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