Methods in drug safety monitoring · November 2009 Tanzania Cohort Event Monitoring Prescription event monitoring (PEM) Dr. David Coulter formerly Research Associate Professor Intensive

Kia Ora!

November 2009November 2009 TanzaniaTanzania

Cohort Event MonitoringCohort Event MonitoringPrescription event monitoring (PEM)Prescription event monitoring (PEM)

Dr. David CoulterDr. David Coulterformerly Research Associate Professorformerly Research Associate Professor

Intensive Medicines Monitoring ProgrammeIntensive Medicines Monitoring Programme& Head NZ Pharmacovigilance Centre& Head NZ Pharmacovigilance Centre

Dr. Geraldine HillDr. Geraldine HillTeaching Fellow, University of Otago Medical School, Teaching Fellow, University of Otago Medical School,

Dunedin, New ZealandDunedin, New Zealand(formerly Research Fellow(formerly Research Fellow

Intensive Medicines Monitoring Programme)Intensive Medicines Monitoring Programme)

33

CEM worldwideCEM worldwide

NZ Intensive Medicines Monitoring NZ Intensive Medicines Monitoring Programme (IMMP), NZ, 1977Programme (IMMP), NZ, 1977

Drug Safety Research Unit (PEM), Drug Safety Research Unit (PEM), Southampton, UK, 1980Southampton, UK, 1980

Tanzania Tanzania CEM of antiCEM of anti--malarialsmalarials

NigeriaNigeria

44

Plan of presentationPlan of presentation

ObjectivesObjectives

What results can you get?What results can you get?Examples and methods from the NZ Intensive Medicines Examples and methods from the NZ Intensive Medicines

Monitoring Monitoring ProgrammeProgramme (IMMP)(IMMP)

How do we get them?How do we get them?

Observations & commentsObservations & comments

55

The objectives of CEMThe objectives of CEM

1.1. Characterise known reactionsCharacterise known reactions–– Mean ageMean age–– GenderGender–– Mean doseMean dose–– Treatment durationTreatment duration–– Time to onsetTime to onset–– Seriousness profileSeriousness profile–– IncidenceIncidence–– OutcomesOutcomes–– Effect on treatment (% withdrawals)Effect on treatment (% withdrawals)–– Part of syndrome?Part of syndrome?

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2.2. Detect signals of unrecognised reactionsDetect signals of unrecognised reactions

3.3. Interactions withInteractions withOther medicinesOther medicinesComplementary and alternative medicinesComplementary and alternative medicinesFoodsFoods

4.4. Identify risk factors so that they can be avoidedIdentify risk factors so that they can be avoidedAgeAge Duration of therapyDuration of therapyGenderGender Concomitant diseaseConcomitant diseaseDoseDose Concomitant therapyConcomitant therapy

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5.5. Assess safety in pregnancy & lactationAssess safety in pregnancy & lactation

6.6. Estimate risk (including comparative)Estimate risk (including comparative)

7.7. Provide evidence for effective risk Provide evidence for effective risk managementmanagement

Safer prescribingSafer prescribingBenefit / harm assessmentBenefit / harm assessmentRegulatory changesRegulatory changes

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8.8. Detect inefficacy, which might be due toDetect inefficacy, which might be due to

Faulty administrationFaulty administration

Poor storage conditionsPoor storage conditions

Out of dateOut of date

Poor quality productPoor quality product

Counterfeit Counterfeit

InteractionsInteractions

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9.9. Hypothesis generationHypothesis generation

10.10. Cohorts for studyCohorts for study

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The objectivesThe objectives

Achieve Achieve maximum maximum benefitbenefit, , least harmleast harm

for patientsfor patients

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What results can you get?What results can you get?

