.Whenfinalized,thisguidancewillalsoextendandcomplementFDA’sCollectionofRaceandEthnicityDatainClinicalTrialsGuidance,which,forcollectingandreportingraceandethnicityinformationinclinicaltrials,recommendedtheuseofthestandardizedapproachdevelopedbytheOfficeofManagementandBudget(OMB).完成指導(dǎo)文件能擴充FDA在《醫(yī)療器械臨床試驗性別差異數(shù)據(jù)評價》實施的政策，增加了年齡、人種和種族不同人群組成。FDA打算整合成最終的指導(dǎo)文件。完成指導(dǎo)文件也能擴展和補充FDA關(guān)于《收集臨床試驗人種和種族數(shù)據(jù)》的指導(dǎo)意見，在該指導(dǎo)意見是為了收集和報導(dǎo)臨床試驗人種和種族的信息，行政管理和預(yù)算局（OMB）建議使用了這個標準方法。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.該指導(dǎo)文件的具體實施目標如下：鼓勵在試驗啟動階段收集和考慮醫(yī)療器械在年齡、人種、種族和相關(guān)變量（如身體大小、生物標記、骨骼密度等）時的安全性、有效性，效益風(fēng)險分析在這些族群中是不一樣的。2)概述亞組群研究數(shù)據(jù)的建議分析，組建綜合考慮人口統(tǒng)計數(shù)據(jù)實驗結(jié)果的框架。3)規(guī)定FDA的期望，總體報告年齡、人種和種族信息，標記醫(yī)療器械同意或批準。FDA'sguidancedocuments,includingthisdraftguidance,donotestablishlegallyenforceableresponsibilities.Instead,guidancesdescribetheAgency’scurrentthinkingonatopicandshouldbeviewedonlyasrecommendations,unlessspecificregulatoryorstatutoryrequirementsarecited.TheuseofthewordshouldinAgencyguidancemeansthatsomethingissuggestedorrecommended,butnotrequired.FDA包括該草案的指導(dǎo)文件不是建立在法律強制手段上的。相反，指導(dǎo)文件敘述的是機構(gòu)現(xiàn)在的主題想法，應(yīng)該只是被當成建議，除非是具體標準或法定要求。用于機構(gòu)的指導(dǎo)文件意味著只是建議，不做要求。II.Scope范圍Thisguidanceisintendedfordevicesthatincludeclinicalinformationinsupportofamarketingsubmission,whetherapremarketnotification(510(k)),premarketapproval(PMA)application,185evaluationofAutomaticClassIIIDesignation(denovorequest),orhumanitariandeviceexemption(HDE)application.Therecommendationscontainedhereinalsoapplytopost-approvalstudysubmissionsandpostmarketsurveillancestudies,wherenoted.該指導(dǎo)文件適用于設(shè)備上市前提交的臨床試驗信息，無論是上市前通知（510（k））、上市前批準（PMA）要求從頭開始),還是人道用途器材的免除申請（HDE）。這里提出的建議也適用于批準后研究提交和上市后監(jiān)督。Age,race,andethnicityarenottheonlydemographicvariablesthatmayaffectdeviceperformance.Whilethisguidancefocusesontheimpactofage,race,andethnicity,someoftherecommendationsmayalsobeusedtopromotestudyenrollmentanddataanalysisadequatelyaccountingforotherdemographicvariables,suchassexandgeographiclocation(e.g.,rural).Otherpatientcharacteristicssuchasemotional,physical,sensory,andcognitivecapabilitiescanoftenbeimportantvariableswhenevaluatingmedicaldevicesafetyandeffectiveness(orprobablebenefitforHDEs);however,thesewillnotbeaddressedwithinthisguidance.ForfurtherinformationrelatedtotheseuserconsiderationspleaseseetheDesignConsiderationsforDevicesIntendedforHomeUseGuidancedocument.一些建議也可用于提高其它統(tǒng)計變量如性別和地理位置（如鄉(xiāng)村）的入組研究和數(shù)據(jù)分析。其它的病人特點，如情緒、身體、感官和認知能力往往是重要的評估醫(yī)療器械安全性和有效性的變量（或者有益于HDEs）;然而，這些將不會被本指導(dǎo)意見中解決。