PHARCOVIGILANCE

Regarding the Pharmacovigilance safety monitoring in clinical trails

1. Pharmacovigilance safety monitoring in clinical
trials

2. •Pharmacovigilance(PV)isthepharmacological
sciencerelatingtothedetection,assessment
,understandingandpreventionofadverseeffects,
particularlylongtermandshorttermsideeffect
ofmedicines.
•Allmedicines(pharmaceuticalandvaccines)have
sideeffectsomeareknownmanyarestill
unknowneventhismedicinehasbeeninclinical
use.
•Theimportanceistomonitorbothknownand
unknownsideeffectsofmedicinesinorderto
determineanynewinformationinrelationto
theirsafetyprofile.

3. •Theclinicaltrialprocessisregulatedbythe
specificregulatoryguidelines(e.gICHGCP,USFDA
guidelinesetc).
•Pharmacovigilancelooksatallavailable
informationtoassessthesafetyprofileofadrug
•Pharmacovigilanceshouldalsotakethebenefitof
thedruginaccount.
•Spontaneousreportingdependsonthehealth
professional.
•Pharmacovigilanceworksby
–ADRSharing
–SuspicionReporting
–AnalysisofFindings

4. AimAndObjectivesofPharmacovigilance
Improvepatientcareandsafety.
Improvepublichealthandsafety.
Encouragesafe,rationalandappropriateuseofdrugs.
Promoteunderstanding,educationandclinicaltraining
inPharmacovigilance.
Toidentifyingnewinformationabouthazardsas
associatedwithmedicines.

5. Adverse Drug Reactions
•ADRisnoxious,unintendedandwhichoccursa
responseatdosesnormallyusedinhumansfor
Prophylaxis,DiagnosisorTherapyofdisease,orfor
modificationofphysiologicalfunction…..(WHO1972)
•TypeA(Augmented)ADR
•TypeB(Bizarre)ADR
•Seriousadversereaction.
•Unexpectedadversereaction.
•DataAnalysisResponse
•Sideeffect
–Anyunintendedeffectofapharmaceuticalproduct
occurringatnormaldosagewhichisrelatedtothe
pharmacologicalpropertiesofthedrug.e.g.antihistamines
producingsedation,anticholinergicsproducingdryness.

6. •IndiaisahubofGlobalClinicaltrials&adestinationfor
DrugDiscovery&Development.
•However,whetherpatientsinIndiareceivesafedrugsor
notisstillverymuchinquestionRapidinductionofNCEs
andhightechPharmaproductsinthemarketthrowupthe
ChallengesofmonitoringAdverseDrugReactions(ADRs)
overlargemultiethnicpopulationbase.
•WhoShouldReportSafetyData
–Physicians
–Pharmacists
–Pharmaceuticalcompaniesqualifiedpersons–
(Pharmacovigilance/Regulatorymanager)
–Investigationalproducts(clinicaltrials)
–Post-approvalreporting–IndividualCaseSafetyReport(ICSR),
PeriodicSafetyUpdateReport(PSUR)
–Inmanycountriespatientsareencouraged(butnotobligated)
toreportsideeffects

7. •WhattoReport?
–ItisimportanttoreportseriousunexpectedADRs.
–MostcasesofunexpectedADRsareassociatedwithmedicinesnewly
introducedonthemarket.
–Allsuspectedadversereactions.
–Everysingleproblemrelatedtotheuseofadrug.
–ADRsassociatedwithradiologycontrastmedia,vaccines,diagnostics,drugs
usedintraditionalmedicine,herbalremedies,cosmetics,medicaldevices
andequipment.
•ImportanceofPharmacovigilance
–Completesafetydata(especiallyforunexpectedandseriousadverseevents)
canonlybecapturedthroughPharmacovigilance.
–Itcannotbecapturedthroughclinicaltrialswhichareconductedinan
“artificialenvironment.”
•Inclinicaltrials
–patientsarenottakinganyothermedications
–donothaveconcomitantdiseases
–aretakingthedrugshort-term(duringthedurationofthetrialsonly)and
–arenotpartofvulnerablegroups(e.g.,children,pregnantwomen,elderly,
etc.)

