Repetitive Transcranial Magnetic Stimulation (rTMS) Systems

A rTMS system is an electromagnetic device that non-invasively delivers a ... FDA recommends that the protocol includes a suicide severity ... Skiptomaincontent SkiptoFDASearch Skiptointhissectionmenu Skiptofooterlinks Inthissection: GuidanceDocuments(MedicalDevicesandRadiation-EmittingProducts) GuidanceDocuments(MedicalDevicesandRadiation-EmittingProducts) Cross-CenterFinalGuidance RecentFinalMedicalDeviceGuidanceDocuments DraftMedicalDeviceGuidance CDRHProposedGuidanceDevelopment ClassIISpecialControlsDocuments Radiation-EmittingProductsGuidance WithdrawnGuidance MedicalDeviceProvisionsofFDAModernizationAct Home MedicalDevices DeviceAdvice:ComprehensiveRegulatoryAssistance GuidanceDocuments(MedicalDevicesandRadiation-EmittingProducts) RepetitiveTranscranialMagneticStimulation(rTMS)Systems-ClassIISpecialControlsGuidanceforIndustryandFDAStaff GuidanceDocuments(MedicalDevicesandRadiation-EmittingProducts) PDFPrinterVersion (182KB) Documentissuedon:July26,2011 ForquestionsregardingthisdocumentcontactAnnH.CostelloPh.D.,[email protected]. U.S.DepartmentofHealthandHumanServices FoodandDrugAdministration CenterforDevicesandRadiologicalHealth OfficeofDeviceEvaluation DivisionofOphthalmic,NeurologicalandEar,NoseandThroatDevices NeurodiagnosticandNeurotherapeuticDevicesBranch Preface PublicComment YoumaysubmitwrittencommentsandsuggestionsatanytimeforAgencyconsiderationtotheDivisionofDocketsManagement,FoodandDrugAdministration,5630Fisherslane,rm.1061,(HFA-305),Rockville,MD20852.Submitelectroniccommentstohttp://www.regulations.gov.IdentifyallcommentswiththedocketnumberlistedinthenoticeofavailabilitythatpublishesintheFederalRegister.CommentsmaynotbeacteduponbytheAgencyuntilthedocumentisnextrevisedorupdated. AdditionalCopies AdditionalcopiesareavailablefromtheInternet.Youmayalsosendane-mailrequesttoCDRH-Guidance@fda.hhs.govtoreceiveacopyoftheguidance.Pleaseusethedocumentnumber1728toidentifytheguidanceyouarerequsting. TableofContents Introduction Scope RiskstoHealth DeviceDescription CoilPositioning MagneticFieldCharacteristics OutputWaveform.. MagneticFieldSpatialDistribution MagneticFieldStrengthGradient DeviceCompatibility SafetyFeatures Non-ClinicalAnalysisandTesting Biocompatibility ElectricalEquipmentSafety ElectromagneticCompatibility(EMC) WirelessTechnology SoftwareLifeCycleandRiskManagement ClinicalTesting Labeling DirectionsforUse IndicationforUse Contraindications Warnings Precautions ProcedurePrecaution AdverseEvents ElectricalSafety ElectromagneticCompatibility UserTraining PatientLabeling. AppendixA.DefinitionsandUnitsofMeasurement GuidanceforIndustryandFDAStaff ClassIISpecialControlsGuidanceDocument:RepetitiveTranscranialMagneticStimulation(rTMS)Systems 1.Introduction ThisguidancedocumentwasdevelopedasaspecialcontrolsguidancetosupporttheclassificationofRepetitiveTranscranialMagneticStimulation(rTMS)systemsforthetreatmentofMajorDepressiveDisorder(MDD)intoclassII(specialcontrols).ArTMSsystemisanelectromagneticdevicethatnon-invasivelydeliversarapidlypulsedmagneticfieldtothecerebralcortexinordertoactivateneuronswithinalimitedvolumewithoutinducingaseizure.ThedeviceisintendedtobeusedtotreatpatientsmeetingclinicalcriteriaforMDDasdefinedintheDiagnosticandStatisticalManualofMentalIllnesses,FourthEdition(DSM-IV).ThisguidanceisissuedinconjunctionwithaFederalRegisternoticeannouncingtheclassificationofrTMSsystemsforthetreatmentofMDD. FDAbelievesthatspecialcontrols,whencombinedwiththegeneralcontrols,willbesufficienttoprovidereasonableassuranceofthesafetyandeffectivenessofrTMSsystemsforthetreatmentofMDDinadultpatientswhohavefailedtoachievesatisfactoryimprovementfromonepriorantidepressantmedicationatorabovetheminimaleffectivedoseanddurationinthecurrentepisode.Thus,personswhointendtomarketadeviceofthisgenerictypemust(1)conformtothegeneralcontrolsoftheFederalFood,Drug,andCosmeticAct(theFD&CAct),includingthepremarketnotificationrequirementsdescribedin21CFR807SubpartE,(2)addressthespecificriskstohealthassociatedwithrepetitivetranscranialmagneticstimulationsystemsidentifiedinthisguidance,and(3)obtainasubstantialequivalencedeterminationfromFDApriortomarketingthedevice. ThisspecialcontrolguidancedocumentidentifiestheclassificationregulationandproductcodeforrTMSsystems(PleaserefertoSection2.Scope).Inaddition,othersectionsofthisspecialcontrolguidancedocumentlisttheriskstohealthidentifiedbyFDAanddescribemeasuresthat,whenfollowedandcombinedwiththegeneralcontrols,willgenerallyaddresstherisksassociatedwithrTMSsystemsforthetreatmentofMDDandleadtoatimely510(k)review.ThisdocumentsupplementsotherFDAdocumentsregardingthecontentrequirementsofa510(k)submission.Youshouldalsoreferto21CFR807.87andtheguidance,FormatforTraditionalandAbbreviated510(k)s1; Designationofthisdocumentasaspecialcontrolmeansthatanyfirmcurrentlymarketingorintendingtomarket,repetitivetranscranialmagneticstimulation(rTMS)systemsforthetreatmentofMDDwillneedtoaddresstheissuescoveredinthisspecialcontrolsguidance.Thefirmwillneedtoshowthatitsdeviceaddressestheissuesofsafetyandeffectivenessidentifiedinthisguidance,eitherbymeetingtherecommendationsofthisguidanceorbysomeothermeansthatprovideequivalentassurancesofsafetyandeffectiveness. Backtothetop 2.Scope Thescopeofthisdocumentislimitedtotherepetitivetranscranialmagneticstimulation(rTMS)system,(21CFR882.5805andproductcodeOBP)describedbelow. 