safety of menafrivac - who · number of saes per study all studies - all vaccine groups - 11443...

SafetyofMenAfrivac<monitoring,challengesandlessons>

GodwinEnwereTheMeningi/sVaccineProjectClosureConference

AddisAbaba,22-26February,2016

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Research,Design/NonClinicalDevelopment

EarlyClinicalDevelopment

Fullclinicaldevelopment

RegulatorySubmission/VaccineLaunch

Scale-up/LargeVaccineIntroduc/on

Vaccinesafety:alifecycleapproach

Con$nuousdatacollec$ontoassess,classifyandminimiserisks

Riskassessmentpost-licensure

>Millionofsubjects

Riskmanagementplan

ICHE2E

RiskIden/fica/on,Preven/onandManagement

Riskassessmentpre-licensure

<10,000subjects

ICHE6

DataandSafetyMonitoringBoard(DSMB)

GlobalAdvisoryCommiWeeonVaccineSafety(GACVS)

Na/onalExpertsCommiWees(NECs)

PharmacovigilanceisdefinedbyWHOas“thescienceandac/vi/esrelatedtothedetec/on,assessment,understandingandpreven/onofadversedrugeffectsoranyotherpossibledrug-relatedproblems”(WHO,2002)

Applica6onofVaccineSafetylifecycleapproachtoMenaAfriVac

•  Safetydatabasepre-licensure–morethan11000subjects(≈2700infants)

•  Ac/vesafetysurveillance–‘solicited’•  DSMB–monitoredallsafetydata•  GACVS–Reviewedthesafetydatapre/postlicensure(advised

phasedintroduc/onandissueofpregnancy)•  RiskManagementPlandevelopedbeforelicensure•  NECestablishedinallcountries–reviewedAEFIdataand

assignedcausality•  Phasedintroduc/onofvaccineacrossthebeltregion•  Safetystudydoneacerimplementa/onofCTC

Method during Clinical Trials

•  Immediateobserva/onfor30to60minutesfollowingvaccina/on•  Dailyfollowupfor4to7daysforpost-immuniza/on

reac/ons•  AdverseEventmonitoredfor28daysfollowingvaccina/on•  SAEmonitoredthroughoutdura/onofstudy

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Methods for AEFI monitoring 5

Surveillance Methods Country

Passivesurveillance -Repor/ngofallAEFI:10daysofcampaign+42daysthereacer(lateoccurringevents)

All

Ac/vesurveillance:RecommendedbytheGACVStoimprovemonitoringforspecificsymptoms(12easilyrecognizableAEFI)

-  Useofjobaidswithsimplifiedcasedefini/ons

-  Effortstosimplifyrepor/ngforms-  WeeklyvisitsHPbydesignatedsupervisors-  Retrospec/veregistryreviewofoutcomes

ofinterestincommunityclinics(PaWernsofclinicaldiagnoses,backgroundrates)

-  Vaccina/onstatusrecorded

-  2010masscampaigninBurkinaFaso

-  2010campaigninMali

Mostintensiveac/vesurveillancestudy

-  250,000pop,invaccinateddistrict(indicatedagerange)underac/vesurveillance

-  Pre-specifiedoutcomesiden/fiedac/velythroughclinicregisters

-  Clinicvisitforanyreasonwasrecordedbyindependentteam

-  Vaccina/onstatusrecorded

-  2011campaigninMali

Safety summary results from clinical trials (within 28 days)

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•  Thelocalandsystemicreac/ons,andtheadverseeventswereequallydistributedbetweenPsA-TTandComparatorvaccines

•  Theyweretransientandresolvedwithoutsequalae

Number of SAEs per study

All studies - all vaccine groups - 11443 subjects

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0 16 5 6

408

11 50 42

538

PsA-TT-001 PsA-TT-002 PsA-TT-003 PsA-TT-003a PsA-TT-004 PsA-TT-005 PsA-TT-006 PsA-TT-007 Total

