simonetta viviani, md - dcvmn
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SimonettaViviani,MDBIO-VIPEConsultingLimited,HongKong
DCVMNClinicalDevelopment&PharmacovigilanceTraining17-21July2016,Bali,Indonesia
7–12years
2-3years
IdentifyAntigens
ProduceAntigens
TestinAnimals
PhaseISafety
Immuno
PhaseIIDoseSafety
PhaseIIIEfficacySafety
File
License
2-3years 2-3years 1-3years
ResearchPhase Registration
Phase
EarlyDevelopmentPhase
LateDevelopmentPhase
VaccineDevelopmentisaRisky,TimeConsumingandExpensiveProcess
Stagesinvaccinedevelopment
Vaccine development
Discovery Research
Non clinical development
Clinical development
Manufacturing Registration Marketing & sales
Efficacy Effectivness
Pharmacovigilance
Vaccinedevelopmentisanintegratedprocess
Preclinicaldevelopment
Regulatory ManufacturingDevelopment
Research&Discovery
ClinicalDevelopment
ClinicalDevelopmentPlan(CDP)� CDPdescribestheclinicalstrategyandmethodologytogenerateaclinicaldatabasethatwillsupportmarketingauthorizationapplication(MAAR)
� requirementofregulatoryguidelines(i.e.WHO,AseanCTD,EMEA)
CDPshouldbefullyintegratedwiththeotheraspects aspectsofvaccinedevelopment
CDPcontent:IntroducBon� DiseaseEpidemiology� Causativeagent� Mechanismofprotectionifknown� Othersimilarvaccines� ScopeofMYVACCINEdevelopment:briefoutlineofMYVACCINEpreclincialdevelopment,justificationoftheadjuvant,ifany,formulationsusedintheclincalphases
CDPcontent:RegulatoryStrategy� Indication
� Age-group,population� Vaccineschedule,booster� Dose:vaccinecomposition,formulation
� WhereMAA:countryoforigin,othercountriesoftheArea(i.eAsiancountries),WHOPQ,Europe,USAFDA)
� RegulatoryguidelinesforclinicaldevelopmentofvaccinesareavailablefromAsean,EMEA,WHO
� SomevaccinesspecificguidelinesissuedbyWHOareavailablealwayscheckat:http://www.who.int/biologicals/vaccines/en/
AssessingSafetyv Most vaccine trials are not aimed at testing specific
hypotheses regarding adverse events. v Consequently, safety assessment is generally
characterized by exploratory data analysis. v Descriptive statistics are presented and confidence
intervals are often informative. v P-values may be useful for detecting signals of possible
vaccine-associated adverse events for further evaluation. v By individual clinical trials v By age-group analysis v All subjects included in the database
CDPcontent:SafetyKeyParameters� Deviationsfromnormallaboratoryvalues(PhaseI)� Localandsystemic(solicited)post-immunizationreactions(duration,agegroups,etc)
� Adverseevents,AEI� SeriousAdverseEvents� Ensureuniformdefinitionasmuchaspossible
PharmacovigilancemustbeinplacewithqualitysystemoroutsourcedtoCRO
DataSafetyMonitoringBoard(independentexperts,reviewSAEs,AEs,futility)
VaccineSafety:samplesizeconsideraBonsfornewvaccine
Local&SystemicReactions Approximately300subjects
Adversereactions≥1:100
AEsAEIs,SeriousAdverseEvents(SAE)andMedically Significant AEs necessitating amedicalofficeorERvisitand/orresultinginpremature withdrawal of subjects from thestudy
Accordingthevaccine,approximately5000subjectsmaybeappropriatetoprovidereasonablereassuranceofpre-licensuresafetyinrandomizedcontrolledstudies
AdverseEvents≥1:1000
WorldHealthOrganizationWHOTechnicalReport,SeriesNo.924,2004
