Pharmacovigilance methods

Active Surveillance, Passive Surveillance, Comparative observational methods, stimulated reporting, targeted clinical investigations

1. PHARMACOVIGILANCE
METHODS
Dr.Ramesh Bhandari
Asst. Professor
Department of Pharmacy Practice
KLE College of Pharmacy, Belagavi

2. PHARMACOVIGILANCE METHODS
1)PASSIVE SURVEILLANCE -SPONTANEOUS REPORTING,
CASE SERIES
2)ACTIVE SURVEILLANCE -SENTINEL SITES, DRUG
EVENT MONITORING, REGISTRIES
3)COMPARATIVE OBSERVATIONAL STUDIES–COHORT,
CASE-CONTROL, AND CROSS SECTIONAL STUDIES
4)STIMULATED REPORTING
5)TARGETED CLINICAL INVESTIGATIONS

3. PASSIVE SURVEILLANCE

4. PASSIVE SURVEILLANCE METHODS
1)SPONTANEOUS REPORTS
2)CASE SERIES
3)CASE REPORT

5. 1. SPONTANEOUS REPORTS
Voluntary reporting or Mandatory reporting
AnUnsolicitedreportsfromhealthcareprofessionalsor
consumerstoacompany,regulatoryauthorityorother
organizationthatdescribesoneormoreADRsinapatientwho
wasgivenoneormoremedicinalproductsiscalled
spontaneousreports.
Physicians,otherhealthcareprofessionals-providedwithforms
forfillingsuspectedADRdetails-oncefilled,theyarenotified
todrugregulatoryauthority.(eg:DCGIforIndia,USFDAfor
UnitedStatesofAmerica,TGA(TherapeuticandGoods
Administration)forAustralia)

6. 1. SPONTANEOUS REPORTS
Forms-aregeneratedbyregulatoryauthoritiesorby
organizationsunderaegisofregulatoryauthorities.
Forms-arecirculatedthroughwebsitesordistributedto
healthcareprofessionalsthroughtrainingprograms
conducted.

7. In INDIA-“ Suspected Adverse Drug Reaction Reporting Form” is used for spontaneous
reporting.( developed by CDSCO, working under the aegis of Directorate General of Health
Services), Government of India.
Suspected ADR reporting form
In UK-“ Yellow Card” is used for spontaneous reporting. Since 1964.
Yellow card-
Patient reporting form
Healthcare professional reporting form
In US-“ Med Watch” forms are used.
Form FDA 3500-Voluntary Reporting-for use by healthcare professionals, consumers and
patients.
Form FDA 3500 A-Mandatory Reporting: for use by manufacturers, distributors, importers
etc.
1. SPONTANEOUS REPORTS

8. Pharmaceuticalmanufacturersarelegallyrequiredtoreportserious
unlabeledadversereactionstotheFDAwithin15workingdaysof
learningofADRs.
Fieldrepresentativesandregulatorypersonnelofmanufacturersare
usuallythefirsttoidentifyreportableeventseventhoughhealthcare
professionalsareencouragedtoreportnewandunusualADRs.Thus
approximately80%ofspontaneousreportsonADRscometothe
FDAthroughdrugmanufacturers.
1. SPONTANEOUS REPORTS

9. Advantages:
Large scale and cost effective
Rare and unexpected adverse reactions are captured more quickly
than any other study designs
Generate hypothesis, signals and
Generate important information on risk groups, risk factors and
clinical features of known serious adverse drug reactions.
1. SPONTANEOUS REPORTS

10. Disadvantages:
Adverse event recognition –subjective
Under reporting
Incomplete reporting
Bias
1. SPONTANEOUS REPORTS

11. Collectionofcasereportsthatsharesomecommoncharacteristicssuchasbeingexposedtothe
samedrug;and,inwhichsameoutcomeisobserved.
Acaseseries,involvesreportsontwoormorepeoplewithcommonexposuretoadrug,ora
commonoutcome.
Seriesofcasereportscanprovideevidenceofanassociationbetweenadrugandanadverse
event.
Usedgenerallyforgeneratinganhypothesisthanforverifyinganassociationbetweendrug
exposureandoutcome.
2. CASE SERIES