Number of SAEs per study

•  538SAEsreportedfromeightstudies,Ø  Twoseriousreac6onsreported:OneFacialOedema,OneSimpleFebrileConvulsion–

bothwereamongPsA-TTrecipients•  SAEswereequallydistributedwithinstudyandreferencevaccinegroupsinallcompleted

studies•  Theinves6gators&theDSMBassessedallSAEsasunrelatedtothestudyvaccinesexceptfortheabovetworeac6ons

Serious Adverse Events All studies - all vaccine groups

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0.6% 0.2% 0.2% 0.2% 0.2% 0.2% 0.4% 0.6% 0.4% 1.1% 0.4% 1.5%

4.5% 3.9%

85.9% 0.0%

Respiratory, thoracic and mediastinal disorders

Hepatobiliary dosorders

Renal and urinary disorders

Neoplasms benign, malignant and unspecified

Ear and labyrinth disorders

Congenital, familial and genetic disorders

Vascular disorders

Pregnancy, puerperium and perinatal conditions

Nervous system disorders

Metabolism and nutritional disorders

General disorder and administrations site condition

Gastrointestinal Disorders

Blood and lymphatic system disorders

Injury, poisoning and procedural complications

Infections and infestations

SAEs by Primary System Organ Class Term

Deaths (SAEs) in Clinical Trials

All studies - all vaccine groups

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•  GlobalAdvisoryCommiHeeonVaccineSafety(GACVS)–  Availabledatadonotindicateanyspecialcauseforconcern–  Postmarke/ngsurveillanceneededtoassessthesafetyprofileofthevaccine–  Establishmentofproac/vepharmacovigilance,withariskmanagement

programmethatincludessafetyevalua/onduringaphasedroll-out,shouldthereforebeanessen/alcomponentofintroduc/onplans1

–  Sincethevaccinewillsoonbeusedinmasscampaigns,theCommiWeereiterateditspreviousadvicethat,wherepossible,phasedintroduc6onofthevaccinewouldbedesirablesothataddi/onalsafetydatamaybeaccumulatedthroughcarefulpostmarke/ngsurveillance2

1.GlobalAdvisoryCommiWeeonVaccineSafety,3–4December2009.WklyEpidemiolRec2010;85:29-362.GlobalAdvisoryCommiWeeonVaccineSafety,16–17June2010.WklyEpidemiolRec2010;85:285-292

MenAfriVacIntroduc/onGACVSPosi$on&Recommenda$ons

AEFI Reported by country -2010-2013

Country

Yearvaccina6on

Vaccinated

(N)

AEFIreported

Total(n) Mild(n) Serious(n) Ratesserious

BurkinaFaso 2010 11,421,502 1,890 1,857 33 0.28

Mali 2010,2011 11,109,484 573 538 35 0.31

Niger 2010,2011 10,575,365 534 486 48 0.45

Chad 2011,2012 8,724,890 3,703 3,657 46 0.52

Cameroon 2011,2012 6,108,772 836 817 19 0.31

Nigeria 2011,2012,2013 51,745,045 15,209 15,137 72 0.13

Ghana 2012 3,038,393 555 555 0 0

Benin 2012 2,718,459 177 173 4 0.14

Senegal 2012 4,216,691 160 151 9 0.21

Sudan 2012,2013 23,586,086 704 670 34 0.14

Gambia 2013 1,229,509 8 8 0 0

Ethiopia 2013 18,625,074 492 349 143 0.76

Total 2010to2013 153,099,270 24,841 24,398 443 0.29

Reported AEFI- Active Search in District of Ziniare 12

Ratesofhealthproblems

Ac/vesearch–2010(N=107,493vaccinated)

Baselinedata–2009(N=97,715surveyed)