Annex1Guidelinesonclinicalevaluationofvaccines:regulatoryexpectations
• Unlessanefficacyisperformed,theclinicaldatabaseisdeterminedbythesafetydatabase
Remember:VaccineSafetyisParamountv Unlikedrugswhicharegiventosickpeople,vaccinesaregiventohealthypeople,soriskmustbeminimal
v Largenumbersofpeopleareexposedtovaccines,sorareandveryrareadverseeventscanbedetected
v Theacceptanceoftheriskofrareorveryrareadverseeventsishighestifthediseaseishighlyendemic,epidemicorcausesdisabilityandmortality
v Risk-benefitchangesovertimeasanefficaciousvaccinereducesthediseaserate
A higher safety standard is required for vaccines than for other medical interventions
CDPContent:Immunogenicity
v The ability of the vaccine to induce an immuneresponse (both at the serological and at the cellularlevel)isdefinedimmunogenicity
v The quantitative and qualitative assessment of thevaccine’s immunogenicity is a typical endpoint of avaccineclinicaltrial
v Immunogenicity endpoints are included at each stageofvaccineclinicaldevelopment(PhaseI-III)andmayormay not predict vaccine efficacy (immunologicalcorrelateofprotection)
CDPContent:Immunogenicityaspectstoconsiderfurther
v Primaryresponsev Persistenceofresponsev Boosterresponsev Memoryresponsev Consistencyofresponse
CDPContent:Immunogenicity� Immunogenicitysectionshouldincludedescription
� ofimmunologicalassayusedtoevaluatetheimmuneresponsetothestudyvaccine
� Casedefinitionofresponder(i.e.cutoffvalue,Xfoldincrease)
� Criteriausedtocomparetoothersimilarlicensedvaccines(ifthisisthecase)
� Strategytolinkimmunogenictytoefficacy(correlatesofprotection)incaseefficacyisrequired
� Otherexploratoryorsupportiveimmunologicalmeasurements(CMI,functionalassay)
VaccineImmunogenicityKeyfeaturesofagoodserologicassay
Agoodserologicassaymustbe:
Assayvalidationisabsolutelycritical!
CDPContent:Ethics
� ItshouldbedescribedhowICH-GCP,DoH,localethicalguidelineswillbecompliedwith
� CTAprocessandapproval� Deliveryofcaretostudyparticipantissue� IndividualConsent,assent,communityconsent� Countriespeculariaty:ethicalacceptabilititesofplaceboorcontrolvaccine
BeforeCTAs:thinkofsettingupascientificandethicalreviewbyrecognizedexperts(ScientificAdvisoryGroup-SAG?Scientificgroupofexperts?)
Ethics
ICandassentprocessinanadolescentsclinicaltrialinColombia-2010-
Ethics
DrJimenez,Bucaramanga,Colombia,explainingtheprocesstoparticipantsandtheirfamilies-Adolescentsclinicaltrial-
CDPcontent:CDPstrategy� Overalldescriptiononhowtoprovethatthevaccineissafeimmunogenic(orefficacious)
� Whetherdemonstrationofefficacyisneeded� Ifnotarationalehastobeexplained
� Correlateofprotectiondoexist(Pneumo,measles,rubella,hib,hepB,))
� Correlateofprotectiondonotexistbutcomparativelicensedvaccinedo(Meningo,Pertussis,
� Ifefficacydemonstrationisneededinwhichtargetpopulationandwhy
CDPContent:CDPstrategy� Indicatewhichstudieswillbeconsideredpivotal(non-inferiority,largesafety,longtermfollow-up,efficacyetcetc)todemonstratesafety,immunogenictyorefficacy
� Refertoexistingguidelines,scientificpublications,vaccinecandidateorsimilardatainthepublicdomain
� alwayscheckat:http://www.who.int/biologicals/vaccines/en/
ClinicalDevelopmentPlan� Foreachstudythefollowingwillbeaddressed:
� Objectiveofconductingthestudy� Studypopulation(agegroup,numberofevaluablesubjects)