8. Partners in Pharmacovigilance
•TheWHOQualityAssuranceandSafety:Medicinesteam
•TheUppsalaMonitoringCentre(UMC)
•TheNationalPharmacovigilanceCenters
•HospitalsAndAcademia
•HealthProfessionals
•Patients
•OtherPartners
–SystemofSafetyDataGathering
–ClinicalTrialsHealthcareProfessionals
–Pre-ApprovalPost-ApprovalPatients
–NationalRegulatoryAuthorityPharmaceuticalCompanies
–InternationalSafetyDatabases

9. Pharmacovigilance in drug regulation
•ClinicalTrialRegulation
–CollectionofADR
–Monitoringclinicaldata
–Reportingofclinicaldata
•PostMarketingsafetyMonitoring
•RaPID:TheRaPIDisaPVprogramwhichconduct
publichealthprogram.
–Itprovidesupporttofocalpoint.
–FocusonRaPIDHIV,T.B,Malariaandotherprogram.
–ItisimportanttoencourageandensurereportingofADR.
–Itconsistofvariousdepartmentforworkingvarioustype
ofdiseases

10. •Clinicaltrialsprovidetheevidentiarybasisfor
regulatoryapprovalsofsafeandeffective
medicines.
•Withlongdevelopmentcyclesandever-
increasingcostsinconductingclinicaltrials,both
thepharmaceuticalindustryandregulatorsare
makingeffortstobemoreproactiveinsafety
evaluations.
•Earlysafetysignaldetectionnotonlyleadsto
betterpatientprotection,butalsohasthe
potentialtosavedevelopmentcosts.

11. •Sinceclinicaltrialsareexperimentsinhumans,
theymustbeconductedfollowingestablished
standardsinordertoprotecttherights,safety
andwell-beingoftheparticipants.
•Thesestandardsinclude
–InternationalConferenceonHarmonizationGood
ClinicalPractice(ICH-GCP)Guidelines.
–InternationalEthicalGuidelinesforBiomedical
ResearchInvolvingHumanSubjectsissuedbythe
CouncilforInternationalOrganizationsofMedical
Sciences.
–TheethicalprinciplessetforthintheDeclarationof
Helsinki.

12. Common Practice in Safety Monitoring
•Stakeholders in Safety Monitoring
•CommunicatingSafetyInformationamongStakeholders
•StatisticalMethodsinSafetyMonitoring
–MethodsforSingleArmTrials
–MethodsforRandomized,ControlledTrials
–HypotheticalClinicalTrial
Stakeholder
sponsors
regulators
Publicand
private
entities
Participants
investigators
IRB/
IECs
Monitors

13. Basic Framework for Pharmacovigilance During Clinical Trials
Collection of safety
data from clinical trial
Safety data
processing
Evaluation of
collected data
Analysis for benefit-
risk balance in a
product
Information from
already known safety
risks

14. •Components of Pharmacovigilance
Components of
Pharmacovigilance
Reporting
Recording
Managing

15. Basic Framework for Pharmacovigilance During Clinical Trials
•Sponsor’sresponsibilitiesinPharmacovigilance
•Reporting
•Protocolinclinicaltrials
•GuidanceinprotocolforPharmacovigilanceandsafetyreporting
•RoleofCRFinPharmacovigilanceclinicaltrial
•RoleofIBinPharmacovigilanceclinicaltrial
•Safetyupdatereports
•Toprovidethesummaryoftheunderstandingandmanagement
•Investigator’sresponsibilityinPharmacovigilance
•ResponsibilityofIEC/IRBinPharmacovigilance
•Managementofcasesafetyreportsduringclinicaltrials
•Riskassessmentduringclinicaltrial
•Benefitsofriskassessment
•Handlingofmedicationerrorduringclinicaltrial