12syndroms n Rate 95%CI n Rate 95%CI

Convulsions 32 29.76 19.44-40.07 26 26.60 16.37-36.82

Ur/caria 18 16.74 9.00-24.47 21 21.49 12.29-30.68

Bronchospasm 14 13.02 6.19-19.84 16 16.37 8.34-24.39

Meningi/ssyndrom 3 2.79 -0.36to+5.94 3 3.07 -0.40to+6.54

Localabsces 1 0.93 -0.89to+2.75 0 0.0 0

Hypotonia 2 1.86 -0.71to+4.43 0 0.0 0

Toxidermia 0 0.0 0 1 1.02 -0.98to+3.02

Flaccidparalysis 0 0.0 0 1 1.02 -0.98to+3.02

Laryngealedema 1 0.93 -0.89to+2.75 0 0.0 0

Encephalomyeli/s 0 0.0 0 0 0.0 0

Purpura 0 0.0 0 0 0.0 0

Anaphylac/cshock 0 0.0 0 0 0.0 0

Total 71 66.05 50.68-81.41 68 69.59 53.04-86.13

ComparisonofBirthOutcomebetweenVaccinatedPregnantWomenandControls

Waketal2015.CID:61(suppl),pg-S489

Outcome GroupAcohort(n=1730)

GroupARate/100

Controlcohort

ControlRate/100

IRR 95%CI P-value

CONCURRENTCONTROLS(n=921)

Miscarriage 16 0.9 6 0.7 1.06 0.65-1.74 0.82

Still Birth 22 1.3 14 1.5 0.95 0.62-1.46 0.80

Prematurity 62 3.6 29 3.1 1.0 0.81-1.34 0.76

NeonatalMortality 12 0.7 9 1.0 0.88 0.50-1.54 0.65

HISTORICALCONTROLS(n=3551)

Miscarriage 16 0.9 36 1.0 0.94 0.58-1.54 0.80

Still Birth 22 1.3 47 1.3 0.97 0.64-1.48 0.89

Prematurity 62 3.6 197 5.6 0.72 0.56-0.93 0.011

NeonatalMortality 12 0.7 42 1.2 0.68 0.38-1.19 0.179

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MenAfrivacisaverysafevaccine

eveninpregnancy

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Challenges-CT

•  Needforuniformityofprocedureacrosstrialsites•  Timelyrepor/ng

•  Variousrepor/ngrequirementforvariousERCandRegulatorybodies

•  HealthSystemsinthedifferentstudysites•  Seasonaldiseases

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Challenges-Introduc6on•  Understandinglocalclinicalstandards:setupsensi/vedetec/onofAEFIs•  Knowingbackgroundratesofcondi/onsofinterest•  Documenta/onofvaccina/onstatus•  Programma/c:

–  Lackofsufficientresourcesforplanningandimplementa/on–  Collabora/on:EPI,PHC,NRA–  UseofPsA-TTamongpregnantandlacta/ngwomen–  MassivehysteriainGouro/Chad

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Lessons ClinicalTrials•  Importanceofrobustvaccinedevelopmentplan•  Valueoftrainingandretraining•  Strictmonitoringprocedureanddocumenta/on•  Con/nuouscommunica/onwithallstakeholdersVaccineIntroduc6on•  Geographicallyseparatecomparisongroupsareocenpoorcontrols•  Valueofproperplanning(earlyandadequate)•  AdequatePVrequiresresources–human,financialandmaterials•  Volumeofdatageneratedcanbelarge

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Looking to the futureSinceriskIden6fica6on,preven6onandmanagementisacon6nuum,•  HowdoweensurethatthePharmacovigilancestructurestrengthened

duringtheintroduc/onofMenAfriVacissustainedandusedtomonitorothernewvaccines?

•  Howdoweensure/melyandsufficientresourcestostrengthenNRAs

capaci/estosupportPVformasscampaignsandRou/neImmuniza/on•  HowdowesustainAEFImonitoringtobeabletoiden/fydelayedevents?•  Howdowefurtherrefinepharmacovigilancetoolstoimprovedetec/onand

documenta/onofAEFI?

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Ourapprecia6ontoeveryonethat

joinedeffortstomakeourworldfreefromepidemicmeningi6s

19/20