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COXCOX--2 inhibitors2 inhibitorscelecoxib, rofecoxibcelecoxib, rofecoxib

Preliminary monitoring Preliminary monitoring datadata

1313

The following will be The following will be summarisedsummarised

Cohort description & drug utilisationCohort description & drug utilisation

Preliminary events dataPreliminary events data

Preliminary review of deathsPreliminary review of deaths

1414

IMMP ProcessIMMP ProcessPrescription

Patient and Prescription details

Follow-up questionnairesEvent information

Cohort data Relationship

assessment

NZHIS

1515

CohortCohort

Prescriptions Patients

Celecoxib 98,975 32,630

Rofecoxib 52,874 26,666

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Profile of Ages at First Prescription

213543

1477

3325

5827 5969

6552

3601

503468

945

1939

3426

4704

4254 4297

2289

280

0

5

10

15

20

25

< 20 20-30 30-39 40-49 50-59 60-69 70-79 80-89 90 plus

% o

f tot

al k

now

n ag

es

Celecoxib Rofecoxib

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IMMP example IMMP example ––COXCOX--22

AgeAge CelecoxibCelecoxib RofecoxibRofecoxib

MeanMean 6363 5858

ModeMode 5959 5353

<40 years<40 years 6.9%6.9% 12.6%12.6%Highly significantHighly significant

70+ years70+ years 32.7%32.7% 25.7%25.7%Highly significantHighly significant

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Gender and termGender and term

CelecoxibCelecoxib RofecoxibRofecoxib

WomenWomen 61.6%61.6% 60.5%60.5%

Short termShort term 6879 (21%)6879 (21%) 9843 (37%)9843 (37%)

1919

Rofecoxib doseRofecoxib dose

12.5 11,695 28.3

25 26,027 63.0

37.5 36 0.1

50 3,546 8.6

mg/day No. %

2020

Celecoxib dose mg/no./%Celecoxib dose mg/no./%

100 6,622 8.1 200 65,591 80.5 300 274 0.3 400 8,927 11.0 600 46 800 30

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assessment

NZHIS

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Indications for useIndications for use((0r type/seriousness of malaria0r type/seriousness of malaria))

CelecoxibCelecoxibNo. %No. %

RofecoxibRofecoxibNo. %No. %

DifferenceDifferenceChiChi--squaresquare

PatientsPatients 6,2006,200 4,5364,536

InflammatoryInflammatory 211 (3.4)211 (3.4) 129 (2.8)129 (2.8) P>0.05P>0.05

OsteoarthritisOsteoarthritis 1805 (29)1805 (29) 775 (17)775 (17) P<0.0001P<0.0001

MusculoskelMusculoskel 1668 (27)1668 (27) 1105 (24)1105 (24) P<0.01P<0.01

Other painOther pain 2479 (40)2479 (40) 2495 (55)2495 (55) P<0.0001P<0.0001

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Baseline information 1Baseline information 1

QuestionsQuestions1.1. Current Acid Related DisorderCurrent Acid Related Disorder

2.2. Past ARDPast ARD

3.3. NSAID exposure NSAID exposure •• Past GI problems Past GI problems •• Direct switch to COXDirect switch to COX--22•• Concurrent aspirinConcurrent aspirin

4.4. Past cardiovascular diseasePast cardiovascular disease•• Hypertension / Heart failureHypertension / Heart failure•• MI / AnginaMI / Angina•• DysrhythmiaDysrhythmia / Stroke / Stroke -- TIATIA

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Baseline information 2Baseline information 2

Questionnaire response rateQuestionnaire response rateCelecoxibCelecoxib: number sent 4635 : number sent 4635

No. returned with information 3985 No. returned with information 3985 (91%)(91%)

RofecoxibRofecoxib: number sent 3050 : number sent 3050 No. returned with information 2725 No. returned with information 2725 (89%)(89%)

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Baseline information 3Baseline information 3No. & % of positive responses to questionNo. & % of positive responses to question

CELCEL ROFROF Rate ratioRate ratio(95% CI)(95% CI)

ARDARD 2281 2281 (68%)(68%)

1341 1341 (60%)(60%)

1.4 1.4 (1.27(1.27--1.58)1.58)

NSAID/ARDNSAID/ARD 2136 2136 (62%)(62%)

1199 1199 (54%)(54%)

1.41.4(1.28(1.28--1.59)1.59)

SwitchSwitch 1345 1345 (36%)(36%)

824 824 (34%)(34%)

1.91.9(0.98(0.98--1.21)1.21)

AspirinAspirin 352 352 (9.3%)(9.3%)

173 173 (6.9%)(6.9%)