16. Sponsor’s responsibilities in Pharmacovigilance:
•UseandadoptPharmacovigilanceprocedure(s)tomonitoradverse
reactionsoccurringinclinicaltrials.
•Modificationsinprotocolduetosafetyorefficacyconcerns(e.g.,dosage
changes,changesinstudyinclusioncriteria,intensificationofmonitoring);
•Restrictionsinstudypopulationorindications;
•Changestotheinformedconsentdocumentrelatingtosafetyissues;
•Formulationchangesforsafetyreasons;
•Additionofaspecialreportingrequirement;
•Issuanceofacommunicationtoinvestigatorsorhealthcareprofessionals;
•plansfornewsafetytrials;
•Ongoingsafetyevaluationoftheinvestigationalmedicinalproducts;
•Immediatenotificationoffindingfromtheclinicaltrialsthatcould
adverselyaffectthehealthofsubjects;
•Preparationofvariousessentialdocumentsvizprotocol,investigator
brochure,casereportforms(CRF).
•ReportingofADRsinClinicalTrial

17. Protocol in clinical trial
•ICHE6definesprotocolas“adocumentthat
describestheobjective(s),design,
methodology,statisticalconsiderations,and
organizationofatrial.
•Theprotocolusuallyalsogivesthebackground
andrationaleforthetrial,butthesecouldbe
providedinotherprotocolreferenced
documents.”

18. Guidance in protocol for Pharmacovigilance and safety reporting
•AdefinitionoftheexpectedandunexpectedAE
•Specificationsofthesafetyparameterstobe
studiedalongwithmethodsandtimingsfor
recordingandanalyzing.
•Standardsforexpeditedreportingwithreporting
timeframes.
•DeclarationfromthePIthathewillaskthestudy
subjectsduringeachscheduledorunscheduled
visitaboutexperienceofanyeventsor
hospitalizations,disabilityorincapacitysince
theirpreviousvisit.

19. Role of CRF in Pharmacovigilance clinical trial
•ACRFis“aprinted,optical,orelectronicdocument
designedtorecordalloftheprotocolrequired
informationtobereportedtothesponsoroneachtrial
subject”
•DuringtheclinicaltrialprocessallAEsreportedare
recordedunlessotherwisespecifiedintheprotocol.
•Forroutinedatacollectionstudyprotocolsclearlydefine
howAEswillbeidentified,managed,reportedand
recordedintheCRF.
•FromthePharmacovigilanceperspectivenonserious
adverseeventsarealsorecordedandreportediftheir
occurrenceisimportanttosafetymonitoringinaclinical
trial.

20. Role of IB (Investigators Brochure) in Pharmacovigilance clinical trial
•Providestheinformationtotheinvestigatorsthat
facilitatetheirunderstandingoftherationalefor
dosage,dosagefrequency/interval,drugadministration
methodsetc.
•Providesproceduresforsafetymonitoring.
•IBactsasanimportantsourcedocumenttodefinethe
‘expectedness’and‘unexpectedness’oftheADR
•IBservesasthesourcedocumentforamedicinal
productinacountrywhereitisnotyetapprovedfor
marketing.
•AsperICHGCP‘InvestigatorsBrochure’(IB)isa
compilationoftheclinicalandnonclinicaldataonthe
investigationalproduct(s)thatarerelevanttothestudy
oftheproduct(s)inhumansubjects’.

21. Safety update reports
•DevelopmentSafetyUpdateReport(DSUR)should
serveasa“stand-alone”documentsuitablefor
submissiontoethicscommitteesandother
stakeholders,ifrequiredbylocalregulations.
•Theprimaryfocusshouldbeontheinvestigational
drug(s)andinformationoncomparatorsisprovided
onlywhererelevanttothesafetyoftrialsubjects.
•SURspresentsafetyprofileofaninvestigationaldrug
andactionsproposed(vizearlyterminationofthe
trial,ongoingstatus,additionofanyextravisitfor
patientforevaluationofsafetyetc).
•ICHE2FguidelinesonDSURdescribeacommon
standardforannualclinicaltrialsafetyreporting
amongtheICHregionstoprovideassuranceof
protectionforclinicaltrialsubjects

22. ObjectivesofDSUR(developmentsafetyupdate
report)
•Toprovidethesummaryoftheunderstanding
andmanagementofidentifiedandpotential
risks.
•Toprovideanupdateonthestatusoftheclinical
investigation/developmentprogramme.
•Todescribenewsafetyissues.
•Toexaminewhethertheinformationobtainedby
thesponsorduringthereportingperiodisin
accordancewithpreviousknowledgeofthe
product’ssafety.