12. ADVANTAGES:
Easy to write
Generate hypothesis
Observations are useful for other researchers.
DISADVANTAGES:
Chances of bias
Lack of comparison group.
2. CASE SERIES

13. Casereportsaredescriptionsofthehistoryofasinglepatientwhohasbeenexposedtoa
medicationandexperiencesaparticularandunexpectedeffect,whethertheeffectisbeneficial
orharmful.
Casereporthaveaprivilegedplace,becausetheycanbethefirstsignalofanadversedrug
event,orthefirstindicationfortheuseofadrugforconditionsnotpreviouslyapproved(off-
labelindications)
Example:Adverseevent(Phocomeliaassociatedwiththeuseofthalidomide)
3. CASE REPORT

14. ACTIVE SURVEILLANCE

15. ACTIVE SURVEILLANCE
Incontrasttopassive,activesurveillanceseekstoascertain
completelythenumberofadverseeventsviaacontinuous
pre-organizedprocess.
Forexample:Followupofpatientstreatedwitha
particulardrugthroughariskmanagementprogram.
Helpsinyieldingcomprehensivedataonindividualadverse
eventreports.

16. ACTIVE SURVEILLANCE
Someofthemethodstoyieldcomprehensivedatathrough
activesurveillanceare:
1)Sentinelsites
2)Drugeventmonitoring
3)Registries

17. 1. SENTINEL SITES
Activesurveillancecanbeachievedbyreviewingmedicalrecordsor
interviewingpatientsand/orphysiciansinasampleofsentinelsitesto
ensurecompleteandaccuratedataonreportedadverseeventsfrom
thesesites.
Theselectedsitescanprovideinformationsuchasdatafromspecific
patientsubgroupsthatwouldnotbeavailableinapassivespontaneous
reportingsystem.
Weaknessesofsentinelsites:selectionbias,smallnumberof
patients,increasedcosts.

18. Thisparticularsystemismoreefficientforthosedrugsused
mainlyininstitutionalsettingssuchashospitals,nursing
homes,hemodialysiscentersetc.whichcanprovidean
infrastructurefordedicatingreporting.
1. SENTINEL SITES

19. 2. DRUG EVENT MONITORING
Inthissystem,patientsarefirstidentifiedfromelectronic
prescriptiondataorautomatedhealthinsuranceclaims.
Afollowupquestionnairecanthenbesendtoeach
prescribingphysicianorpatientatpre-specifiedintervalsto
obtainoutcomeinformation.
Relevantinformationincludingdemographics,indicationfor
treatment,durationoftherapy,dosage,clinicalevents,and
reasonsforthediscontinuationoftherapycanbeincludedin
thequestionnaire.

20. Strengths:
•Detailed information on adverse events from a large number of
physicians and/or patients might be collected.
Limitations:
Poor physician and patient response rates
Unfocused nature of data collection
Maintenance of patient confidentiality may be a concern
2. DRUG EVENT MONITORING

22. 3. REGISTRIES
Aregistryisalistofpatientspresentingwithsame
characteristics.Thischaracteristiccanbeadisease(disease
registry)oraspecificdrugexposure(drugregistry).
Diseaseregistriessuchasregistriesforblooddyscriasis,
severecutaneousreaction,orcongenitalmalformationcan
helpcollectdataondrugexposureandotherassociated
factorswithaclinicalcondition.
Adiseaseregistrycanalsobeusedasabaseforacase-
controlstudycomparingthedrugexposureofcasesidentified
fromtheregistryandcontrolsselectedfromtheregistries
(withotherconditions)oroutsidetheregistries.