1.41.4(1.15(1.15--1.69)1.69)

CardiovascCardiovasc 1361 1361 (36%)(36%)

797 797 (31%)(31%)

1.21.2(1.11(1.11--1.38)1.38)

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Baseline information 4Baseline information 4Cardiovascular diseaseCardiovascular disease

CelecoxibCelecoxib RofecoxibRofecoxib Rate ratioRate ratio(95% CI)(95% CI)

HypertensionHypertension 843 (22%)843 (22%) 498 (19%)498 (19%) 1.11.1(1.04(1.04--1.26)1.26)

MI/anginaMI/angina 547 (14%)547 (14%) 298 (12%)298 (12%) 1.21.2(1.09(1.09--1.42)1.42)

HFHF 206 (5.4%)206 (5.4%) 115 (4.5%)115 (4.5%) 1.21.2(0.97(0.97--1.51)1.51)

DysrhythmiaDysrhythmia 141 (3.7%)141 (3.7%) 86 (3.3%)86 (3.3%) 1.11.1(0.85(0.85--1.44)1.44)

Stroke/TIAStroke/TIA 40 (1.0%)40 (1.0%) 17 (0.7%)17 (0.7%) 1.61.6(0.90(0.90--2.80)2.80)

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The eventsThe events

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Profile of Events - Celecoxib and Rofecoxib n=1714 n=982

64

2222

156

103

7858

123532

8

44

1932

293301

22

273

33

4050

5139

28

122121

912

28

123

17

179

5

198

181

13

0

5

10

15

20

25

Accide

ntsAlim

entar

yAuto

nomic

Circula

tory

Died

Endo

crine

/Meta

bolic

ENT

Eyes

Haemato

logica

lHep

atobil

iary

Immun

ologic

alInf

ectio

ns

Muscu

loske

letal

Neopla

sms

Neuro

logica

lPs

ychia

tric

Respir

atory

Skin

Uroge

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System Organ Class

Perc

enta

ge

of T

otal

Eve

Celecoxib Rofecoxib

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Most common events 1Most common events 1rates /1000 patientsrates /1000 patients

CelecoxibCelecoxib RofecoxibRofecoxib

EventEvent No.No. RateRate No. No. RateRate RRRR

ARDARD 129129 3.43.4 8989 3.33.3 NSNS

RashRash 8686 2.62.6 3030 1.11.1 2.3 (1.62.3 (1.6--3.6)3.6)

HFHF 7474 2.32.3 5555 2.12.1 NSNS

IHDIHD 5757 1.81.8 3838 1.41.4 NSNS

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Most common events 2Most common events 2CelecoxibCelecoxib RofecoxibRofecoxib

EventEvent No.No. RateRate No. No. RateRate RRRR

LRTILRTI 5656 1.71.7 2929 1.11.1 1.6 1.6 (1.0(1.0--2.5)2.5)

DysrhythmiasDysrhythmias 4949 1.51.5 1919 0.70.7 2.1 2.1 (1.2(1.2--3.6)3.6)

AngioedemaAngioedema 4848 1.51.5 1414 0.50.5 2.8 2.8 (1.6(1.6--5.1)5.1)

StrokeStroke 3737 1.11.1 1818 0.70.7 NSNS

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Most common events 3Most common events 3CelecoxibCelecoxib RofecoxibRofecoxib

EventEvent NoNo RateRate No. No. RateRate RRRR

DiarrhoeaDiarrhoea 3636 1.11.1 1717 0.60.6 NSNS

AsthmaAsthma 3434 1.01.0 1313 0.50.5 2.1 (1.12.1 (1.1--4.1)4.1)

RFRF 3333 1.01.0 2828 1.11.1 NSNS

VomitingVomiting 3333 1.01.0 3434 1.31.3 NSNS

HTHT 1313 0.30.3 2828 1.11.1 2.6 (1.42.6 (1.4--5.0)5.0)

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Signals identified 1Signals identified 1

CoughingCoughingVisual field defect / temp blindnessVisual field defect / temp blindnessAcute psychiatric eventsAcute psychiatric eventsPancreatitisPancreatitisHepatotoxicityHepatotoxicityPsoriasisPsoriasisAcute urinary retentionAcute urinary retention