21CFR882.5805RepetitiveTranscranialMagneticStimulation(rTMS)System Arepetitivetranscranialmagneticstimulation(rTMS)systemisanexternaldevicethatdeliversrepetitivepulsedmagneticfieldsofsufficientmagnitudetoinduceneuralactionpotentialsintheprefrontalcortextotreatthesymptomsofmajordepressivedisorder(MDD)withoutinducingseizureinpatientswhohavefailedatleastoneantidepressantmedicationandarecurrentlynotonanyantidepressanttherapy. Backtothetop 3.RiskstoHealth Inthetablebelow,FDAhasidentifiedtheriskstohealthgenerallyassociatedwiththeuseoftherTMSsystemaddressedinthisdocument.Themeasuresrecommendedtomitigatetheseidentifiedrisksaregiveninthisguidancedocument,asshowninthetablebelow.Werecommendthatyoualsoconductariskanalysis,beforesubmittingyour510(k),toidentifyanyotherrisksspecifictoyourdeviceandincludetheresultsofthisanalysisinyour510(k).Ifyouelecttouseanalternativeapproachtoaddressaparticularriskidentifiedinthisdocument,orhaveidentifiedrisksadditionaltothoseinthisdocument,thenyoushouldprovidesufficientdetailtosupporttheapproachyouhaveusedtoaddressthatrisk. IdentifiedRisk MitigationMeasures Failuretoidentifycorrectpatientpopulation Section10.ClinicalTesting Section11.Labeling Ineffectivetreatment Section5.NonclinicalAnalysisandTesting Section9.SoftwareLifeCycleandRiskManagement Section10.ClinicalTesting Section11.Labeling Seizure Section5.NonclinicalAnalysisandTesting Section10.ClinicalTesting Section11.Labeling Scalpdiscomfort,scalpburn,orotheradverseeffects Section5.NonclinicalAnalysisandTesting Section9.SoftwareLifeCycleandRiskManagement Section10.ClinicalTesting Section11.Labeling Magneticfieldeffectsonfunctioningofothermedicaldevices Section5.Non-clinicalAnalysisandTesting Section11.Labeling Adversetissuereaction Section6.Biocompatibility Hazardsassociatedwithelectricalequipment Section7.ElectricalEquipmentSafety Section11.Labeling Hazardscausedbyelectromagneticinterferenceandelectrostaticdischargehazards Section8.ElectromagneticCompatibility Section11.Labeling Hearingloss Section11.Labeling Backtothetop 4.DeviceDescription WerecommendyouidentifyyourdeviceusingtheregulationandproductcodedescribedinSection2.Scope,andprovideacompletedescriptionofyourrTMSsystem.Youmustprovideinformationtoshowhowthenewdeviceissimilartoanddifferentfromthelegallymarketedpredicatedevice("predicatedevice")(21CFR807.87(f)).Sidebysidecomparisons,wheneverpossible,aredesirable;forexample,werecommendyouuseatabularformatsuchasshownbelowinTable1.ExampleofaDeviceandPredicateComparison.Wealsorecommendthatyoudescribehowanydifferencesbetweenyourdeviceandthepredicatedevicemayaffectthecomparativesafetyandeffectivenessofyourdevice. Table1.ExampleofaDeviceandPredicateComparison DescriptiveInformation Device PredicateDevice Areaofbraintobestimulated     Applicator: Configuration Diameter Corematerial     OutputStimulationParameters: AmplitudeinStandardMotorThreshold (SMT)units Pulsewidth(±accuracy) Frequency(±accuracy) Pulsetrainduration(±accuracy) Inter-traininterval(±accuracy) Trainspersession Maximumnumberofpulsespersession(cumulativeexposure)     Physicalunitofamplitudesetting(e.g.,coilcurrent,peakmagneticfield)atcoilanditsrelationtotheSMTunit     MagneticField: Peakmagneticfieldstrengthat2cm MaximumdB/dt     Temperatureonsurfaceatmaximumoutput     TheMaximumSafeTrainDurationLimitsforAvoidingSeizure,describedinTable2,arebasedonliteraturearticlesbyWassermann2andRossi3.Pulsetraindurationsthatareabovecertainlimitsincreasetheriskofseizures.3Therecommendedmaximumtrainduration(inseconds)forhealthyadultsfortheintensity(%ofMotorThreshold)levelsandfrequenciesareshowninTable2.SeeAppendixAfordiscussionoftermsusedinTable2.NotethatthepaperbyWassermann3andthisguidancedocumentaddresssafelimitsfortheuseofrTMSwhenusedasastandalonetherapy. YoushouldindicatewhetheryourdevicefallswithinthelimitslistedinTable2.Ifyourdevicedoesnotfallwithintheseparameters,FDAmayrecommendthatyouprovidedatafromaclinicalstudytodemonstratethatyourdevice'soutputparametersareassafeasthoseofthepredicatedevice.SeeSection10.ClinicalInformation. Table2.MaximumSafeTrainDuration(seconds)LimitsforAvoidingSeizure Freq (Hz) INTENSITY(%ofMotorThreshold) 80-100 100 110 120 130 140 150 160 170 180 190 200 210 220 1 >1800 >1800 >1800 360 >50 >50 >50 >50 27 11 11 8 7 6 5 >10 >10 >10 >10 >10 7.6 5.2 3.6 2.6 2.4 1.6 1.4 1.6 1.2 10 >5 >5 >5 4.2 2.9 1.3 0.8 0.9 0.8 0.5 0.6 0.4 0.3 0.3 20 2.05 2.05 1.6 1.0 0.55 0.35 0.25 0.25 0.15 0.2 0.25 0.2 0.1 0.1 25 1.28 1.28 0.84 0.4 0.24 0.2 0.24 0.2 0.12 0.08 0.12 0.12 0.08 0.08 Yourdevicedescriptionshouldalsoinclude: theareaofthebraintobestimulated(e.g.,motorcortex); anillustrationorphotographthatshowsthepositionsandorientationsofthestimulatingcoilwhenstimulatingtheidentifiedlocation;and acompletelistinganddescriptionofallofthedevicecomponentsandaccessories(e.g.,console,treatmentcoil,userinterfaces,datamanagementsystems,cables). Inaddition,youshouldincludethefollowinginformationdescribingyourdevice. CoilPositioning YoushoulddescribethefeaturesofyourdeviceintendedtoensuretherepeatabledeliveryofrTMStreatment.YoushoulddiscussthedesignfeaturesthatareusedforpositioningthecoilandpatientforrTMStreatment.Thisdiscussionshouldalsodescribehowyouhaveensuredpositioningconsistencyandrepeatability. Youshoulddescribethemethodusedfordeterminingthestrengthofthemagneticfieldfluxneededfortherapy.Ifyourdevicereliesonmotorthreshold(MT)fordeterminingthemagnitudeoftheoutput,youshoulddescribethedesignfeaturesthatareusedforpositioningthecoilforlocatingtheMTpositionandhowyouhaveensureditspositioningrepeatability.TheprocedurefordeterminingMTlocationshouldresultinareproducibleandaccurateMTlocationinordertoensurereliableMTlevelsettingand,ifusedtoidentifythetreatmentlocation,toproviderepeatablenavigationfortreatmentwhenperformedbydifferentclinicians.Moreover,thesettingforyourdeviceshouldbetraceabletoareproduciblephysicalparameter(seeMagneticFieldCharacteristics,below). Youshouldalsodescribethemethodusedtoensurethatthecoilisinproperpositionandcontactwiththepatient’sheadduringMTandrTMStreatmentprocedures.Thisshouldincludeadescriptionofanydesignfeatures(e.g.,sensors,alarms)usedtoensurepropercontactandposition.Thisshouldbeincludedinthedevicelabeling.Themagneticfielddecreasesquicklywithdistancefromthefaceofthetreatmentcoil,thereforeanylossofcontactmayresultinchangesineffectiveness. MagneticFieldCharacteristics Werecommendyoudescribethephysicalcharacteristicsofthemagneticfieldproducedbyyourdeviceandcomparethemtothoseofthepredicatedevice.Youshouldalsoincludeadescriptionofthemethodusedforthesemeasurementsandhowtheyhavebeenvalidated.Ifthephysicalcharacteristics(includingdifferencesinspatialandtemporalcharacteristics)ofyourdevice’smagneticfielddifferfromthepredicate’smagneticfield,youshouldprovidevalidscientificevidencethatthesedifferenttechnicalcharacteristicsdonotaffectthesafetyoreffectivenessofyourdevice,ascomparedtothepredicatedevice.Youshouldprovideadescriptionandcomparisonofthefollowingtothepredicatedevice: pulseshape,timing,width,andamplitude; spatialdistributionoftheoutputlevel;and linearityoftheoutputlevel. OutputWaveform Werecommendyouprovideoscilloscopetracingsofthesignalmagneticoutputwaveform(withtheapplicatorattached)overthedevice’srangeofoutputsettings(includingminimum,maximum,andasamplingofintermediatesettings).Youshouldidentifyallsalientfeaturesofthewaveform(e.g.,pulsewidth)andspecifythehorizontalandverticaloscilloscopegainsettings.Inaddition,youshouldsupplementtheoscilloscopetracingswithagraphicalrepresentationoftheoutputwaveformwithallstimulationparametersandtemporalcharacteristicsclearlylabeled.Inadditiontographicalrepresentations,atabularformatthatsummarizestheoutputspecificationsisdesirable. MagneticFieldSpatialDistribution Werecommendyouprovidethedimensionsofthetreatmenttargetstimulationvolumeanditslocationrelativetotheapplicator.Ifthespatialdistributiondiffersfromthatofthepredicatedevice,youshouldexplainhowyourdeviceisassafeandaseffectiveasthepredicatedevicedespitethedifference.Fieldspatialdistributionmeasurementshouldincludea3-dimensionalarrayofpointsusingacalibratedtestfixturethatmeasureseithertheelectricormagneticfieldforclinicallyrelevantlocations.Youshouldincludetherationalesupportingyourselectionofsamplelocationsandgridspacing.Testingshouldincludethemagnitudeofthefieldintheareaofthestimulationvolume,nearthecoilsurfaces,andareaswheretheremaybelocalfieldmaximaoutsidetheintendedstimulationvolume.YoushoulddefineyourstimulationvolumeastheregionwithintheStandardMotorThreshold(SMT)setat1.0. MagneticFieldStrengthGradient YoushouldprovideameasurementoftheratioofthemaximumdB/dt(timerateofchangeofthemagneticfieldstrength)atthesurfaceofthescalpversusdB/dtatanappropriatereferencepointinthebrain. ScalpstimulationmayresultincutaneouspainandcouldaffectthetolerabilityoftherTMSprocedure.rTMSdevicesmaymitigatethesurfacefieldusingdifferingmethods.AratioofpeakdB/dtonthescalprelativetopeakdB/dtattheselectedreferencepointbelowthescalpmayhelptocharacterizeresultingdifferencesinperformance.Werecommendyoumeasurethisratioandcompareittothepredicatedevice.Inaddition,werecommendthatyouprovideacalibrationcurvebetweenthesettingsonyourdeviceandmeasurethemagneticfieldstrengthatanappropriatestandardlocationandcomparethistothepredicatedevice. DeviceCompatibility Ifyourdeviceislabeledascompatiblewithothermedicaldevices(includingactiveandpassiveimplants),youshouldprovidedatatoestablishthesafetyofusingyourdevicewiththosedevices.ThepulsedrTMSmagneticfieldhasthepotentialofinteractingwithpacemakersandotheractiveimplanteddevices,potentiallycausingtheirmalfunctionandsubsequentpatientinjury. SafetyFeatures Werecommendthatyoudescribethesafetyfeaturesofyourdeviceasfollows. Youshouldincludeadescriptionofthedesignfeaturesandcomponentsincorporatedintothedevicetopreventoverheating.Yourdescriptionshoulddiscussthepotentialfortheapplicatortobecomeoverheatedduringtreatment,whichpresentsariskofburnstothepatient. Youshoulddescribeanyalarmsincludedtoensuresafeoperation;providethedefaultalarmlimits;andindicatewhetherlimitscanbeadjustedbytheuser. Youshoulddescribethemethodusedbyyourdevicetorecalltreatmenthistory,suchaspriorpatienttreatmentsettings.rTMStreatmentmayrequireseveralsessionswiththetreatmentcoillocatedatthesamepositionontheheadandwithstimulationatthesamelevelasatprevioussessions.ThedeterminationofMTlevelandtreatmentlocationistypicallynotrepeatedateverysession.Therefore,recallofprevioustreatmentsettingsisimportantfordeliveryoftheappropriaterTMStreatmentatthecorrectlocation. Youshouldalsodescribefeaturesandqualitymeasuresincludedinyoursystemtoensurepropersystemoutputforeachtreatmentandfromunit-to-unit.rTMSsystemoutputcouldchangeovertimeduetocomponentfailureordrift,whichmaybedifficultfortheusertodetect.TheinabilitytodetectcomponentfailureordriftmayaffectthesafetyoreffectivenessofrTMStreatment.Therefore,werecommendthedeviceincludeameanstovalidatethedeliveryofthemagneticfieldateachtreatmentsessionandfromunit-to-unittoreducethechanceofinadequatetreatment. TheconsensusconcerningthelimitsofsaferTMSintermsoftherisksofseizureinduction(Wassermann,19983)iscitedinSection4.DeviceDescription.Thelimitsdependupontheamplitudeofstimulation,pulsefrequency,anddurationofthepulsetrain.SeeAppendixA.DefinitionsandUnitsofMeasurementformoredetailsregardingknownsafelimitsofrTMS.Iftheoutputparameters(amplitude,frequency,trainduration)ofyourdeviceexceedtheseestablishedlimitsandexceedthoseofthepredicatedevice,youshouldprovidefurtherevidenceofsafetythatmayincludeclinicaldata.NotethatthepaperbyWassermann3andthisguidancedocumentaddressessafelimitsfortheuseofrTMSwhenusedasastandalonetherapy. Backtothetop 5.Non-ClinicalAnalysisandTesting Foreachtest,youshouldprovide: adescriptionofthetestmethodology; thetestobjective; equipmentused; numberofsamplestested; testspecifications; standardstowhichconformanceisdemonstrated; pass/failcriteria; arationalefortheappropriatenessofanyconsensusstandardsused; asummaryoftheresults(includinggenerateddata),includingananalysisexplaininghowthetestingresultsdemonstratethatthedeviceperformsasintended;and adescriptionoftestfailures. Ifanytestfailureswereidentifiedandsamplesofthedevicemodifiedasaresult,youshouldprovidetheresultsfromthenewtestingwiththemodifiedsamples. Youshouldalsoprovideasummaryofthetestingthatyouperformed,tabularformatisdesirable.Werecommendyouincludethefollowing: thetest(e.g.,electricalcharacterization,electromagneticcompatibility(EMC)); thetestmethod; themodeofdeviceoperationduringthetest; acceptancecriteria; thestandardtowhichconformancewasdemonstrated;and thelocationofthetestreportinthesubmission. Backtothetop 6.Biocompatibility