23. Drugregistriesaddresspopulationsexposedtodrugsof
interest(eg:registryofrheumatoidarthritispatientsexposed
tobiologicaltherapies)todetermineifthedrughasaspecial
impactonthisgroupofpatients.
Somedrugregistriesaddressdrugexposuresinspecific
populations,suchaspregnantwomen.
Patientscanbefollowedovertimeandincludedinacohort
studytocollectdataonadverseeventsusingstandardized
questionnaires.
3. REGISTRIES

24. Strengths:
Singlecohortstudiescanmeasureincidence
Usefulforsignalamplificationforrareoutcomes
Examiningsafetyofanorphandrugindicatedforspecific
condition
3. REGISTRIES

25. COMPARATIVE
OBSERVATIONAL STUDIES

26. 1.Cohortstudy
2.Case-Controlstudy
3.Crosssectionalstudy
COMPARATIVE OBSERVATIONAL STUDIES

27. FromLatin“Cohors”–Groupofsoldiers
Usedtodescribeagroupofindividualswithacommon
characteristicsorexperience.
Experiencemaybeexposuretomedicine,vaccine,procedure
orenvironmentaltoxin.
Inacohortstudy,apopulationatriskforthedisease(or
event)isfollowedovertimetodeterminetheincidenceofthe
disease(oranevent).
1. COHORT STUDY

28. AlsoknownasFollow-up,incidenceandlongitudinalstudies
Incohortstudies,participantsaregroupedbytheirexposure
andarefollowedovertimetostudythedifferencesintheir
outcome.
Informationonexposurestatusisknownthroughoutthe
follow-upperiodforeachpatient.
Sincethepopulationexposureduringfollow-upisknown,
incidenceratecanbecalculated.
1. COHORT STUDY

29. Population
Sample
Drug
Exposed
ADR
No ADR
Drug
Unexposed
ADR
No ADR
TimeOnset of Study
1. COHORT STUDY
Present
Future
= a
= b
= c
= d

30. Cohortstudyattemptstoestablisharelationshipbetween
anexposure/riskfactorandasubsequentoutcome.
Relativeriskisusedtodeterminethisrelationship.
Therelativerisk(RR)/riskratioistheriskofdeveloping
anadversereaction/eventinthoseparticipantsexposedto
aspecificdrugcomparedtothosenotexposedtothat
drug.
RR values can be greater, less than or equal to one.
RR= [a/(a +b)]/ [c/(c +d)]
1. COHORT STUDY

31. TypesofCohortstudies:
i.Prospective
ii.Retrospective
iii.Ambispective/Ambidirectional
1. COHORT STUDY

32. Cohortstudiesareusefulwhenthereisaneedtoknowtheincidence
ratesofadverseeventsinadditiontotherelativerisksoftheevents.
Multipleadverseeventscanalsobeinvestigatedusingthesamedata
sourceinacohortstudy
Howeveritcanbedifficulttorecruitsufficientnumberofpatientswho
areexposedtoadrugofinterest(suchasanorphandrug)ortostudy
veryrareoutcomes.
Likecasecontrolstudies,theidentificationofpatientsforcohortstudy
cancomefromlargeautomateddatabasesorfromdatacollected
specificallyforthestudyathand.
1. COHORT STUDY

33. Advantages
Incidenceratecanbecalculated
Cohortstudiesprovideadirectestimateofrelativerisk.
Canestablishtiminganddirectionalityofevents
Disadvantages
Ittakeslongtimetocompletethestudyandobtainresults
Comparativelyexpensive
Exposuremaybelinkedtohiddenconfounder
Forrarediseaselargesamplesizeorlongfollow-upisrequired
Certainadministrativeproblems:
Lackofexperiencedstaff
Lackoffunding
Extensiverecordkeeping
1. COHORT STUDY

34. Alsoknownascasereferent,casehistoryorretrospective
studies.
Typeofcomparativeobservationalstudythatisalternativeto
cohortstudies.
Seekstoretrospectivelyidentifypotentialriskfactorsof
diseaseoroutcomes.
2. CASE CONTROL STUDY