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Signals 2Signals 2

Mouth ulcerationMouth ulceration

Lower bowel effectsLower bowel effects

Cardiac dysrhythmiasCardiac dysrhythmias

Cardiac arrestCardiac arrest

Myocardial infarction / strokeMyocardial infarction / stroke

AnaphylaxisAnaphylaxis

Serious skin infectionSerious skin infection

Acute labyrinthitisAcute labyrinthitis

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Signals 3Signals 3

InteractionsInteractionsTricyclicsTricyclics causing arrhythmiascausing arrhythmiasWarfarin causing increased INR Warfarin causing increased INR (rofecoxib)(rofecoxib)

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DeathsDeathsCauses by SOC Causes by SOC (% of total deaths)(% of total deaths)

CelecoxibCelecoxib No. (%)No. (%) RofecoxibRofecoxib No. (%)No. (%)

All deathsAll deaths CausalCausal All deathsAll deaths CausalCausal

CirculatoryCirculatory 116 (40)116 (40) 34 34 (11.6)(11.6) 68 (38)68 (38) 23 23 (12.9)(12.9)

MalignancyMalignancy 115 (39)115 (39) NilNil 92 (51)92 (51) NilNil

RespiratoryRespiratory 59 (20)59 (20) NilNil 24 (13)24 (13) NilNil

RenalRenal 23 (8)23 (8) 18 18 (6)(6) 8 (5)8 (5) 8 8 (5)(5)

InfectionInfection 13 (4)13 (4) NilNil 11 (6)11 (6) NilNil

AlimentaryAlimentary 10 (3)10 (3) 10 10 (3)(3) 8 (5)8 (5) 4 4 (2)(2)

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Risk factors 1Risk factors 1

by multiple logistic regressionby multiple logistic regression

Renal failureRenal failure–– AgeAge–– Inflammatory arthritisInflammatory arthritis

Heart failureHeart failure–– AgeAge–– P/H heart failureP/H heart failure–– Inflammatory arthritisInflammatory arthritis

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Ischaemic heart diseaseIschaemic heart disease–– AgeAge–– P/H of any type of heart diseaseP/H of any type of heart disease–– Inflammatory arthritis (celecoxib)Inflammatory arthritis (celecoxib)

Cardiac dysrhythmiasCardiac dysrhythmias–– AgeAge–– Past history of heart failurePast history of heart failure–– Inflammatory arthritis (celecoxib)Inflammatory arthritis (celecoxib)

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Stroke / TIAStroke / TIA–– AgeAge–– HypertensionHypertension–– Inflammatory arthritisInflammatory arthritis

3939

Did we reach the objectives?Did we reach the objectives?

4040

Study demonstratesStudy demonstrates

High complianceHigh complianceDemographics of cohortsDemographics of cohortsBackground dataBackground data–– IndicationIndication–– Relevant past/current historyRelevant past/current history

Prescribing practicesPrescribing practicesEarly signal identificationEarly signal identificationSignificant eventsSignificant eventsComparative ratesComparative ratesRisk factorsRisk factors

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Concerns raisedConcerns raised

High volume of prescribingHigh volume of prescribingHigh doses of High doses of rofecoxibrofecoxibSubstantial prescribing to patients at Substantial prescribing to patients at high riskhigh risk–– very elderlyvery elderly–– history of cardiovascular diseasehistory of cardiovascular disease–– history of ARDhistory of ARD

Apparent high death rateApparent high death rate

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ConcernsConcerns

High rate of cardiovascular eventsHigh rate of cardiovascular events–– Heart failureHeart failure–– DysrhythmiasDysrhythmias–– ProthromboticProthrombotic effectseffects

Myocardial infarctionMyocardial infarctionStrokeStrokeRenal infarctionRenal infarction

High rate of alimentary eventsHigh rate of alimentary events

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How do we get results like How do we get results like this?this?

The principlesThe principles

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Cohort event monitoringCohort event monitoringHow is it done?How is it done?