Youshouldselectbiocompatibilitytestsappropriateforthedurationandnatureofcontactwithyourdevice.WerecommendyouconductbiocompatibilitytestingonanypatientcontactingmaterialsusedinyourdeviceasdescribedintheFDAguidance,UseofInternationalStandardISO-10993,BiologicalEvaluationofMedicalDevicesPart-1:EvaluationandTesting4forexternaldevicesincontactwiththeskinforalimitedduration(i.e.,lessthan24hours).Ifyouusematerialsinyourdevicethatareidenticaltoyourpredicatedeviceandhavethesamebodycontactclassification(e.g.,surface,externalcommunicating,implant)anddurationofpatientcontact(e.g.,limited,prolonged,permanent),youmayidentifythepredicatedeviceandleveragepreviousbiocompatibilitydatainlieuofperformingnewbiocompatibilitytesting.FDArecognizesthatitisdifficulttodocumentthatmaterialsinyourdeviceandapredicatedeviceareidenticalwithrespecttocompositionandmanufacturingprocesses.Therefore,ifyouhavedocumentationtosupporttheidenticalnatureofthematerials,werecommendthefollowingstatementforbiocompatibilitycertificationofpreviouslyusedmaterials: The[polymer/metal/ceramic/compositename][componentname]ofthe[subjectdevicename]isidenticaltothe[componentname]ofthe[predicatedevicename]asitwasapproved/clearedin[PMA/510k/IDEnumber,approvaldate]informulation,processing,andsterilization,andnootherchemicalshavebeenadded(e.g.,plasticizers,fillers,coloradditives,cleaningagents,moldreleaseagents,etc.). Backtothetop 7.ElectricalEquipmentSafety WerecommendthatyoudemonstratetheelectricalandmechanicalsafetyofthedevicebyperformingelectricalandmechanicalsafetytestingasdescribedintheFDA-recognizedstandard,IEC60601-1,MedicalElectricalEquipment–Part1:GeneralRequirementsforSafetyorbyanequivalentmethod. 8.ElectromagneticCompatibility(EMC) Youshouldperformtestingforelectromagneticcompatibilityforalldeviceoutputmodes.Thetestingshouldinclude: aclearsummaryofallEMCtesting(emissionsandimmunity)ofthisdevicewiththetestresultsanddatatosupportanyclaimsforimmunitytoelectromagneticinterference(EMI); abriefexplanationofhoweachEMCtestwasperformedandhowthetestingforeachmodeaddressestherisksforEMIanddemonstratesEMCtotheclaimedlevels; abriefexplanationofhowthetestingaddressesthetimingofthedevicefortherapydelivery; referencestoappropriateEMCtestingstandards(e.g.,FDA-recognized,IEC60601-1-2:2001StandardforMedicalElectricalEquipment)alongwithexplanationsandjustificationsforanydeviationsfromthereferencedstandardsormodificationstothedevicetested; pass/failcriteriaforeachEMCtests,howthesewerequantifiedandmeasured,andjustificationsforthesecriteria. WirelessTechnology IfthedeviceincorporatesRadio-Frequency(RF)wirelesstechnologytoperformsomeofitsfunctions,youshouldaddresssafetyandeffectivenessconcernsinvolvingthewirelesstechnology. Backtothetop 9.SoftwareLifeCycleandRiskManagement Werecommendthatyousubmittheinformationforsoftware-controlleddevicesdescribedinGuidancefortheContentofPremarketSubmissionsforSoftwareContainedinMedicalDevices(theSoftwareGuidance).5Thekindofinformationwerecommendyousubmitisdeterminedbythe“levelofconcern,”whichisrelatedtotherisksassociatedwithsoftwarefailure.Thelevelofconcernforadevicemaybeminor,moderate,ormajor.FDAbelievesthatthesoftwareusedtooperatearTMSdevicepresentsa“moderatelevelofconcern”asdescribedintheSoftwareGuidancebecauseafailureorlatentdesignflawcouldeitherdirectlyresultinminorinjurytothepatientoroperatororcouldindirectlyresultinminorinjurytothepatientoroperatorthroughincorrectordelayedinformationorthroughtheactionofacareprovider. Backtothetop 10.ClinicalTesting Clinicaltestingwillgenerallybeneededfornewdevices,unlesstheproposeddeviceissufficientlysimilartothepredicatedeviceintermsofindications,devicespecifications,andenergyoutput,suchthatrelianceonbenchand/oranimaltestingmaybesufficient.Incaseswhereclinicaltestingisneeded,FDArecommendsthattheclinicalstudybedesignedtodemonstratethesubstantialequivalenceofsafetyandeffectivenessofyourdevicewhenusedasdescribedintheIndicationsforUsestatement.Sponsorsmustconductclinicalstudiesincompliancewith21CFRparts50,56,and812.Recommendationsforaclinicalstudyareprovidedbelow.6 Theclinicaltrialdesignshouldaddresstheconcernsdiscussedbelow. Indicationforuse:Theindicationforuseshouldidentifythepatientpopulationforwhomthedeviceisindicated,includingtheDSM-IVdiagnosis,treatmentseverity,andmedicationresistance. InclusionandExclusionCriteria:Theinclusionandexclusioncriteriashouldcharacterizethepopulationfortheproposedindicationforuse.YourinclusionandexclusioncriteriashouldspecifytheDSM-IVdiagnosis,medicationresistanceandtreatmentseverity.Duetosafetyconcerns,werecommendyouexcludesubjectswhohaveanymetalimplantedinthehead(exceptthemouth),e.g.,subjectswithcochlearimplants,implantedbrainstimulators,ocularimplants,aneurysmclipsorstents.Inaddition,youshouldaddressothersubjectcharacteristics,including: age, comorbidpsychiatricandneurologicaldisorders, pregnancy, lengthofcurrentepisode,singleorrecurrentepisode, baselinedepressionseverity,basedonvalidateddepressionscale, riskofsuicide,basedonavalidatedsuicideseverityscale, priortreatmentwithantidepressanttherapies.Doseanddurationofantidepressanttrialsshouldbedocumentedusinganantidepressanttreatmenthistoryform(ATHF), cardiacpacemakers,cardioverterdefibrillators,orneurostimulators, implantedmedicationpumpsorintracardiaclines, significantheartdisease,cerebrovasculardisease,orhearingloss, historyofepilepsy,cerebrovasculardisease,dementia,headtrauma,increasedintracranialpressure,orcentralnervoussystem(CNS)tumors. Treatmentparameters:Treatmentparametersshouldbestandardizedandshouldbespecifiedindetailinyourprotocol.Youshouldincludeadescriptionofthemethodandtimingofmotorthresholddeterminations,identificationoftreatmentlocation(e.g.dorsolateralprefrontalcortex),andthespecifictechnicalparametersforstimulation.Youshouldspecifythenumberandfrequencyoftreatmentsandoveralldurationoftreatmentexposure.TreatmentparametersthatexceedthoseprescribedinTable2willrequireadequatejustificationandriskassessment.FDArecommendsyouprovidedetailsaboutwhethertreatmentsessionswillbeindividualized(i.e.,whethertreatmentparameterswillbeadjustedbasedonthestudysubjectresponse).Subjectsshouldberequiredtowearearplugsduringthetreatmentsessions. Studydesign:FDArecommendsaprospectiverandomizeddoubleblindsham-controlledmulticenterstudy,sincethespecificparameteroftherTMSsignalthatiscorrelatedwiththebeneficialclinicaleffecthasnotbeendetermined.Duetoplaceboeffectsindepressionstudies,thecontrolgroupconditionshouldbedesignedsuchthatunblindingdoesnotoccurduetostimulationinducedsideeffects. Duetoclinicalvariationsintheseverityofdepression,werecommendthatyouincorporateabaselinephase,priortotherandomizedphaseofthestudy.Whenwithdrawingsubjectsfromantidepressanttherapies,youshouldfollowthedrugmanufacturer’slabelingregardingthetimeperiodthatisnecessarytoassurethattheantidepressantmedicationshasbeenwashedout.Multiplebaselinedepressionassessmentsshouldalsobeperformedtoassurethatthesubject’sdepressionhasstabilized. Sincedepressionisachronicdisease,thelengthoftherandomizedphaseofthetrialandthefollow-upphaseshouldbeofsufficientdurationtodemonstrateaclinicallymeaningfuleffectondepressionandbeconsistentwithstandardofcare.FDAalsorecommendsthattheadequacyofblindingbeassessed. Deviceeffectiveness:Youshouldspecifytheprimaryandsecondaryeffectivenessendpointsforthestudy.Endpointsshouldbechosentoassureaclinicallymeaningfuleffect. Validateddepressionassessmentscalesshouldbeusedastheprimaryendpoint.FDArecommendsthatacomparisonoftheproportionofsubjectswhomeetthecriteriaofresponseandremissioninboththeactiveandcontrolgroupsbeperformed.Inaddition,FDArecommendsthatyouassessapatientreportedoutcomesuchasqualityoflifeasoneofyoursecondaryendpoints.Additionaloutcomemeasuresshouldincludepatientglobalimpressionofimprovementandclinicianglobalimpressionsofimprovementandseverity. Devicesafety:ClinicalstudiesconductedintheUSmustcomplywiththeapplicablereportingrequirementsof21CFR812.150(b).ForclinicalstudiesofrTMSdevices,devicesafetydatashouldincludetheincidenceofseriousadverseevents,e.g.,worseningdepression,suicidalideation,suicideattempt,suicide,switchingtohypomania/mania,seizure,death,anddevicemalfunctionresultinginpatientoroperatorinjury.FDArecommendsthattheprotocolincludesasuicideseverityratingscale,suchastheColumbiaSuicideSeverityRatingScale7,toassessbothsuicideintentandbehavior. Youshouldalsocollectincidenceofcommonadverseeventssuchasheadache,applicationsitepain,anddiscontinuationrateduetoadverseevents.Werecommendthatyoucollecttargetedsafetyoutcomesforauditorythreshold,suchaspre-andpost-audiograms,andcognitivefunction.Youshouldalsodeterminetheseverityanddurationofeachadverseevent.Dataoneachadverseeventshouldincludeinformationabouttheinterventionthatwasperformedandwhethertheeventwasresolved. Training:Youshoulddescribeanytrainingprovidedtostudyinvestigators,includingbothtrainingontheuseofthedeviceandonanyassessmenttools.Supportinginformationtosubstantiateanadequateleveloftrainingshouldbeprovided,suchasapre-studyreliabilitycertificationprogramandreliabilityassessmentforclinicalratersduringthestudy. ReportingofStatisticalOutcomesforClinicalStudyResults Thefollowingstudydesignfeaturesshouldbestatedclearlyinthestudyprotocoldocument. SampleSizeEstimation YoushouldprovideasamplesizecalculationthatspecifiesanacceptabletypeIerrorandpower,theanticipatedminimumdetectabletreatmentdifferenceforsuperioritystudies,andtheanticipatedcontrolandtreatmentresultsandanagreed-uponnon-inferioritymarginfornon-inferioritystudies. Hypotheses Youshouldspecifyyournullandalternativehypotheses.Yourstatisticalhypothesisshoulddescribethespecificstatisticalmodelproposedforthemainanalysisandanyrelevantsecondaryanalyses. RandomizationandBlinding Youshoulddescribeanapriorimethodofrandomizationandprovideamethodtoensureintegrityofthestudyblindindetail.Werecommendthatyouassesstheadequacyofblinding,byaskingpatientstoguesstheirtreatmentgroupandthereasonfortheirguess.Inaddition,werecommendthatyouperformsensitivityanalyses,suchasexaminingthecorrelationbetweenadverseeventsandtheobservedtreatmenteffecttoexaminethepossibilityofunblindingduetoadverseevents. EffectivenessAssessments Youshouldincludeanoverallassessmentofsafetyandeffectiveness.Inyourassessmentyoushouldreport: theprimaryefficacyendpointwhichshouldbebasedonavalidatedassessmenttool; thesecondaryefficacyendpointswhichshouldalsobebasedonvalidatedassessmenttoolsandshouldassessanybenefitsforwhichyouplantoclaimeffectiveness;and thestandardizedeffectsizeforcontinuousoutcomemeasuresand/orthenumber-needed-to-treat(NNT)forcategoricalendpoints. StatisticalAnalysisPlan Analysispopulations:Thepreferredanalysispopulationforasuperioritystudyistheintent-to-treatpopulation,consistingofallsubjectsasoriginallyrandomized.Fornon-inferioritystudieswithanactivecontrol,youshouldbasethedeterminationofeffectivenessontheintent-to-treatpopulations.Inaddition,supportinganalysesshouldincludeper-protocolandastreatedanalyses.Aper-protocolpopulationreferstopatientswithnoprotocolviolationsandcompletefollow-up.As-treated,althoughsimilartointent-to-treat,referstoallpatients,butisgroupedaccordingtothetreatmentactuallyreceivednottherandomizationassignment. Primaryandsecondaryendpoints:Youshouldreporttheprimaryandsecondaryendpoints,comparingtheresultsoftheactivegrouptothecontrolgroup.Fordepressionstudies,werecommendthatyoureportchangeasacontinuousmeasure,aswellastherateofresponse,definedasa50%reductionontheassessmentscale,andalsotherateofremission. Ifyouwishtomakeanylabelingclaimsbasedonyoursecondaryendpoints,youshouldprespecifyastatisticalmethodtocontrolmultiplicity,suchasahierarchicaltestingorderorthestep-downmethodofHolm. Missingdata:Yourstudyanalysisplanshouldincludemethodsforhandlingmissingdata.Thisincludesimputationmethods,suchasmultipleimputation,andsensitivityanalyses,suchasimputingvariousproportionsofmissingoutcomes(ofabinaryendpoint)as“successes”or“failures.” CovariateAnalysis:Werecommendyouspecifymethodsforhandlingsignificantcovariatesinthestatisticalmodel.Foranycovariatetermincludedintheproposedstatisticalmodeltoevaluateeffectiveness,werecommendyouinvestigateatreatmentgroupbycovariateinteraction.Ifsuchaninteractiontermisfoundtobestatisticallysignificant,yourstatisticalsummaryshouldincludeadiscussionoftheimplicationofthestatisticallysignificantinteractionontheoverallinterpretationofthestudyresults. Treatmentbysiteinteractions:Multicenterstudiesshouldincludeameasuretoassessanysignificanttreatmentbycenterinteractionontheprimaryeffectivenessmeasure.Werecommendbothtreatmentandcontrolgroupsbestudiedatthesamesite(s).Wealsorecommendyouapplyanappropriaterandomizationblockingproceduretobalancethenumberofsubjectsineachparticipatingcenterbetweencontrolandtreatmentgroupsinordertofacilitateanassessmentofthepoolabilityofdataacrosscenters.Inaddition,yourstatisticalanalysissectionshouldincludeadiscussionoftheimportanceofanystatisticallysignificanttreatment-by-siteinteractiontotheoverallinterpretationofthestudyresults. ReportingResultsfromJournalArticlesorMeta-analyses