safety of menafrivac - who · number of saes per study all studies - all vaccine groups - 11443...
TRANSCRIPT
SafetyofMenAfrivac<monitoring,challengesandlessons>
GodwinEnwereTheMeningi/sVaccineProjectClosureConference
AddisAbaba,22-26February,2016
2
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
4
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)
6
• Thelocalandsystemicreac/ons,andtheadverseeventswereequallydistributedbetweenPsA-TTandComparatorvaccines
• Theyweretransientandresolvedwithoutsequalae
Number of SAEs per study
All studies - all vaccine groups - 11443 subjects
7
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
8
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
9
• 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
13
MenAfrivacisaverysafevaccine
eveninpregnancy
14
Challenges-CT
• Needforuniformityofprocedureacrosstrialsites• Timelyrepor/ng
• Variousrepor/ngrequirementforvariousERCandRegulatorybodies
• HealthSystemsinthedifferentstudysites• Seasonaldiseases
15
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
16
Lessons ClinicalTrials• Importanceofrobustvaccinedevelopmentplan• Valueoftrainingandretraining• Strictmonitoringprocedureanddocumenta/on• Con/nuouscommunica/onwithallstakeholdersVaccineIntroduc6on• Geographicallyseparatecomparisongroupsareocenpoorcontrols• Valueofproperplanning(earlyandadequate)• AdequatePVrequiresresources–human,financialandmaterials• Volumeofdatageneratedcanbelarge
17
Looking to the futureSinceriskIden6fica6on,preven6onandmanagementisacon6nuum,• HowdoweensurethatthePharmacovigilancestructurestrengthened
duringtheintroduc/onofMenAfriVacissustainedandusedtomonitorothernewvaccines?
• Howdoweensure/melyandsufficientresourcestostrengthenNRAs
capaci/estosupportPVformasscampaignsandRou/neImmuniza/on• HowdowesustainAEFImonitoringtobeabletoiden/fydelayedevents?• Howdowefurtherrefinepharmacovigilancetoolstoimprovedetec/onand
documenta/onofAEFI?
18
Ourapprecia6ontoeveryonethat
joinedeffortstomakeourworldfreefromepidemicmeningi6s
19/20