Two PrinciplesTwo PrinciplesIdentifying patients exposed (cohort) Identifying patients exposed (cohort) -- the the denominatordenominator–– as complete as possibleas complete as possible

Systematically soliciting adverse Systematically soliciting adverse EVENTSEVENTS -- the the numeratornumerator–– as complete as possibleas complete as possible

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1. Identifying the patients1. Identifying the patients

How can this be done?How can this be done?The cohort of patients is established using The cohort of patients is established using the best source of usage data availablethe best source of usage data available–– DispensingsDispensings (pharmacies or central records)(pharmacies or central records)–– Patient recordsPatient records

DoctorsDoctorsClinicsClinicsHospitalsHospitalsOtherOther

–– Programme recordsProgramme records

Adequate cohort (10,000 patients)Adequate cohort (10,000 patients)

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assessment

NZHIS

Other Rx Sources

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Cohort sizeCohort size

General aim 10,000 (IMMP 11,000)General aim 10,000 (IMMP 11,000)Greater numbers required to detect Greater numbers required to detect differences differences –– if events naturally commonif events naturally common–– for subfor sub--group analysesgroup analysesSmaller numbers still produce good dataSmaller numbers still produce good data–– fluoxetine <7000fluoxetine <7000Signals can be identified / confirmed with Signals can be identified / confirmed with much smaller numbers (<1000)much smaller numbers (<1000)–– egeg nifedipinenifedipine & eye pain & eye pain

4848

2. Soliciting the events2. Soliciting the eventsHow can this be done?How can this be done?

ActivelyActively asking for the eventsasking for the events

SystematicallySystematically asking for the eventsasking for the events

4949

Soliciting the eventsSoliciting the eventsHow is it done?How is it done?

The events are collected using the best The events are collected using the best source(ssource(s) available) available–– Survey prescribers (questionnaires or other)Survey prescribers (questionnaires or other)–– Survey patients (questionnaires or other)Survey patients (questionnaires or other)–– RealReal--time recording*time recording*–– Telephone, or visit*Telephone, or visit*–– Record searches (manual, electronic)Record searches (manual, electronic)–– Registers of death or morbidityRegisters of death or morbidity–– Record linkage with registers or hospital Record linkage with registers or hospital

recordsrecords–– Intensified spontaneous reportingIntensified spontaneous reporting–– OtherOther–– SeveralSeveral

5050


Patient and Prescription detailsFollow-up

questionnairesEvent information


assessment

NZHIS

Other Rx Sources

Other Sources

5151

Actively & systematically askingActively & systematically asking

Ask after every treatmentAsk after every treatment

Patients in cohort checked to see that Patients in cohort checked to see that followfollow--up information receivedup information received

Repeat request for missed patientsRepeat request for missed patients

Make strenuous efforts to avoid missing Make strenuous efforts to avoid missing anyoneanyone

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Adverse event (experience)

Definition (WHO)

Untoward medical occurrence

temporally associated with the use

of a medicinal product, but not

necessarily causally related

5353

It is It is EVENTEVENT monitoringmonitoring

Any new clinical experience Any new clinical experience

(favourable or unfavourable) that is (favourable or unfavourable) that is

worthy of a record in the patientworthy of a record in the patient’’s s

file, regardless of its severity and file, regardless of its severity and

without judgement on its causality.without judgement on its causality.

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Events = reactions + incidentsEvents = reactions + incidents

ReactionsReactions11 DefiniteDefinite22 ProbableProbable33 PossiblePossible

IncidentsIncidents (background noise)(background noise)4 Unlikely4 Unlikely5 Unclassified (conditional) 5 Unclassified (conditional) 6 6 UnassessableUnassessable

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IncidentsIncidents((MakingMaking music from the noisemusic from the noise))

Should represent background morbidityShould represent background morbidity

May contain unrecognised signalsMay contain unrecognised signals–– unexpected profilesunexpected profiles

Useful for assessing reporting biasUseful for assessing reporting bias–– as withinas within--drug controlsdrug controls–– as betweenas between--drug controlsdrug controls

UnmaskingUnmasking

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Why adverse events?Why adverse events?To identify signals of new reactionsTo identify signals of new reactions

If only known or expected adverse reactions are If only known or expected adverse reactions are reported, unexpected adverse reactions will not reported, unexpected adverse reactions will not be identifiedbe identified

It is important to identify signals, validate them, It is important to identify signals, validate them, determine the incidence, understand their determine the incidence, understand their significance and identify the risk factors as soon significance and identify the risk factors as soon as possible. as possible.