35. Agroupofpatientswithdiseaseoreventofinterest(cases)is
comparedwithagroupofindividualswithoutdiseaseorevent
ofinterest(controls).Boththegroupsarefollowedbackwards
intimetodeterminetheassociationwiththeriskfactor.
Inacasecontrolstudy,casesofdisease(orevents)are
identified.
Controls,orsubjectswithoutthediseaseoreventofinterest,
arethenselectedfromthesourcepopulationthatgiveriseto
thecases.
2. CASE CONTROL STUDY

36. Casecontrolstudiesareparticularlyusefulwhenthegoalis
toinvestigatewhetherthereisanassociationbetweenadrug
andonespecificrareadverseevent,aswellastoidentifyrisk
factorsforadverseevents.
Riskfactorscanincludeconditionsuchasrenalandhepatic
dysfunctionthatmightmodifytherelationshipbetweenthe
drugexposureandtheadverseevent.
2. CASE CONTROL STUDY

37. Population
Case-Control Studies
Cases and
Control
Cases
(ADR)
Drug
Exposed
Drug
Unexposed
Control
(No ADR)
Drug
Exposed
Drug
Unexposed
Time
Onset of Study
Past
Present
a =
b=
c=
d =

38. 2. CASE CONTROL STUDY
The exposure status of the two groups is compared using the
odds ratio.
Oddsratioisameasureofthestrengthofassociation
betweentheriskfactor(exposuretoadrug)andthedisease
oroutcome.
Oddsratiomaybe<1,1,and>1.
Odds ratio (OR)= ad / bc

39. Characteristicsofcasecontrolstudy:
Bothexposureandoutcomehaveoccurredbeforethestartof
thestudy.
Thestudyproceedsbackwardsfromeffecttothe
cause(retrospective)
Itusesacontrolorcomparisongrouptosupportorrefusean
inference
2. CASE CONTROL STUDY

40. Advantages
Easytocarryout,rapidandinexpensive
Comparativelyfewsubjectsrequired
Suitableforrarediseases.
Disadvantages
Problemofbias
Selectionofappropriatecontrolgroupmaybedifficult
Temporalassociationisnotclear
2. CASE CONTROL STUDY

41. 3. CROSS -SECTIONAL STUDY
Datacollectedonapopulationofpatientsatasinglepointof
time(orintervaloftime)regardlessofexposureordiseasestatus
constituteacross-sectionalstudy.
Thesetypesofstudiesareprimarilyusedtogatherdataforsurveys
orforecologicalanalyses.
Crosssectionalstudiesareparticularlyusefulindrugutilization
studiesandinprescribingstudies,becausetheycanpresentthe
pictureofhowadrugisactuallyusedinapopulationorhow
providersareactuallyprescribingmedications.
41

42. Themajordrawbackofcross-sectionalstudiesisthatthetemporal
relationshipbetweenexposureandoutcomecannotbedirectly
addressed.
Thesestudiesarebestusedtoexaminetheprevalenceofadisease
atonetimepointortoexaminetrendsovertime,whendatafor
serialtimepointscanbecaptured.
Thesestudiescanalsobeusedtoexaminethecrudeassociation
betweenexposureandoutcomeinecologicanalyses.
Cross-sectionalstudiesarebestutilizedwhenexposuresdonot
changeovertime
42
3. CROSS -SECTIONAL STUDY

43. Advantages:
Relativelyinexpensiveandtakesuplittletimetoconduct
Prevalenceofoutcomeofinterestcanbeestimated
Assessmentofmanyoutcomesandriskfactors
Thereisnolosstofollowup
Disadvantages:
Difficulttomakecausalinference
Onlyasnapshot:thesituationmayprovidedifferingresultsifanothertime
framehadbeenchosen.
43
3. CROSS -SECTIONAL STUDY

44. 1.HealthresearcherwanttoknowtheprevalenceofADRamong
cancerpatientinahospitalwhichheisworking.Whatstudy
designheshouldselect?
2.Physicianwanttoinvestigatethelongtermadverseeffectsof
usingRemdesivirdruginCOVIDPatients.Whichisthe
appropriatestudydesign?
3.Pharmacistwanttoknowhowmanyofthepatientsvisitinghis
pharmacyhashighbloodsugarlevel.Whichistheappropriate
studydesign?
44
QUESTIONS

