Briefing Document.docx

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