It is not logical to specify the types of events to It is not logical to specify the types of events to be recorded. Unexpected reactions cannot be be recorded. Unexpected reactions cannot be identified by recording only the known or identified by recording only the known or expected.expected.

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Reporting requirementsReporting requirementsAll new events even if common & minorAll new events even if common & minor

Change in a preChange in a pre--existing conditionexisting condition

Abnormal changes in laboratory testsAbnormal changes in laboratory tests

AccidentsAccidents

All deathsAll deaths with date & causewith date & cause

Possible interactionsPossible interactions–– NB alcohol, NB alcohol, OCsOCs, , CAMsCAMs

5858

Reasons for stoppingReasons for stoppingPoor compliance (adherence)Poor compliance (adherence)

No longer necessaryNo longer necessary

Change of diagnosisChange of diagnosis

Inadequate responseInadequate response

Suspected ADRSuspected ADR

DeathDeath

Lost to followLost to follow--upup

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PregnancyPregnancyRoutine questions about pregnancy and lactation Routine questions about pregnancy and lactation for all women of child bearing age for all women of child bearing age ––computer computer generatedgenerated

Pregnancy register establishedPregnancy register established

Time / period of exposure identifiedTime / period of exposure identified

Routine followRoutine follow--up of all pregnancies after up of all pregnancies after expected delivery dateexpected delivery date

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NonNon--serious eventsserious eventsMay indicate serious problemMay indicate serious problem

May affect complianceMay affect compliance–– nauseanausea–– Rash / pruritusRash / pruritus–– DiarrhoeaDiarrhoea

May be more important than serious reactionsMay be more important than serious reactions

Recording all events is easier than being selectiveRecording all events is easier than being selective

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CEM in the IMMPCEM in the IMMP

Prospective observational cohort Prospective observational cohort studies on new drugs in normal studies on new drugs in normal clinical practiceclinical practice

Cohorts established from prescription Cohorts established from prescription data from pharmaciesdata from pharmacies

Events data mainly from Events data mainly from questionnaires sent to prescribersquestionnaires sent to prescribers

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ComplianceCompliance

Voluntary / unpaidVoluntary / unpaid

Doctors 80%Doctors 80%

–– Limiting factor is workloadLimiting factor is workload

Patients higherPatients higher

Pharmacists 93%Pharmacists 93%

Good feedback essentialGood feedback essential

Value appreciatedValue appreciated

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‘‘ControlsControls’’

Controls create an artificial situationControls create an artificial situation

The aim is a nonThe aim is a non--interventional study in normal interventional study in normal

clinical practiceclinical practice

Comparators are desirableComparators are desirable–– not always possiblenot always possible–– possibility of confoundingpossibility of confounding

A good study of a single drug A good study of a single drug –– provides valuable dataprovides valuable data–– has benchmark valuehas benchmark value

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Record linkageRecord linkage

Linking databases using unique IDLinking databases using unique ID

IMMP IMMP --routine link with routine link with –– NZHIS NZHIS ––identify deathsidentify deaths–– Register of deaths for certified Register of deaths for certified cause(scause(s))

IMMP IMMP ––special studiesspecial studies–– Suicide & antidepressantsSuicide & antidepressants–– Reactions of long latency Reactions of long latency ––cancer registers / cancer registers /

hospital discharge diagnoseshospital discharge diagnoses–– Conditions of interest Conditions of interest egeg MIMI

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Cohort investigationsCohort investigationsPatient questionnairesPatient questionnaires–– Eye pain and Eye pain and nifedipinenifedipine / taste disturbance and / taste disturbance and captoprilcaptopril

Doctor questionnairesDoctor questionnaires–– Angina and Angina and bezafibratebezafibrate((confounding by indicationconfounding by indication))

Reactions of long latencyReactions of long latency–– OmeprazoleOmeprazole

Case control studies (nested)Case control studies (nested)–– Genetic studiesGenetic studies