� Studydesign,duration,studyvaccinedose� CriteriaforassessmentandGOorNOGOdecisionpoints
� Samplesize� 20-50smallnumberofsubjects
� Subjectscharacteristics� Healthyadultvolunteers
� Aims� Firstuseinhuman,closelymonitoredtrials� Clinicallaboratorydata� Excludefrequentandseriousadverseevents,andfirstinformationonreactogenicity(localandsystemic)
� Obtainpreliminaryinformationonimmunogenicity,forlivevaccineviralshedding,viremiaetc
� Formulation-finding,dose-finding
CDP:ClinicaltrialsdescripBon-PhaseI
CDP:ClinicaltrialsdescripBon-PhaseII� Samplesize
� Severalhundreds(appropriatesamplesize)
� Subjectscharacteristics
� Targetpopulation(agede-escalationapproach)� Stepwisetestingofadults,adolescents,children,infants(agede-
escalationapproach)� Includestudyparticipantsrepresentativeofthosetobetargetedin
phase3trials
� Aims� Formulation/dose/schedule-finding� Definitionofimmunoresponse,(type,quality,kineticsetc)� Definitionofsafetyprofile� Comparisonwithlicensedvaccines(non-inferiority),interference
withconcomitantvaccines(co-administration)� Typicallyrandomized&controlled� Determinedoseandscheduletobeusedinphase3
CDP:ClinicaltrialsdescripBon-PhaseIII� Samplesize
� Fromseveralhundredstothousands(appropriatesamplesize)
� Subjectscharacteristics� Targetpopulation
� Aims� Clinicalefficacy� Confirmationofsafety� Clinicaldemonstrationofproductionconsistency(lot-to-lot-)
� “Bridging”studies
PhaseIIIClinicalEfficacyTrials� Aimedtodefinevaccineinducedclinicalprotection(primaryendpointispreventionofdisease)
� Typicallydouble-blind,randomized,controlled� Backgroundepidemiologyessentialforsamplesizecalculation(maybeverylargetrials)
� Casedefinition� Well-definedclinicalcriteriaandvalidatedassaysforlaboratorydiagnosis(culture,serology,etc.)
� Clinicalrelevance� Casesurveillance
� Primaryandsecondaryendpoints� DataSafetyMonitoringCommittee
PhaseIIIClinicalTrials
� Routinevaccinesco-administrationstudies� Obtainsafetyandimmunogenicitydatainpre-licensurestudiestosupportsimultaneousadministrationofroutinevaccines
� Bridgingstudies� Supportmanufacturingchanges� Extrapolateefficacyandsafetydatatoadifferentpopulation
� Supportanewdoseoranewschedule� Clinicallotconsistencystudies
� Supportphysicochemicalassessmentofmanufacturingconsistency
RouBnevaccinesco-administraBonstudies(1)Potentialissues
� Safety:potentialforadditiveorsynergisticeffects� Immunogenicity:potentialforinterferencefrommultiplelive
orinactivatedvaccines� Similarconjugatecarriers(e.g.,diphtheriaandtetanustoxoids)
inmultipleproducts:� Potentialforproteincarriersuppression� Exuberantresponsestocarrier
� Uncertaintyaboutnovelproducts,e.g.,livevirusorbacterialvectors;noveladjuvants
� Co-administrationstudiesareneededforalabelclaim-indication-ofimmunenon-interferenceandsafety
Surprises
Vaccinesco-administraBonstudiesEnhancedimmuneresponseresponseduetoconcomitantadministraBon
Vaccinesco-administraBonstudiesDiminishedresponseduetoHibco-formulatedwithothervaccines
Co-administraBonstudy
ClarkeE.etal.Safetyandimmunogenicityofinactivatedpoliovirusvaccinewhengivenwithmeasles-rubellacombinedvaccineandyellowfevervaccineandwhengivenviadifferentadministrationroutes:aphase4,randomised,non-inferioritytrialinTheGambia.LancetGlobalHealth2016Jun27.