Ifapplicable,safetyresultsobtainedwiththerTMSdevicethatwerereportedinthemedicalliteratureshouldbesummarizedandincludedinthepremarketnotification.Inaddition,effectivenessdataforyourrTMSdeviceforyourindicationsforusethatareavailablefromjournalarticlesormeta-analysesmaybesubmittedassupportiveinformation. Backtothetop 11.Labeling Thepremarketnotificationmustincludelabelinginsufficientdetailtosatisfytherequirementsof21CFR807.87(e).Thefollowingsuggestionsareaimedatassistingyouinpreparinglabelingthatsatisfiestheapplicablerequirementsof21CFRPart801.8FortherTMSsystem,suchlabelingincludespatientlabeling(describedbelow)withinstructionstothephysiciantoprovidethepatientlabelingtothepatientsothatthepractitionerwhoislicensedbylawtoadministerthedevicecanusethedevicesafelyandforthepurposeforwhichitisintended(21CFR801.109(c)). DirectionsforUse Thelabelingshouldincludeanoperator’smanualwithclearandconciseinstructionsthatdelineatethetechnologicalfeaturesofthespecificdeviceandhowthedeviceistobeused.Instructionsshouldencouragelocal/institutionaltrainingprogramsdesignedtofamiliarizeuserswiththefeaturesofthedeviceandhowtouseitinasafeandeffectivemanner. CoilPositioning LabelingshoulddescribehowtodeterminetherTMStreatmentlocationinsufficientdetailfortheusertounderstandhowtoidentify,transitionto,andrecordanycoordinatesneededforreproduciblepositioningfromsessiontosession. SafetyInstructions Youshoulddescribeanysafetyfeaturesincludedtoaddresstheriskofseizure.WerecommendthattherTMSdevicehavefeaturesthatallow: rapidaccesstothepatient; immediateterminationofpulsing; rapidremovalofthecoilfromthepatient;and theabilitytoplacethepatientinasafepositionforseizuremanagement. Usersofthedeviceshouldmonitorpatientsforseizuresby: electromyography(EMG)monitoringofcontralateralabductorpollicisbrevisorfirstdorsalinterosseousactivation;or electroencephalography(EEG)monitoringforafter-dischargesduringrTMSsessions;or visualand/orvideomonitoringforsignsofseizuresormuscletwitching. Instructionsforseizuremanagementproceduresshouldinclude: presenceofphysicianornursetrainedinseizuremanagement; presenceoforreadyaccessto,life-supportequipment(oxygen,suction,bloodpressuremonitor,intravenousequipment,CPRequipment);and accesstoanti-seizuremedications. IndicationforUse Thelabelingshouldincludeanindicationforusethatisconsistentwiththatdescribedin21CFR882.5805(seeSection2.Scope).Thelabelingshouldalsocontainadescriptionoftheclinicaltrialpopulationthatidentifiesthestudypopulationaccordingtotreatmentseverityanddurationofdisease. Contraindications Thecontraindicationssectionofthelabelingshouldaddresstheconcernsrelatedtoimplantedelectronicdevicesandelectricalconductiveobjectsasdescribedbelow.Eachcontraindicationinthelabelingshoulddescribetheconsequencesofcontraindicateduse. MetallicObjectsinorneartheHead rTMSdevicesarecontraindicatedforuseinpatientswhohaveconductive,ferromagneticorothermagnetic-sensitivemetalsimplantedintheirheadorwithin30cmofthetreatmentcoil.Examplesincludecochlearimplants,implantedelectrodes/stimulators,aneurysmclipsorcoils,stents,bulletfragments,jewelryandhairbarrettes.Failuretofollowthisrestrictioncouldresultinseriousinjuryordeath. ImplantedStimulatorDevicesinorneartheHead rTMSdevicesarecontraindicatedforuseinpatientswhohaveactiveorinactiveimplants(includingdeviceleads),includingdeepbrainstimulators,cochlearimplants,andvagusnervestimulators.Contraindicatedusecouldresultinseriousinjuryordeath. Warnings Thewarningssectionoftheoperator’smanualshouldaddresstheconcernsdescribedbelow. WorseningDepressionorSuicidality Labelingshouldincludeawarning,presentedinboldtext,regardingtheriskofworseningdepressionand/ortheemergenceofsuicidalideationandbehavior(suicidality)orunusualchangesinbehaviorduringtreatment.Labelingshouldalsowarnthatpatientsundergoingtreatmentshouldbeobservedcloselyforclinicalworseningandsuicidalityand,ifworseningofsymptomscontinues,physiciansshouldconsiderdiscontinuingrTMStreatment. RiskofIneffectiveTherapy Thelabelingshouldincludeappropriatewarnings(considerusingboldtext)foruseinpatientpopulationswhereefficacyhasnotbeenestablishedandwheretreatmentmayrepresentarisktothepatient. ThetherapeuticeffectsofrTMSareknowntorequireseveraltreatmentsoveraperiodoftime,thereforewerecommendlabelingwarningagainstuseinresponsetoacutecirumstances. ImplantsControlledbyPhysiologicalSignals ThelabelingshouldincludeawarningregardingthepossibleeffectsoftherTMSdevicewhenusedinpatientswhohaveimplanteddevicesthatareactivatedorcontrolledinanywaybyphysiologicsignals,irrespectiveofthedistancefromthetreatmentcoil.Thisincludespatientswithpacemakersandimplantablecardioverterdefibrillators(ICDs),aswellaspatientsusingwearablecardioverterdefibrillators(WCDs),evenifthedeviceisremoved,duetothepotentiallyunstablecardiacconditionofsuchpatients.Usecouldresultinseriousinjuryordeath. MedicalDevicesContainingElectronicsorFerromagneticMaterial ThelabelingshouldincludeawarningregardingthepossibleeffectsoftherTMSdeviceondevicesimplantedorlocatedinareasofthebodynearthemagneticfieldiftheycontainelectronicsorferromagneticmaterials.ThewarningshoulddescribetheappropriatedistancebetweentherTMSdeviceandotherdevices,sothemagneticfielddoesnotcausemovement,heating,ordysfunctionoftheseotherdevices. Wearable/RemovableMedicalDevices,ConductiveObjectsandOtherDevices