關(guān)于這些考慮使用者需要方面的更多信息請參考用于家庭使用設(shè)備的設(shè)計注意事項的指導(dǎo)文檔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.人口統(tǒng)計學(xué)變量對某些設(shè)備的安全性、有效性（可能有利于HDEs申請）或利益風(fēng)險狀況的影響可能更適用。例如，某些治療皮膚病的設(shè)備用于在一個特定的人種或種族應(yīng)該不同的考慮。同樣，某些骨科器械對特定的年齡組使用應(yīng)有不同考慮。僅用于某些特定組群（例如，兒科）醫(yī)療設(shè)備的研究，除對潛在使用對象研究外，不要求對各個組群進行潛在的結(jié)果研究。此外，一些體外診斷（IVD）設(shè)備臨床研究是通過識別剩余的標本進行的，因此它可能無法獲得人口統(tǒng)計信息，諸如年齡、人種或種族。其結(jié)果是，在這些情況下不能評估年齡、人種和種族的數(shù)據(jù)。在一般情況下，當相關(guān)臨床治療效果的差異跨越年齡、種族或族群預(yù)期的，在研究設(shè)計時應(yīng)考慮這些影響，在設(shè)備標識時應(yīng)進行合適的報告。FDArecommendstheuseofthisguidancedocumentasasupplementtootherFDAguidancewhereapplicable,inparticular,anyrelevantdevice-specificguidance,aswellasFDA’sCollectionofRaceandEthnicityDatainClinicalTrialsguidance.ConsultationwiththeFDAprimaryreviewingDivisionorBranchisadvised.FDA建議使用本指導(dǎo)文件用以補充其他適用的FDA指南，特別是任何特定相關(guān)設(shè)備的指南，以及FDA收集人種和種族臨床試驗數(shù)據(jù)的指南。建議咨詢FDA主審部門或分部。Ⅲ.Background背景CertainelementsdescribedinthisguidancehavebeenemphasizedinAgencyregulationsand/orpolicyinthepast.OverrecentdecadestheAgency’sviews,aswellasthoseofthemedicalcommunityingeneral,haveevolvedregardingage,race,andethnicityinclinicalstudies.在本指南中強調(diào)的某些影響元素，以往在機構(gòu)規(guī)定和政策里都有描述。近幾十年來監(jiān)管機構(gòu)的觀點，以及醫(yī)學(xué)界普遍觀念，已經(jīng)演變?yōu)橛嘘P(guān)年齡、人種和種族在臨床試驗的研究。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，F(xiàn)DA公開從各種專家和利益相關(guān)者征求關(guān)于年齡、人種和種族在對醫(yī)療器械臨床研究中的研究和評估。在2015年4月9日，美國醫(yī)學(xué)研究所召集各級政府機構(gòu)、醫(yī)師專業(yè)協(xié)會和病人權(quán)益團體公召開了一場公開研討會，確保臨床試驗的多樣性、包容性和有意義性。這個指導(dǎo)文件反映了本文章和其它公共論壇的建議。它的目的是為通過或批準新的醫(yī)療器械提供指導(dǎo)，在臨床試驗設(shè)計、實施和臨床試驗報告中提高和改善年齡、人種和種族有關(guān)安全性和有效性信息。A.Section907oftheFoodandDrugAdministrationSafetyandInnovationActof2012(FDASIA)2012食品藥品監(jiān)督管理局安全和創(chuàng)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食品藥品監(jiān)督管理局安全和創(chuàng)新法案（FDASIA）第907令指導(dǎo)機構(gòu)依據(jù)行動計劃大綱發(fā)表和提交報告給國會，提高完整性和提高設(shè)備產(chǎn)品對人口子群（包括性別、年齡、人種和種族）等統(tǒng)計數(shù)據(jù)安全性和有效性的分析質(zhì)量。要標明有這樣的數(shù)據(jù)，或缺乏這樣的數(shù)據(jù)，提高這些數(shù)據(jù)的可用性，給病人、醫(yī)療服務(wù)提供者和研究人員?！霸谠撔袆佑媱澲?，CDRH致力于完善這一指導(dǎo)意見草案，提高醫(yī)療器械臨床試驗人口統(tǒng)計子群數(shù)據(jù)的完整性、質(zhì)量和公眾可用性。B、Terminology術(shù)語（1）Age年齡Whenevaluatingage-specificdata,clinicalstudiesshouldplantogroupsubjectsbyagegroupsasappropriateforthediseasecondition.Standardizingagecategoriesmaynotbeappropriateforalldevices;however,morediscreteagegroupingsshouldbeconsidered.Forexample,youmaygroupolderpatientsforanalysisat65-74yearsold,and75-84yearsold,ratherthansimplyolder/youngerthan65.當評估年齡數(shù)據(jù)時，臨床試驗應(yīng)按病情依據(jù)受試者的年齡進行合適的分組。按年齡標準化分組可能不適合所有的設(shè)備，可以進行分散式年齡分組。例如，你可以把老年患者按65-74歲和75-84歲分組，而不是簡單年齡大于或/小于65。