Bridgingstudies(1)� Bridgingstudiesarecommonlyperformedinvaccineclinicalresearch
to define acceptability of the safety and immunogenicity of a newvaccine/immunization regimen, based on comparison with previousonesalreadyacceptedbyaregulatoryagency
� Bridgingstudiesmayevaluate:� Effectofmanufacturingchange� Effectofformulationchange� Effectofdose/schedulechange� Effectofothervaccinesgivenconcomitantly
� Populationbridgingstudiesareaspecialtypeofbridgingstudieswhichareaimedtoevaluatethepossibilitytoextrapolateaneffectobservedinonepopulation(e.g.,clinicalefficacy)tootherpopulations
� Giventhatevaluationofclinicalefficacyindifferentpopulationsmaybeunpracticalorevenimpossible,thecomparisonofimmuneresponsesisthefundamentalobjectiveofthesetrials
Bridgingstudies(2)� Bridgingstudiesaregenerallyrandomizedandwellpowerednoninferioritystudies
� They are designed to rule out clinically importantdifferencesinparametersofimmuneresponse(i.e.,notlessimmunogenicthanthecontrolvaccine)orinparametersofsafety (i.e.,notmore reactogenic than the control vaccine)suchas:
� Ratio of geometricmean concentration of post immunizationantibodies
� Per cent “responders” (immune response above a certainthreshold)
� Rateofseriousadverseevents
Clinicallotconsistencystudies� Unlikedrugs,whicharechemicalcompoundsandthereforethevarious
lots of the same substance induce the same pharmacological effect,vaccines are biological substances and may induce variable biologicalresponses
� Therefore these peculiar vaccine studies, which are aimed to evaluate
the reproducibility of response (both safety and immunogenicity)inducedbydifferentproductionlotsofthesamevaccine,areanecessarypre-requisiteforvaccineregistration
� Clinical non-inferior immunogenicity amongst three consecutiveproductionlot(finalscale,finalformulation)needtobeproduced(USAFDA)
TorresiJetal.Lot-to-lotconsistencyofatetravalentdenguevaccineinhealthyadusltsinAustralia:Arandomizedstudy.Vaccine.2015Sep22;33(39):5127-34
CDPforavaccineagainstmeningiBsprequalifiedbyWHO.IndicaBon:oneinjecBonattheage1-29years
Study Phase Total Subjects
VAC vaccine
Control/ Reference
vaccine age-
group Study Design
VAC-001 I 60 20 40 18-35 y Safety and immunogenicity of one dose -10 µg of VAC vaccine in healthy adult volunteer.
VAC-002 II 600 200 400 12-23 mo
Safety and immunogenicity of one dose of VAC vaccine in comparison to a control (Hib vaccine) or
to MenPsACYW vaccine VAC-002
B* III 600 200 400 24-35 mo
Safety and immunogenicity of one booster dose of either PsA (memory) or VAC or Hib vaccine in
subjects included in VAC-002
VAC-003 II 700 350 350 2-29 y Safety and immunogenicity of one dose of VAC in
comparison to MenPsACYW vaccine (non inferiority).
VAC-004 III 520 390 130 2-5 y Safety and immunogenicity of one dose of 3
consecutive production lots of VAC vaccine (lot-to-lot consistency). For safety comparison
MenPsACYW vaccine group. VAC-005 And
VAC-006 III 4.500 2.250 2.250 1-29 y
Safety of one dose of VAC vaccine and immunogenicity in a subset of subjects, in 1-29
years old in comparison to MenPsACYW vaccine.