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DonDon’’t ask for too mucht ask for too much

The more you ask for, the less you getThe more you ask for, the less you get

A delicate balanceA delicate balance

Concomitant therapyConcomitant therapy

Information can be requested if neededInformation can be requested if needed

Unnecessary data increases workloadUnnecessary data increases workload

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Be open mindedBe open mindedUnexpected reactions will occurUnexpected reactions will occur

Predictions of safety unreliablePredictions of safety unreliable

Experience based only on spontaneous reporting unreliableExperience based only on spontaneous reporting unreliable–– 2.1 million patient exposures with 2.1 million patient exposures with olanzapineolanzapine

’’no significant safety concernsno significant safety concerns’’

No dominant preNo dominant pre--conceived ideasconceived ideas

All dataAll data should be collected & should be collected & analysedanalysed in a totally in a totally objectiveobjectivemannermanner

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Cohort event monitoringCohort event monitoring

Is an early warning systemIs an early warning system

New drugs (postNew drugs (post--marketing surveillance)marketing surveillance)

Can be used to validate signalsCan be used to validate signals

Can be used to characterize reactionsCan be used to characterize reactions

Normal clinical practice, real life situationsNormal clinical practice, real life situations

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Cohort event monitoringCohort event monitoring

Exposure in pregnancy / lactationExposure in pregnancy / lactation

Death ratesDeath rates

Reasons for stopping therapyReasons for stopping therapy

InefficacyInefficacy

Limited study periodLimited study period

Reactions of long latencyReactions of long latency

Events examined clinically and epidemiologicallyEvents examined clinically and epidemiologically

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The epidemiologyThe epidemiology

observational cohort studiesobservational cohort studies

prospectiveprospective

longitudinallongitudinal

nonnon--interventionalinterventional

inceptionalinceptional

dynamicdynamic

descriptivedescriptive

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AnalysisAnalysisCollation and signal identificationCollation and signal identification

Rates and profilesRates and profiles–– Comparisons by drug, age group, etcComparisons by drug, age group, etc–– By system organ classBy system organ class–– Within system organ classWithin system organ class–– Individual eventsIndividual events

Life table or survival analysisLife table or survival analysis

Multiple logistic regressionMultiple logistic regression–– esp. for risk factorsesp. for risk factors

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Advantages of CEMAdvantages of CEMProvides comprehensive informationProvides comprehensive information

Provides near complete informationProvides near complete information–– On the target populationOn the target population–– Drug Drug utilisationutilisation–– EffectivenessEffectiveness–– Risks and how to prevent themRisks and how to prevent them

Provides the information needed toProvides the information needed to–– Handle drug scaresHandle drug scares–– MinimiseMinimise harmharm–– Ensure treatment successEnsure treatment success

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Advantages of CEMAdvantages of CEM

Stimulates interest in drug safetyStimulates interest in drug safety

Improves spontaneous reportingImproves spontaneous reporting

Can concentrate resources on drugs of particular Can concentrate resources on drugs of particular

importance to a country or programmeimportance to a country or programme

Can be applied regionally Can be applied regionally

AdaptableAdaptable

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The essentialsThe essentials

Identify the cohortIdentify the cohort

Identify the eventsIdentify the events

With this information, you can find With this information, you can find all you need to know (almost) all you need to know (almost)

concerning safetyconcerning safety

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PEM referencesPEM references

Mann & Andrews Mann & Andrews PharmacovigilancePharmacovigilance

Title:Title: PharmacovigilancePharmacovigilance (2(2ndnd Edition) 2007Edition) 2007Publisher:Publisher: John Wiley & Sons, Ltd.John Wiley & Sons, Ltd.Author:Author: Mann, Ronald D.; Andrews, Elizabeth B. Mann, Ronald D.; Andrews, Elizabeth B.

Includes chapters on:Includes chapters on:PEM in the UKPEM in the UKPEM in NZPEM in NZ

7676

Thank-you

Documents

Methods in drug safety monitoring · November 2009 Tanzania Cohort Event Monitoring Prescription event monitoring (PEM) Dr. David Coulter formerly Research Associate Professor Intensive