23. Investigator’s responsibility in Pharmacovigilance
•TheinvestigatorshallreportallSAEsimmediatelyto
thesponsorexceptforthosethattheprotocolorIB
identifiesasnotrequiringimmediatereporting.
•Forreporteddeathsofasubject,theinvestigator
shallsupplythesponsorandtheEthicsCommittee
withanyadditionalinformationrequested.
•ThesponsorshallkeepdetailedrecordsofallAEs
reportedtohimbytheinvestigator.
•Inblindedclinicaltrials,Pharmacovigilanceroleof
investigatorgetsextendedtothemanagementof
blindedtherapycases.

24. Responsibility of IEC/IRB in Pharmacovigilance
•IRB/IECreviewstheessentialdocumentsviztrial
protocols/amendments,writteninformedconsent
forms(andconsentformupdates),IBandavailable
safetyinformationabouttheinvestigational
medicinalproduct.
•IRB/IECshouldbepromptlyreportedfor:
–bothseriousandunexpectedADRs;
–anychangesordeviationsintheprotocoltoeliminate
immediatehazardstothetrialsubjects;
–anychangescreatinganincreaseintheriskstosubjects
and/orchangesintheprotocolthatareaffectingthe
conductofthetrial
–anynewinformationthatmayadverselyaffectthesafety
ofsubjectsortheconductofthetrial.

25. Management of case safety reports during clinical trials
•SponsorhastomaintainadetailedrecordofallAEsthat
arereportedtohimbytheinvestigator.
•Adetailedanalysisfortheseriousness,causalityand
expectednesshastobeperformedbythesponsoronthe
individualcasesafetyreports(ICSRs).
•AllthecollectedAEsfromallthesites(multicentrictrial)
needtobeassessedsothatsponsorcanbroadlydepict
thenatureandoccurrenceoftheadverseeventfromthe
pooledanalysesofallparticipatingsites.
•Note:Causalityreportedbythesponsoronthe
investigationalmedicinalproductcannotbeoverruledby
sponsor.
•Insuchcircumstancessponsormaycomment(‘sponsors
section’oncommentsinADRreport)regardingthe
disagreement.Theopinionfrombothinvestigatorand
sponsorshouldbesubmittedwiththereport.

26. Risk assessment during clinical trial
•Ifaproductisintendedtobechronicallyusedand
/orhasdose-relatedtoxicities.
•Ifaproduct’sproposeddosingincludesaproposed
titrationscheme.
•WhenadrughasthepotentialforAEswhicharenot
likelytobedetectedorreportedbypatients.
•Ifaproductistobestudiedinpediatricpatients,
specialsafetyissuesshouldbeconsidered.
•Incircumstanceswhenearliersafetydatasignalan
unusualorimportantconcerntheninsuchcasesa
sponsormayconsiderreservingbloodsamplesfrom
someorallpatientsinphase3studies.

27. Handling of medication error during clinical trial
•Themedicationerrorscanbeminimizedby
assessing,priortomarketing,commonsources
ofmedicationerrors,whichmayariseduetothe
product’sinherentpropertiesorbecauseofthe
inadvertentcontributionoftheproposed
proprietaryname,theestablishedname,the
proposedlabelingandtheproposedpackaging.
•Medicationerrorsaredefinedasanyerrorinthe
prescribing,dispensing,oradministrationofa
drug,irrespectiveofwhethersucherrorsleadto
adverseconsequencesornot.

28. •Theseerrorscanoccuratanystageofthe
medicationuseprocess.
•Duringclinicaltrials,improperdilutionor
administrationtechniques,mayresultinnon-
optimaldosing.
•Theseshouldbecarefullyexaminedaswarning
signsthattheproductcouldbesubjecttodosing
errorsthatmaywarrantchangesinlabeling,
packaging,ordesign.

29. •Iferrorsarenotobservedintrials,thencareful
considerationshouldbegivenduring
developmenttotheimplicationsofthedesign
oftheproduct,itspackaging,andanydevice
usedtoadministerordelivertheproduct.
•Anyoccurrencesseenorconsideredduring
productdevelopmentshouldbedocumented,
reported,andanalyzedforpotentialremedial
actions