FDAdoesnotdefineaspecificageforthegeriatricpopulationduetothedifferentconsiderationsforthewidevarietyofmedicaldevicesanddiagnostics.However,werecommendstratifyingagebasedonrelevantdiseasecharacteristics(e.g.65-74,≥75years).FDA沒有為老年人界定一個特定的年齡段，考慮到醫(yī)療設(shè)備和診斷的廣泛性。然而，我們可以在相關(guān)疾病特征的基礎(chǔ)上進行年齡分組（如65-74，≥75年）。Deviceregulationsdefinethepediatricpopulationasanypatientlessthan22yearsofage.9Itshouldbenotedthatthismaydifferfromthedrugandbiologicregulationsbutforpurposesofthisguidance,thedefinitionofpediatricpatientin21CFR814.3(s)shouldbeused.Thispopulationisfurthersubdividedintoseveralagegroupsasdescribedinguidanceorbydevelopmentalmilestonesasappropriate.設(shè)備法規(guī)規(guī)定兒科病人為任何小于22周歲的病人。這可能有別于藥物和生物學(xué)上的規(guī)定，但在本次指導(dǎo)方案中，21CFR814.3(s)里界定的兒科病人在這里適用。（2）RaceandEthnicity人種和種族InaccordancewithFDA’sguidanceCollectionofRaceandEthnicityDatainClinicalTrials11,patientsmayself-identifyinbothanethnicandracialcategory(e.g.,Hispanic-White,Hispanic-Black).Thisguidancespecifiedthat“theOfficeofManagementandBudget(OMB)statedthatitsraceandethnicitycategorieswerenotanthropologicorscientificallybaseddesignations,butinsteadwerecategoriesthatdescribedthesocioculturalconstructofoursociety.TheDepartmentofHealthandHumanServices(HHS)chosetoadoptthesestandardizedcategoriesforitsagenciesthatreportstatisticsbecausethecategoriesarerelevanttoassessingvarioushealthrelateddata,includingpublichealthsurveillanceandresearch.”FDAacceptsapplicationscontainingclinicalstudydatawithethnicandracialdemographicdatacapturedasonecategoryorseparately,althoughthegenerallypreferredmethodistocollectethnicityandraceseparately.根據(jù)FDA收集人種和種族臨床試驗數(shù)據(jù)的指導(dǎo)原則，要自動確認病人的人種和種族（如西班牙裔白人，西班牙裔黑人）。被指南規(guī)定：“管理和預(yù)算辦公室（OMB）所說的種和種族的分類不是人類學(xué)的或是科學(xué)上的分類，而是描述社會文化構(gòu)成的分類。美國衛(wèi)生和人類服務(wù)部所屬機構(gòu)采用的標準化的分類來統(tǒng)計是因為這些類別影響各類健康相關(guān)數(shù)據(jù)的評估，包括公共衛(wèi)生監(jiān)測和研究?！盕DA可以單獨或整體性的接受人種和種族的臨床研究數(shù)據(jù)的申請，首選方法是分開申請。Moregranularracedatamaybeimportantdependingonthediseaseorcondition(e.g.,iftheconditionissubstantiallymoreprevalentorvariedincourseforAshkenaziJewishorHanChinese).Additionally,FDAacknowledgesthatotherethnicandracialcategoriesmaybeappropriatedependingonthestudypopulation,e.g.,inglobalstudiesinvolvingsitesandpatientsoutsidetheUnitedStates(OUS).Thecategoriesandidentificationmethodshouldbedefinedinthestudyprotocol.更多單獨的依據(jù)病情或條件的（如在德系猶太人或漢族普遍存在或變化的）人種數(shù)據(jù)是必要的。另外FDA承認其它的根據(jù)研究人群確定的人種和種族的分類，如全球性的和美國以外的（OUS）。分類和確認方法應(yīng)該在研究協(xié)議了表明。