Briefing Document.docx
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Briefing Document.docx
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BriefingDocument
BriefingDocument
BiologicalResponseModifiersCommitteeMeeting#37
CellularProductsfortheTreatmentofCardiacDisease
March18-19,2004
INTRODUCTION1
MEETINGGOALS1
BACKGROUND2
General:
2
Regulatory:
3
MANUFACTURINGINFORMATION4
CellularProductsManufacturedWithoutinvitroCultureMethodology4
CellCollection5
BMSC&PBSCProcessing5
CellularProductsManufacturedWithinvitroCultureMethodology5
MyoblastCollectionandProcessing6
MesenchymalStemCell(MSC)CollectionandProcessing6
UniqueIssueswithCellularProducts6
MicrobiologicalSafety6
ProductFormulation7
ProductCharacterization7
ManufacturingQuestions7
PRECLINICALSTUDIES8
CellularProductsManufacturedWithoutinvitroCultureMethodology9
CellularProductsManufacturedWithinvitroCultureMethodology9
PreclinicalSummary11
PreclinicalQuestions:
11
INVESTIGATIONALCATHETERSFORDELIVERYOFCELLULARPRODUCTSTOTHEHEART12
InfusionofCellularProductsintoCoronaryArteries:
12
IntramyocardialInjectionofCellSuspensionsthroughCardiacCatheters:
15
DeviceQuestion:
18
CLINICALSTUDIES18
CellularProductsDerivedfromBoneMarrow:
18
Overview:
18
DeliveryMethods:
19
Outcomes:
19
CellsDerivedfromSkeletalMuscle:
20
Overview:
20
Administration:
21
Outcomes:
21
ClinicalQuestions:
22
ListofQuestions:
24
Manufacturing:
24
Preclinical:
24
Device:
25
Clinical:
26
Attachments:
27
CitedReferences28
INTRODUCTION
ThisBiologicalResponseModifiersAdvisoryCommittee(BRMAC)isconvenedtoprovidetheFDAwithinsightandperspectivesregardingthemajorissuesconfrontingthedevelopmentofcellularproductsforthetreatmentofcardiacdiseases.Theseissuesincludemanufacturing,catheter-productinteractions,thenatureandquantityofpreclinicaldataandconcernsrelatedtoearlyphaseclinicalstudies.Controversysurroundstheextentandnatureofmanufacturinginformationandpreclinicaldatanecessarytosupporttheintroductionofthesecellularproductsintoclinicalstudies.Becausethemajorityofthesecellularproductsareautologous,someinvestigatorshavecitedthemasinherentlysafeandhavesuggestedthatpreclinicalstudiesmaybeunnecessary.Someinvestigatorshaveproposedinitiationofphase2clinicalstudieswithoutexplorationofsafetyinphase1studies.Othershavesuggestedthatwithoutadetailedunderstandingofthecellularproducts’characteristicsandexplorationofsafetyandmechanismsofactioninpreclinicalstudies,itisimpossibletodesignandsafelyconductclinicalstudies.Giventhesewidelydivergentopinions,FDAhasconvenedthisBRMACtodiscusstheissuesinapublicforum.
NospecificproductsarebeingpresentedforregulatoryreviewatthismeetingandnodatapresentedatthemeetingwillhaveundergoneFDAreviewforcompletenessoraccuracy.Instead,publishedinformationwillbepresentedandleadingresearchersinthefieldwillpresenttheirviewpointsonthemajorissuesconfrontingthisareaofresearch.MembersoftheBRMACwillberequestedtoconsiderthesepublicationsandviewpointsandprovidearesponsetoFDAquestions.Whileaconsensusresponsetothesequestionsisdesirable,noconsensusisrequired.Sincethefieldisrapidlydeveloping,FDAanticipatesthatallopinionsaretentativeandsubjecttoreconsiderationbaseduponaccumulatingdata.
MEETINGGOALS
Thismeetingisorganizedtoachievethefollowinggoalsregardingthedevelopmentofcellularproductsforthetreatmentofcardiacdiseases:
∙ProvideFDAwithperspectivesonthetypesofmanufacturingandpreclinicaldatacriticaltotheinitiationofclinicalstudies
∙ProvideFDAwithperspectivesonthemajorissuesinthedesign,conductandanalysesofexploratoryclinicalstudies
∙Provideapublicforumtodiscussthemajorcontroversiesindevelopingtheseproducts
BACKGROUND
General:
Despitemanyrecentadvances,ischemicheartdiseaseandcongestiveheartfailure(CHF)remainthemajorcausesofmorbidityandmortalityintheUSA.Despitetheimportantadvancesintherapyofthelasttwodecades,CHFcontinuestobeadiseasecharacterizedbyhighmorbidityandmortality.CHFbecauseofitshighprevalence(1-2%oftheadultpopulationintheU.S.A)andfrequentrequirementforhospitalizationisamongthemostcostlymedicalproblemsinthecountry.CHFcontinuestoincreaseinprevalencebecause1)theincidenceisrelatedtoageandtheaverageageoftheAmericanpopulationisincreasingand2)reperfusiontherapyhasledtogrowingnumbersofpatientssurvivingacutemyocardialinfarctionwithdiminishedcardiacreserve.