Thelabelingshouldincludeawarningthatwearable/removablemedicaldevices,otherdevicesorconductiveobjects(includingpersonalitems)thatmaybeaffectedbythemagneticfieldshouldberemovedfromthepatientareabeforetreatmenttopreventpossibleinjurytothewearerordamagetothedevice.Examplesofthesetypesofproductsincludewearablemonitors,bonegrowthstimulators,earringsandotherjewelry,hearingaids,eyeglasses,cellphones,andMP3players. ThewarningsectionofthelabelingshouldincludeatablethatlistsalldevicesthatareknowntobeadverselyaffectedbytherTMSdevice.Thelabelingshouldinstructtheprescribingphysiciantoscreeneachpatientforthepresenceofthesedevices. Inaddition,thewarningsshouldsummarizethecompatibilityrequirementsforeachdeviceandelectricallyconductiveobjectinthevicinityoftherTMSdevicetreatmentcoil.Theserequirementsshouldindicatewhetherthedevice’sproximitytothetreatmentcoiliscontraindicated,shouldbekeptatasafedistancefromthemagneticcoil,orshouldberemovedfromthepatientarea.Thewarningshouldalsonotethatthislistisforguidanceinscreeningapatientformagneticfieldcompatibilityandisnon-comprehensive,soprudentjudgmentshouldbeappliedforcasesnotlisted,includingcontactingthedevicemanufacturerifcompatibilityisuncertain. RiskofSeizure ThelabelingshouldindicatethatseizureisapotentialriskoftreatmentwithrTMSdevices.AsummaryofthenumberofseizuresreportedwiththeuseoftherTMSdeviceinclinicalstudiesshouldbeincluded;thepatientpopulationsshouldalsobedescribedsince,forexample,useofrTMSasanadjuncttocertainmedicationsmayincreasethelikelihoodofaseizure.Thelabelingshouldstatethatpatientswhohaveahistoryofseizure,orpotentialalterationinseizurethreshold,shouldbecloselymonitoredwhenthedeviceisused.Thisincludespatientswithahistoryofseizureorepilepsy,stroke,headinjury,highintractranialpressure,severeheadaches,orpresenceofotherneurologicdiseasethatmaybeassociatedwithanalteredseizurethreshold,orconcurrentmedicationuseassuchastricyclicantidepressants,neurolepticmedicationsorotherdrugsthatareknowntolowertheseizurethreshold,secondaryconditionsthatmaysignificantlyalterelectrolytebalanceorlowerseizurethreshold,orwhereaquantifiablemotorthresholdcannotbeaccuratelydetermined. Labelingshouldalsociterelevantguidelines(e.g.,1998NationalInstituteofNeurologicalDisordersandStroke(NINDS)Workshop)forrTMSstimulationparameters3whicharealsosummarizedinSection4.DeviceDescription,intendedtoreducethepotentialriskofseizure.Inaddition,labelingshouldrecommenduseofthedevicewithinanyguidelinescited. Precautions Thefollowingprecautionsshouldbeprovided,unlessotherwisejustified. LackofEvidenceforEfficacyorSafetyinSpecificPatientPopulations LabelingshouldincludeprecautionsfortheuseofrTMSdevicesinthetreatmentofpatientswithdepressiveorrelatedconditionswheresafetyandefficacyhasnotbeenestablished.Thismayincludepatientswiththesecharacteristics: agelessthan22; suicideplanorrecentsuicideattempt; varyingdegreesofmedicationresistanceineitherthecurrentorpreviousepisode; onconcurrentantidepressantmedication,i.e.,cannottoleratediscontinuationofcurrentantidepressantmedication; historyorconcurrentuseofelectroconvulsivetherapyorvagusnervestimulation; depressionsecondarytoageneralmedicalconditionorsubstance-induced; seasonalaffectivedisorder; historyofsubstanceabuse,obsessivecompulsivedisorderorpost-traumaticstressdisorder; apsychoticdisorder,includingschizoaffectivedisorder,bipolardisease,ormajordepressionwithpsychoticfeatures; neurologicaldisorders,includingahistoryofseizures,cerebrovasculardisease,primaryorsecondarytumorsinCNS,cerebralaneurysm,dementia,ormovementdisorders; historyofincreasedintracranialpressureorheadtrauma; cadiacpacemakers,implantablecardioverterdefibrillators,occularimplants,deepbrainstimulators,vagusnervestimulators,implantedmedicationpumps,intracardiaclines,orsignificantcardiacdisease;or pregnantornursing. HearingProtection LabelingshouldincludeaprecautionthathearingprotectionisrequiredduringtheuseofrTMSdevices.Patientsandthoseoperatingthedeviceshouldalwayswearearplugsorsimilarhearingprotectiondeviceswitharatingof30dBofnoisereductionduringrTMStreatment. Long-TermEffects LabelingshouldincludeaprecautionthatdescribesthelimitationsofavailableinformationonthesafetyandeffectivenessoflongtermtreatmentwiththerTMSdevice. Labelingshouldstatetheknownlongtermeffectsandindicatethatotherlongtermseffectsmaybeunknown. ProcedurePrecaution Labelingshouldincludeaprecautiontoaddresstheriskofexplosionduetothepresenceofflammablematerials,riskofelectricalshock,riskofoverheatingofthemagneticcoil,anddiscontinuationoftreatmentforanypatientwhohasacontinuedsignificantadversereactionordiscomfortduringorimmediatelyafteruse.Asampleofsuchaprecautionthatmaybeconsideredisasfollows: “Toavoidtheriskofexplosion,donotusethisdeviceinthepresenceofflammableanesthetics” AdverseEvents Aspecificsectionoftheoperator’smanualshouldpresentasummaryofadverseeventsthatoccurredwiththerTMSdeviceinclinicaltrials.ReportsofheadacheandapplicationsitepainshouldbecitedinnumberandseverityasthesearefrequentlyassociatedwithrTMStreatment.Inaddition,thenumberandincidenceofdeaths,suicides,seizuresorworseningofdepressionshouldbeprovided.Effectsoncognitivefunctionorauditorythresholdusingtargetedmeasuresofanalysisshouldbereported. ElectricalSafety ElectricalsafetyrequirementsfortherTMSdeviceshouldbestatedclearlyintheproductlabeling.AlistoftechnicalstandardstowhichthedevicehasbeentestedandshowntomeetspecificationsasindicatedinSection8.ElectromagneticCompatibilityalsoshouldbeprovided. ElectromagneticCompatibility ElectromagneticcompatibilitysafetyrequirementsfortherTMSdeviceshouldbeclearlystatedintheproductlabeling.AlistoftechnicalstandardstowhichthedevicehasbeentestedandshowntomeetspecificationsasindicatedinSection9.SoftwareLifeCycleandriskManagementshouldalsobeprovided. UserTraining Werecommendthatacliniciantrainingprogrambedevelopedthatincludesinformationonthecharacteristicsoftheintendedpatientpopulationandhowtodifferentiatethesepatientsfrompatientsforwhomevidenceofefficacyisnotavailable.ItshouldalsocoverthedesignfeaturesoftherTMSdevice,methodsfortrainingintheuseofthedeviceandappropriatemethodstodescribethesafetyandrisksofthedeviceinthetreatmentofpatientswithmajordepression.Thetrainingshouldensureoperatorcompetencyanduniform,optimaltreatmenttechniquetosafelyandeffectivelyusethedeviceforthepurposesdescribedintheindication. PatientLabeling