CollectionandpoolingofdatafromOUSstudysitesmayresultinconfoundingissuesofethnicityandstandardofcare.OUSsitesmaynotcategorizeraceandethnicityinthesamemannerasUSsitesormaydefinecertainraceorethnicitygroupsdifferentlythandoUSsites(e.g.,“Caucasian”vs“white”inEuropeanvsUSdata).Additionally,thestandardofcareatOUSsitesmaynotbeequivalent.ThesedifferencesmaymakeitdifficulttopoolraceandethnicitysubgroupdatafromOUSsites.從美國以外的試驗結(jié)構(gòu)搜集和集中數(shù)據(jù)可能導(dǎo)致種族分組標準混亂。美國以外的試驗機構(gòu)可能沒有像美國一樣分組人種和種族、界定特定人種或種族分組不同（歐洲“白種人”和美國“白種人”）。此外美國以外的試驗機構(gòu)的護理標準可能是不平衡的。這些差異導(dǎo)致匯集人種和種族子集數(shù)據(jù)的困難。C、WhyConsiderAge,Race,andEthnicityDifferences為什么考慮年齡、人種和種族的差異（1）Age年齡Considerationofdifferentagepopulations,particularlypediatricandolderpatients,whichareoftenunderrepresentedinclinicaltrials,canbeimportantforpropercharacterizationofadevice’ssafetyandeffectiveness(orprobablebenefitforHDEs)inthepatientpopulation.Inthe2013FDASIA907Report12,oftheapprovedPMAsevaluatedforthereport,only40%publiclyreportedanagebasedanalysisofoutcomesdata.Theamountofageinformationavailablewasinconsistentandoftennotdetailedenoughtoanalyzedeviceperformancerelatedtoage.Themannerinwhichtheagedescriptivestatisticsarepresented(e.g.,mean,median,standarddeviation,distribution)inasubmissionmayaffectdatainterpretation.Properstudyofdeviceuseinbotholderandpediatricpopulationsisimportantwhenthedeviceislikelytobeusedforthesesubgroups.考慮不同年齡的人群，特別是未成年人和老年人可以適當表征設(shè)備安全性和有效性，往往在臨床試驗中代表數(shù)量不足。2013FDASIA907批準的上市前申請報告，只有40%的報告公開了基于年齡的數(shù)據(jù)分析結(jié)果?？捎玫哪挲g信息往往不一致并且不夠詳細，不能分析設(shè)備有關(guān)年齡方面的性能。遞交的申請里關(guān)于年齡描述性的統(tǒng)計分析（如平均值、中位數(shù)、標準偏差、分布）可能影響數(shù)據(jù)的理解。當設(shè)備適用于兒童和老年人時，關(guān)于這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發(fā)癥、伴隨治療或者發(fā)育考慮，這可能影響設(shè)備研究的性能。老年人身體會發(fā)生與年齡相關(guān)的變化如骨骼密度、代謝、消化、滑膜液等，這可能影響醫(yī)療設(shè)備的性能。同時醫(yī)療設(shè)備可能對兒童的發(fā)育有積極或消極的影響，而對成年人沒有影響。例如人工耳蝸植入不建議用于一些兒童人群，出于移植物體積和兒童神經(jīng)發(fā)育階段的考慮。使用人工晶體治療失明，器械可能也會提高兒童將來的視力。出于這些原因，始終考慮醫(yī)療器械在年齡方面的潛在影響并進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為未成年人亞群（如新生兒、嬰兒、兒童和青少年）醫(yī)療設(shè)備的發(fā)展提供了指導(dǎo)文件。FDA正在進行幾項醫(yī)療器械相關(guān)的舉措旨在解決未成年人亞群的問題。2007年，國會頒布了兒科醫(yī)療設(shè)備安全和改進法案（PMDSIA），作為食品和藥品監(jiān)督管理局修正法案的一部分，在合適的時候可以推斷成人的數(shù)據(jù)。PMDSIAalsorequirescertainmedicaldeviceapplicationstoinclude,ifreadilyavailable,adescriptionofanypediatricsubpopulationsthatsufferfromthediseaseorconditionthatthedeviceisintendedtotreat,diagnose,orcureandthenumberofaffectedpediatricpatients.16FDAissuedaguidancedocumentoutliningtheimplementationofthisprovision.PMDSIA也需要一些特定醫(yī)療器械的申請，如果現(xiàn)成的，一份醫(yī)療設(shè)備治療、診斷和治愈兒科病人病情和條件的詳細說明，受影響未成年人的數(shù)量。FDA發(fā)布一個指導(dǎo)文件概述了這一規(guī)定的進展情況。