Total 6.980 3.410 3.570
Jan Jun Jan Jun Jan Jun Jan Jun Jan Jun Jan Jun Jan Jun Jan Jun Jan Jun Jan Jun 2008 2009 2010 2011 2012 2013 20124 2015 2016 2017
Safety Immunogenicity Immune Persistence
Carriage
Safety Immunogenicity
Memory Immune Persistence
Phase II/III 2-29 yr-olds
Phase II 12-23 month-olds
Phase II/III 2-10 year-olds
Phase I 18-35 year-olds
Phase III 5-10 yr-olds
Lot to Lot Consistency
Ongoing Scheduled
Phase III 2-29 year-olds
Safety
Safety Immunogenicity
Immune Persistence
CTDCTDsubmissiontoNRAandWHO
ExpectedlicensureandWHOPQ
ClinicalDevelopmentPlan–VAC-
CDPGO/NOGOdecisionpoints� ResultswilldetermineanddefineGo/NOGOdecisionpoints:
� PhaseI� PhaseII� PhaseIII
FinallytheReferenceList� 1.GreenwoodB.MansonLecture.MeningococcalmeningiBsinAfrica[publishedversion&manuscriptversioninfile].TransRSocTropMed
Hyg1999;93:341-53.� 2.JodarL,LaForceFM,CeccariniC,AguadoT,andGranoffDM.MeningococcalconjugatevaccineforAfrica:amodelfordevelopmentofnew
vaccinesforthepoorestcountries.Lancet2003;361:1902-4.� 3.WHO.Meningococcalvaccines:polysaccharideandpolysaccharideconjugatevaccines.WklyEpidemiolRec2002;77:331-9.� 4.DintzisRZ.RaBonaldesignofconjugatevaccines.PediatrRes1992;32:376-85.� 5.DonnellyJandLiuM.Immunobiologyofproteincarriers.In:EllisRWGDMed.NewYork:1994:71-90.� 6.KniskernPJandMarburgS.ConjugaBon:Design,chemistry,andanalysis.In:EllisRWGDMed.NewYork:1994:37-69.� 7.BlackS,ShinefieldHR,FiremanBetal.Efficacy,safetyandimmunogenicityofheptavalentpneumococcalconjugatevaccineinchildren.
PediatrInfectDisJ2000;19:18795.� 8.BorrowR,GoldblalD,AndrewsNetal.AnBbodypersistenceandimmunologicalmemoryatage4yearsamermeningococcalgroupC
conjugatevaccinaBoninchildrenintheUnitedkingdom.JInfectDis2002;186:1353-7.� 9.KeyserlingH,PapaT,KoranyiKetal.Safety,immunogenicity,andimmunememoryofanovelmeningococcal(groupsA,C,Y,andW-135)
polysaccharidediphtheriatoxoidconjugatevaccine(MCV-4)inhealthyadolescents.ArchPediatrAdolescMed2005;159:907-13.� 10.AdegbolaRA,SeckaO,LahaiGetal.EliminaBonofHaemophilusinfluenzaetypeb(Hib)diseasefromTheGambiaamertheintroducBonof
rouBneimmunisaBonwithaHibconjugatevaccine:aprospecBvestudy.Lancet2005;366:144-50.� 11.CDC-MMWR.ProgresstowardeliminaBonofHaemophilusinfluenzaetypebdiseaseamonginfantsandchildren--UnitedStates,
1987-1995.MMWRMorbMortalWklyRep1996;45:901-6.� 12.PeltolaH.WorldwideHaemophilusinfluenzaetypebdiseaseatthebeginningofthe21stcentury:globalanalysisofthediseaseburden25
yearsamertheuseofthepolysaccharidevaccineandadecadeamertheadventofconjugates.ClinMicrobiolRev2000;13:302-17.� 13.TrolerCL,AndrewsNJ,KaczmarskiEB,MillerE,andRamsayME.EffecBvenessofmeningococcalserogroupCconjugatevaccine4years
amerintroducBon.Lancet2004;364:365-7.
CDPlan:thinkaheadandintegratewithothercompanyfuncBons� Overallplanningandcoordination:
� Productcharacterization&manufacturing(cGMP)
� Anticipateneedsoffuturetrials,e.g.,criticalassays
� Accumulatesufficientsafety,immunogenicity&efficacydataduringdevelopment
� Clinicalbridgingstudies,e.g.,population;productscale-up
� ContinuosandProspectiveapplicationofGoodClinicalPractices
ThankYou
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