Physicianlabelingshouldincludepatientlabelingwithinstructionstothephysiciantoprovidesuchlabelingtothepatient.Patientlabelingshouldprovideaprospectivepatientinformationthatwillassistthepatientinunderstandingwhomaybenefitfromthetreatmentwiththedevice,whatthosepotentialbenefitsare,relevantcontraindications,warnings,precautions,adverseeffects/complications,andalternativetreatments.Providingsuchinformationtothepatientpriortoschedulingtreatmentshouldhelpensureeffectivecommunicationbetweenthepatientandpractitionerconcerningthesafeuseofthedeviceandthepurposesforwhichitisintended.Eachpatientshouldhaverealisticexpectationsofthetreatment,thepotentialcomplications,andunderstandwhattypesoffeedback,e.g.,headache,worseningdepression,maybeimportanttoprovidethepractitioner.Thepatientlabelingshoulduseterminologythatiswellknownandunderstoodbytheaveragelayperson. WerecommendyoufollowtherelevantprinciplesdiscussedintheCDRHguidancedocumententitled,GuidanceonMedicalDevicePatientLabeling.9ForrTMSsystems,werecommendphysiciansprovidepatientswiththepatientlabelingthatincludesthefollowinginformation. InformationonTreatment Describehowthedeviceoperatestoachieveitseffectsandthecourseoftreatment.PatientlabelingforrTMSsystemsshouldstatethefollowing: AcourseofrTMStraditionallyrequiresmultipletreatments. Patientsshoulddiscussthenumberoftreatmentsandtreatmentschedulewiththeirphysicians. rTMStreatmenteffectsinreducingdepressionaretemporary,andpatientsmayneedtocontinueotherformsofdepressiontherapy. Relapseintodepressionislikelywithoutfollow-uptreatment. CandidatesforTreatment Basedupontheinformationfromyourclinicaltrial,describethepatientpopulationforthedevice. Benefits Describethepotentialbenefitsofyourdeviceandprobabilityofsuchbenefitsbaseduponyourclinicaltrial. Risks DescribetheknownrisksfromyourdeviceandrTMSingeneral. AlternativeTreatments Patientlabelingshoulddescribethealternativetreatmentssuchasmedications,psychotherapy,andelectroconvulsivetherapy. Backtothetop AppendixA.DefinitionsandUnitsofMeasurement Forthepurposesofthisguidancedocument,thefollowingdefinitionsandrecommendationsformeasurementareused: Frequency:ThenumberofpulsespersecondexpressedinHertz(Hz). MagneticFieldStrength:MagneticfieldstrengthisexpressedasB,themagneticfluxdensity,inunitsofTesla.ThetimerateofchangeofBdeterminesthecurrentdensitylevelinducedinthecortex;therefore,dB/dtisusedtoexpressthestrengthofthefieldinducedbythemagneticfieldatagivenpoint.Theunitsformagneticfieldflux(i.e.,dB/dt)areTesla/second.Magneticfieldstrengthisdeterminedbymeasuringthevoltageinducedacrossasmallpickuploopplacedatthelocationofinterest. MotorThreshold(MT)/MTIntensity:Themotorthresholdlevelistheminimumstimulatorsetting,inStandardMotorThreshold(SMT)units,thatinducesanobservablemotorresponsebythepatientin50%oftheappliedpulses,usuallyasobservedbymovementofthethumb.“MTlevel”isdeterminedwiththerTMStreatmentcoilpositionedoveraspecificlocationwithinthemotorstrip,calledthemotorthresholdlocation(MTlocation).10TheMTlocationmaybeusedasananatomicreferencepointfornavigatingthecoiltotherTMStreatmentlocation.TheMTlevelisusedasareferencepointforsettingtherTMStreatmentintensity,usuallyexpressedasapercentmultipleoftheMTlevel,e.g.120%MT. PulseWidth:WhenyourrTMSoutputisadampedsinusoidalwave,thepulsewidthisdefinedasthetime(duration)fromtheinitialpeaktonextpeakofthewave;itisalsodescribedastheperiodofthesinusoidalwave.Formonophasicpulseshapes,werecommendreportingpulsewidthasthetimebetweentherisingphaseandfallingphaseofthewavemeasuredatastandardamplitude(e.g.,10%oftotalamplitude).Thepick-uploopformakingthismeasurementshouldbelocatedatthesamedistancefromthecoilasthetargettissueinthebrain. SMTUnit:Sothatmeasurementofstimulatormagneticfieldoutputmaybestandardized,theSMTunitissuggested.1.0SMTistheoutputsettingofarTMSdevicethatcorrespondstoaninducedelectricfieldof130V/matapointlocatedatthefixeddistanceofthetargetalongthecentralaxisofthecoilfromthesurfaceofthescalpintothecortex.Thisinducedelectricfieldismeasuredwithapick-uploopwiththedipoleorientedalongthefront-to-back(i.e.,normallyanterior-posterior)axisofthetreatmentcoil. StimulationVolume:Stimulationvolumedefinestheregionofcorticaltissuewithinthemagneticfieldthatisabovethethresholdofcorticalstimulation,i.e.,the3-dimensionalvolumewithinwhichtheinducedelectricfieldachievesavaluegreaterthanorequalto80%oftheelectricfieldatthe2.0cmreferencepoint.Forexample,foratreatmentatthe120%MTlevel,thefieldattheboundaryofthestimulationvolumeisequivalenttotheMTlevelandalltissuewithinthestimulationvolumeisabovetheMTlevel. Backtothetop 1FormatforTraditionalandAbbreviated510(k)s 2Wassermann,E,etal.“Riskandsafetyofrepetitivetranscranialmagneticstimulation:reportandsuggestedguidelinesfromtheInternationalWorkshopontheSafetyofRepetitiveTranscranialMagneticStimulation,June5–7,1996,”ElectroencephalographyandclinicalNeurophysiology108(1998)1–16. 3RossiSetal.“Safety,ethicalconsiderations,andapplicationguidelinesfortheuseoftranscranialmagneticstimulationinclinicalpracticeandresearch”,ClinicalNeurophysiology120(2009)2008–2039. 4http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080735.htm 5http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089543.htm 6WerecommendthatyourequesttheAgency’sreviewofyourprotocolspriortoinitiatingclinicalstudiesforyourdevice.Thisprocessmayhelpensurethatanyissuesareaddressedpriortosubmittingyourpremarketsubmission.TorequesttheAgency’sreviewofyourprotocols,youcansubmitapre-submissiontotheAgency. 7Seehttp://www.cssrs.columbia.edu 8Althoughfinallabelingisnotrequiredfor510(k)clearance,finallabelingmustcomplywiththerequirementsof21CFRPart801beforeamedicaldeviceisintroducedintointerstatecommerce.Inaddition,finallabelingforprescriptionmedicaldevicesmustcomplywith21CFR801.109.LabelingrecommendationsinthisguidanceareconsistentwiththerequirementsofPart801. 9http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm070782.htm 10RothwellJC,HallettM,BerardelliA,EisenA,RossiniP,PaulusW,Magneticstimulation:motorevokedpotentials.ElectroencephClinNeurophysiolSupp1999;52:97-103.   Contentcurrentasof: 03/23/2018 RegulatedProduct(s) MedicalDevices Topic(s) Premarket GuidanceDocuments(MedicalDevicesandRadiation-EmittingProducts) Cross-CenterFinalGuidance RecentFinalMedicalDeviceGuidanceDocuments DraftMedicalDeviceGuidance CDRHProposedGuidanceDevelopment ClassIISpecialControlsDocuments Radiation-EmittingProductsGuidance WithdrawnGuidance MedicalDeviceProvisionsofFDAModernizationAct BacktoTop