45. 4. STIMULATED REPORTING
Unsolicitedinnatureandconsideredasaformofspontaneous
reporting
Stimulatedreportsarethosethatmayhavebeenmotivated,
promptedorinducedandcanoccurincertainsituationssuchas:
Notificationsbyauthoritiesconcerned
Literaturereport
Publicationinthepress,etc.
Dataobtainedfromstimulatedreportingcannotbeusedtogenerate
accurateincidencerates,butcanbeusedtoestimatereportingrates.

46. Severalmethodsareusedtoencourageandfacilitatereportingby
healthprofessionalsinspecificsituationsfornewproductsorfor
limitedtimeperiods:
OnlinereportingofAdverseevents
Systematicstimulationofreportingofadverseeventsbasedon
pre-designedmethods.
4. STIMULATED REPORTING

47. Limitations:
SelectiveReporting
Incompleteinformation
4. STIMULATED REPORTING

48. 5.TARGETED CLINICAL INVESTIGATIONS
Whensignificantrisksareidentifiedfrompre-approvalclinical
trials,furtherclinicalstudiesmightberequiredtoevaluatethe
mechanismofactionfortheadversereaction.
Insomeinstances,Pharmacodynamicandpharmacokineticstudies
mightbeconductedtodeterminewhetheraparticulardosecanput
patientsatanincreasedriskofadverseevents.
Genetictestingcanprovidecluesaboutthegroupofpatientsatan
increasedriskofadversereaction.
48

49. Specificstudiestoinvestigatepotentialdrug-druginteractionsand
food-druginteractionsmightalsoberequired.
Studiescanincludepopulationpharmacokineticstudiesanddrug
concentrationmonitoringinpatientsandnormalvolunteers.
Sometimes,potentialrisksorunforeseenbenefitsinspecial
populationmightbeidentifiedfrompre-approvalclinicaltrials,but
cannotbefullyquantifiedduetosmallsamplesizeortheexclusion
ofsubpopulationofpatientsfromtheseclinicalstudies.
49
5.TARGETED CLINICAL INVESTIGATIONS

50. Thesepopulationsmightincludetheelderly,childrenorpatients
withrenalorhepaticdisorder.
Furtherevaluationmightbeusedtodetermineandtoquantifythe
magnitudeoftherisk(orbenefit)insuchpopulations.
Toelucidatethebenefit-riskprofileofadrugortofullyquantify
theriskofacriticalbutrelativelyrareadverseevent,alarge
simplifiedtrialmightbeconducted.
Patientsenrolledinalargesimplifiedtrialareusuallyrandomized
toavoidselectionbias.
50
5.TARGETED CLINICAL INVESTIGATIONS

51. One limitation of this method is that the outcome measure might be
too simplifiedand this might have an impact on the quality and
ultimate usefulness of the trial.
51
5.TARGETED CLINICAL INVESTIGATIONS

52. OVERALL PHARMACOVIGILANCE METHODS
Drug
Discovery
Pre-Clinical
Development
Clinical
Development
Regulatory
approval
Drug
Marketed
IND
Application
Developed
Compound
Regulatory
Submission
Drug Approved
for marketing
Drug Candidate
Targeted Clinical
Studies
Passive
Surveillance
Stimulated
Reporting
Active
Surveillance

53. 1.S.K.Gupta.TextbookofPharmacovigilance.2
nd
Edition.
JaypeeBrothersMedicalPublishers.2019.
2.ElizabethB.Andrews,NicholasMoore.Mann’s
Pharmacovigilance.3
rd
Edition.WileyBlackwell.2014.
3.BortonCobert.Cobert’sManualofDrugSafetyand
Pharmacovigilance.2
nd
Edition.JonesandBartlett
Learning.2012.
REFERENCES