（2）RaceandEthnicity人種和種族WhiletheU.S.populationdemographicischanging,diverserepresentationinclinicaltrialsremainsachallenge,andinconsistentanalysisandreportingcontributestoapersistentlackofpubliclyavailabledataondeviceperformanceindiverseethnicandracialgroups.The2013FDASIA907Reportshowedadistinctlackofpubliclyreportedraceandethnicitydataformedicaldevices.18Only27%ofthestudiesreviewedcontainedaraceorethnicitysubgroupanalysis,andonly16%hadpublicstatementsregardingaraceorethnicityanalysis.由于美國人口分布一直在發(fā)生變化，不同代表性的臨床試驗仍然是一個挑戰(zhàn)，不一致性的分析和報告導(dǎo)致了醫(yī)療設(shè)備性能在不同人種和種族上的公眾可用數(shù)據(jù)的缺少。2013FDASIA907報告明顯表現(xiàn)出醫(yī)療設(shè)備在人種和種族方面公眾報道數(shù)據(jù)的缺乏。評審的研究只有27%包含人種或種族亞群的分析，只有16%有關(guān)于人種或種族分析的公開聲明。Thereareseveraldeviceswheredifferencesineffectwereobservedthatwerecorrelatedwithraceandethnicity.Forexample,differencesinskinstructureandphysiologycanaffectresponsetodermatologicandtopicallyappliedproducts.19Mortalityratesofpatientsondialysishavebeenshowntodifferacrossraceandethnicitygroups.20FDAencouragessponsorstocollectraceandethnicitydataaccordingtotherecommendationsinthe2005CollectionofRaceandEthnicityGuidanceDocument.觀察到有幾種設(shè)備效能上與使用者人種和種族有關(guān)。例如不同的皮膚機構(gòu)和生理機能影響皮膚病外用產(chǎn)品的功效。結(jié)果表明不同人種和種族透析病人的死亡率不同。FDA鼓勵發(fā)起人依據(jù)2005人種和種族收集指導(dǎo)文件進行人種和種族數(shù)據(jù)的收集。D、ParticipationofAge,Race,andEthnicitySubgroupsinClinicalTrials臨床試驗中參與者的年齡、人種和種族Itisimportantthatclinicaltrialsincludediversepopulationsthatreflecttheintendedpopulation,especiallywhenclinicallymeaningfuldifferencesinsafety,effectiveness,(probablebenefit,forHDEs),orbenefit-riskprofileareexpectedacrossthesegroups.Ingeneral,toachieveanunbiasedestimateoftreatmenteffectinthegeneralpopulation,sponsorsshoulddevelopastrategytoenrolldiversepopulationsincludingrelevantage,race,andethnicgroups.在臨床試驗中包括不同的目標人群是很重要的，尤其是在具有安全性、有效性和風(fēng)險預(yù)計方面的臨床統(tǒng)計意義上的差異時。一般要在普通人群中完成公正的治療效果評估時，申辦者應(yīng)該制定一個包括年齡、種族和人種等不同組群的試驗方針。Wherepossible,itisalsoimportanttoenrolldiversepopulationsthroughouttheenrollingsites,particularlyinstudieswheresurgicaloroperatorskillmaybeofkeyimportance.Ifpatientsenrolledatonesitearepredominantlyofonedemographicsubgroup,itmaybepossibletoincorrectlyattributedifferencesindeviceperformanceorsurgicalskilltodemographicsubgroups;thisshouldbeconsideredwhenplanningandanalyzingtrials.必要時，在所有的入組機構(gòu)都要入組不同的人群，特別是外科手術(shù)和操作技能是重要關(guān)鍵時。如果一個實驗單位只入組了一類人群，可能造成器械性能的誤判或?qū)θ巳鹤咏M手術(shù)技能的差異。當計劃和分析試驗時應(yīng)該考慮到這點。Ingeneral,studyprotocolsshouldincludepre-specifiedstatisticalplansforaddressingtheseandotherissuesoutlinedinthisguidance.Unplannedsubgroupanalysesorthosewithinadequatesamplesizearegenerallynotconsideredtobeadequatetosupportstatementsinthelabelingregardingthesafetyoreffectivenessofthedevice.However,theoverallbenefit-riskprofileofthedevicewillbeconsidered.