Similarly,despiteadvancesinmedicaltherapyandpercutaneousinterventionaltechniques,ischemicheartdiseaseremainsamajorcauseofmorbidityandmortality.Arecentpaperestimatedthat100,000to200,000patientsperyeardevelopcoronaryarterydiseasenotamenabletoconventionalrevascularization,eithercoronaryarterybypassgrafting(CABG)orpercutaneouscoronaryintervention(PCI)(Mukherjee,Bhattetal.1999).Further,manymorepatientswouldbenefitfromrevascularizationtechniquesthatarelessinvasive,moredurable,andmorecomplete.
Cellulartherapiesforcardiacdiseaseareaburgeoningfieldofclinicalresearchaspotentialtreatmentsforpatientswithcongestiveheartfailureand/orischemicheartdisease.Thisresearchtodatehasinvolvedcellsderivedfromautologousmusclebiopsies,hematopoieticstemcellsfromautologousperipheralbloodaftermobilization,ormesenchymalorhematopoieticstemcellsobtainedfrombonemarrow.Theyhavebeen/orareproposedtobeadministeredthroughcathetersintothecoronaryarteries,transendocardiallythroughinjectioncathetersintotheleftventricularmyocardium,ortransepicardiallythroughaneedleduringconcomitantCABG.
Cellularproductstobediscussedatthismeetingconsistofthefollowing:
∙Cellularproductsmanufacturedwithoutinvitroculturemethodology,agroupthatincludesmostperipheralbloodand/orbonemarrow-derivedcells,and
∙Cellularproductsmanufacturedwithinvitroculturemethodology,agroupthatincludescellsderivedfromskeletalmusclebiopsiesandcertaintypesofbonemarrow-derivedcells.
Ingeneral,thecellularproductstobediscussedareadministeredbyoneofthefollowingroutes:
∙Bytransepicardialinjectionintotheleftventricularmyocardiumduringthoracotomy;inthisprocedurethecellularproductisinjectedintothemyocardiumusinganeedleandsyringeunderdirectvisualization,
∙Bytransendocardialinjectionintotheleftventricularmyocardiumviapercutaneouscatheterization;inthisprocedurethecellularproductisinjectedusinganinvestigationalcatheterwhichispassedretrogradethroughtheaortaintotheleftventricle;theinvestigationalcathetercontainsaneedleandoncethecatheterisplacedagainsttheleftventricularendocardium,theneedleisextruded,andthecellularproductinjectedintomyocardium,
∙Byinjectionthroughacatheterintothecoronaryarterylumen;thecoronaryarterylumenisoccludedbyaballoonandthecellularproductinfusedintothedistalcoronaryarterylumen
Discussionsofperipheralbloodand/orbonemarrow-derivedcellsandcellsderivedfromskeletalmusclebiopsieswillfocusprimarilyontheuseofautologouscellularproducts,becauseonlyautologouscellshavebeendescribedinpublishedclinicalreports.
Citationsto“stemcells”willoccurfrequentlyinthisdocument.Bonemarrowandgrowthfactormobilizedperipheralbloodhavebeenwidelydescribedascontainingstemcells,capableofregeneratingandassumingphenotypiccharacteristicsofavarietyoftissues,includingcardiactissue.Consequently,inthisdocumentthesecellswillbereferredtoas“bonemarrowstemcells”(BMSC)”or“peripheralbloodstemcells”(PBSC).
Cellularproductsderivedfromskeletalmusclebiopsiesaremostcommonlycitedasconsistingofdifferentiatedskeletalmusclecellsthatarecapableofregeneration.Thesecellsarecommonlyreferredtoas“myoblasts”andarenotusuallycitedas“stemcells.”
ThereaderisreferredtotheNIHdocumentattachedtothisdocumentforaglossaryofthetermsrelatedtostemcells.Ofnote,stemcellproductsderivedfromhumanembryonictissuearenotadiscussionfocusforthismeeting.
Regulatory:
FDAregulatescellularproductsforcardiacdiseasesasdrugsandbiologicalproducts.Thisregulatoryparadigmisbased,inpartonmanufacturingprocedures,theuseofinvestigationaldevicesinsomestudies,thenon-homologoususeofthecellularproductsandsafetyconcernsassociatedwithadministrationoftheseproducts.Consequently,FDArequiresInvestigationalNewDrugApplications(IND)forcellularproductsbeingevaluatedforthetreatmentofcardiacdiseases.
Theregulatorypathwayforcellularproductsisanevolvingprocessandcertainissuesrelatedtotheultimatelicensureofcellularproductsremaintoberesolved.Hence,thismeetingwillfocussolelyuponthescientificbasisforclinicaldevelopmentofcellularproductstobeusedinthetreatmentofcardiacdiseases.Conceivably,FDAmayrequestfutureBRMACmeetingsorothervenuestodiscusstheregulatoryissuesassociatedwithlate-phaseclinicaldevelopmentofthesecellularproducts.
Foreaseofreference,questionstotheBRMACarecitedwithinthetextofthisdocumentandalsoarelistedattheendofthedocument.
MANUFACTURINGINFORMATION
Mostinvestigationalcellularproductsareintendedtoreplacemissing,damagedordiseasedcellswithcellsthatarehealthyandfunctional.Attemptstodevelopacellularproductthatcanrestoredefectivecardiacfunctionwithcellsnotderivedfromcardiactissueassumesthepresenceofundiffere
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