一般試驗方案應(yīng)當包括預(yù)先明確的統(tǒng)計學(xué)計劃，解決本指導(dǎo)文件中概述的這些和其它問題。無計劃的子組分析或沒有足夠樣本量就不能提供足夠標識設(shè)備安全性和有效性的聲明。因而將會考慮設(shè)備的整體受益風(fēng)險。（1）BarrierstoEnrollment招募入組障礙Recruitingparticipantstoclinicalstudieswhorepresenttherangeofage,race,andethnicgroupsconsistentwiththeintendedusepopulationofthedevicemaypresentadditionalchallenges.Therearenumeroussuspectedreasonsforlowminorityparticipationandlowparticipationofolderandpediatricpatients.22In2009,FDApublishedaReporttoCongressonidentifiedbarrierstoenrollmentinclinicaldrugtrialsandrecommendationsonhowtoaddressthedisproportionatelylowenrollmentofcertainpopulationsinclinicaltrials,especiallythosetrialsinwhichthesepopulationsarehighlyaffectedbyorarelikelytosufferworseoutcomesfromthediseasebeingevaluated.23FDAbelievesmuchofthisinformationisrelevanttomedicaldeviceclinicaltrialsaswell.臨床試驗招募設(shè)備目標人群，代表不同年齡、人種和種族的受試者存在額外的困難。受試者參與人少和未成年人和老人參與人少是因為存在諸多的懷疑。2009年，F(xiàn)DA向國會提交報告，確認了藥物臨床試驗的障礙和提出一些建議用于解決一些特定人群入組率低、有失平衡問題，尤其是那些有高度影響或有嚴重后果的試驗。FDA相信許多信息都與醫(yī)療器械臨床有關(guān)。Thefollowinghavebeenidentifiedaspotentialbarrierstoenrollment:以下確認為招募入組潛在的障礙：?lackofunderstandingaboutmainobstaclestoparticipationofdifferentage,缺乏臨床試驗關(guān)于不同年齡、人種和種族主要障礙的理解?inclusion/exclusioncriteriawhichunintentionallyexcludedifferentage,race,orethnicgroups(e.g.,creatininelevelsforAfricanAmericans)納入/排除標準無意中排出了不同的年齡、人種和種族組群（如非裔美國人的肌酐水平）?lackofunderstandingaboutdifferencesindiseaseetiologyandpathophysiologymayleadtounder-diagnosisandunder-referralofspecificdemographicsubgroups缺乏疾病病因和生理上的差異的理解可能導(dǎo)致特定人口亞群的診斷和轉(zhuǎn)診?patientconcernsrelatedtotreatmentgroup,randomization,possiblesideeffects,privacy,andhistoricalmistrustofclinicaltrialethics;病人關(guān)注相關(guān)治療、隨機、可能的副作用、隱私和歷史性的臨床試驗倫理不信任?language,cultural,andhealthliteracygapsbetweeninvestigatorsandpatients;研究者和病人之間語言、文化和健康素養(yǎng)的差異?investigatorandsponsoravoidanceofspecificage,race,orethnicgroupsofpatientsduetotheperceptionthatitismoredifficultandpotentiallymoreexpensivetorecruitandmaintainparticipation研究者和申辦者排除一些特定年齡、人種和種族的病人，預(yù)感到入組這些病人更困難和花費更高?pressureoninvestigatorstoquicklyenrollpatientsregardlessofdemographiccharacteristics;迫于壓力研究者不顧人群特征快速的入組病人?perceivedethicalconcernsamonginvestigatorsregardingenrollmentofcertaindemographicgroupsinclinicaltrials;臨床試驗中研究者關(guān)于特定人群倫理上的考慮?triallogistics(e.g.,transportation,childcare)maydisproportionatelyaffectspecificage,raceandethnicgroups’abilitytocompletestudyfollow-upvisits;試驗的流動性（如流動、幼托）可能不成比例的影響特定年齡、人種和種族的人群來完成后續(xù)的研究回訪。?disproportionatedropoutandlost-to-follow-uprates;and不成比例的脫落率?typeorlocationofstudysitesmaylimitparticipationofspecificage,race,orethnicgroups研究地點的類型和地點可能限制特定年齡、人種和種族組群的參與（2）EnrollmentResources招募入組資源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.在研究中入組的數(shù)據(jù)顯示某特定組群代表性不足，鼓勵申辦者調(diào)查缺乏入組的原因，在IV部分考慮這個問題增加入組?？梢蕴峁┬畔碓u估在不同關(guān)鍵時間點人口統(tǒng)計分布變化（如，篩選中，評估研究納入/排除標準后，經(jīng)同意后和后續(xù)的不同時間點）。在關(guān)鍵時間點臨床研究的分布、入組和后續(xù)人口分布變化的信息能找出這些組群入組率低的根本原因。這有助于確定方法大幅度解決年齡、人種和種族入組的障礙，在其它研究子組里已經(jīng)證明這可以提高入組率和研究保持率（如在后續(xù)隨訪過程中中靈活考慮兒童護養(yǎng)和老人護理服務(wù)問題）。必要時，可基于人口分布信息改變試驗方案和知情協(xié)議，要通知IRB和FDA并得到批準。SponsorsmayalsowishtoconsiderresourcesdevelopedbytheNationalInstitutesofHealth,discussionwithacademicandcontractresearchorganizations,andpracticesofhigh-enrollingclinicalstudysites,indeterminingpracticesbestsuitedtoachieveappropriateenrollmentofdemographicgroups,andtoprovideinvestigatortrainingaboutthesetechniques.SomespecificexamplesofstrategiestoincreaseinclusionofdiversestudypopulationsarediscussedinSectionIVbelow.申辦者還應(yīng)考慮利用國家健康研究所的資源，和學(xué)術(shù)機構(gòu)、CRO、高入組率臨床試驗機構(gòu)進行討論，確定最好最合適的人口組群入組方法，對研究者進行培訓(xùn)這些技能。一些具體提升不同研究人群納入率策略在第四部分進行討論。Ⅳ.RecommendationsforAchievingAppropriateEnrollment完成合適入組的建議Historically,manymedicaldeviceclinicalstudieshavenotenrolledproportionsofage,race,andethnicsubgroupsthatreflecttheunderlyingdiseasedistributionintheaffectedpopulation.Thiscanbeproblematicbecausetheabilitytodetectdifferencesinresponsetotreatmentismarkedlydiminishedifthereisnoorlimitedclinicalexperiencewiththeproductinthesubgroupofinterest.Thishascontributedtoasubstantiallackofavailabledataregardingtherisksandbenefitsofmedicaldeviceuseinage,race,andethnicsubgroups.Thus,itisimportantthatclinicaltrialsincludediversepopulationsthatreflecttheintendedpopulationwheneverpossibleandappropriate.以往很多臨床研究沒有入組年齡、人種和種族比例的子群，這些影響潛在的疾病分布。這是有問題的，因為如果沒有這些子組的臨床研究，檢測治療效果的能力會顯著下降。這就會導(dǎo)致關(guān)于醫(yī)療器械在年齡、人種和種族子組缺乏風(fēng)險效益可用數(shù)據(jù)的嚴重缺乏。因此臨床試驗考慮各類任何可能合適的目標人群是很重要的。Ingeneral,toachieveanunbiasedestimateoftreatmenteffectinthegeneralpopulation,sponsorsshouldideallyplantoenrollrepresentativeproportionsofage,race,andethnicitysubgroups,whichareconsistentwiththeintendedusepopulationofthedevice,orjustifyintheinvestigationalplanhowtheenrollmentcriteriawillprovidereasonablerepresentationofthe468intendedoraffectedpopulation.一般來說，為了完成在普通人群中治療效果的一個合理估測，申辦者應(yīng)該進行合理的計劃，入組具有年齡、人種和種族代表性特點的子組，保持與器械目標使用人群的一致性，合理解釋研究計劃入組標準代表目標人群的合理性。Incaseswhereknowndiseasescienceorpriorclinicalstudyresultssuggestaclinicallymeaningfuldifferenceinbenefitsorrisksinoneormoreage,racial,orethnicsubgroups,sponsorsshouldaimtoenrollsufficientnumbersof