Identifying early signals - WHO · 11/27/2009 · Physicians Desk Reference(PDR). ... Dar es...

27 Nov 2009Dar es Salaam 1

David Coulter

Summary of content

What is a signal?Recognising a signalWhat can be achieved by you?Clinical assessment of individual eventsClinical review of collated eventsPrinciples of signal detectionTa


Definition 1

A signal refers to ‘reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously’.

WHO


Definition 2

In practice it means, a strong suspicion of an adverse reaction that has not been recognised previously



Recognising a signal

Signal identification

Record

Collate

Look!!


Recognition of a signal 1

How do we know when events are not recognised reactions?Martindale*DrugDex*Physicians Desk Reference (PDR). All available on website of Micromedex Healthcare Series www.thomsonhc.com



You don’t need to do data mining (BCPNN), or proportional reporting ratios (PRR), or disproportionality analysis to identify signalsCareful clinical assessment of your own events data is the quickest and most satisfying way.



Routine clinical appraisal facilitates the earliest possible generation of hypotheses Automated signal detectiongood for testing hypothesesidentifying missed signalsstill needs clinical confirmation



Clinical review the quickest methodcarefulinformedsystematicstandardisedclinical reviewIn your centre



What can be achieved –by you?

What can be achieved?

Example: IMMP ‐omeprazoleHyponatraemiaDry mouth Taste disturbanceInterstitial nephritisPolydypsia / polyuria Polymyositis


Omeprazole

Hepatitis Angioedema / urticariaBone marrow depression Carcinoid tumourGastric polypsDiarrhoea


Omeprazole

HallucinationsAmnesia / confusionHeadache MyalgiaGynaecomastia / galactorrhoea


Omeprazole

Paraesthesia Pruritus RashExtrapyramidal symptomsBlood dyscrasias



Clinical assessment of individual events


COX‐2 inhibitors and disturbance of vision

Example 1

M 78Shoulder painRofecoxib 50 mg onceWoke next morning with

no vision right eye6/18 left eye

Recovered next day


Example 1

M 81Osteoarthritis kneeCelecoxib 100mg dailyCentral loss of visionOnset after each morning dose, recovering after a few hoursNo recurrence after withdrawal


Example 1

These 2 case reports can be called the INDEX CASESContain good information

close time relationshippositive dechallengeone had rechallenge


Example 1

Now we look for information that may strengthen the signal:Other case reportsWHO database (Vigibase)LiteratureMechanism


Example 1Other reports of eye problems‐blurred vision

Patient Dose Onset

Rof M 58 ? 1 week

Cel F 53 200mg 4 months

Cel F 59 200mg 1 week

Cel F71 200 ?

27 Nov 2009 Dar es Salaam 23

Example 1WHO reports

CelecoxibBlindness 12Temporary blindness 4Vision abnormal 181

RofecoxibBlindness 22Temporary blindness 5Vision abnormal 167


Example 1Literature search

One case report with celecoxibOrange spots in both visual fields. (Lund & Neiman, 2001)

No reports with rofecoxibVisual field defects have been reported rarely with the traditional NSAIDs


Example 1Mechanism

Interference with retinal blood flow by inhibition of prostaglandins and related substances.


Example 1Conclusion

Two good index casesSeveral supporting casesSupporting cases in WHO databaseSimilar reports for related drugsA plausible mechanismOnly one similar report in the literatureWe have a signal!



Clinical review of collated events


COX‐2 inhibitors and prothrombotic disorders

Demo

Cluster of events



Profile of Incidents - Celecoxib and Rofecoxib n=131 n=71

00

64

23

56

1

54

332

4

51

1

4

934

7

00

21

8

00001

3

5

29

8

5

0

5

10

15

20

25

30

35

40

45

Acciden

tsAlim

entary

AutonomicCirc

ulatory

Endocrine/M

etabolic ENT

Eyes

Haemato

logica

lHep

atobilia

ryIm

munologic

alInfec

tions

Musculosk

eletal

Neoplas

msNeu

rologic

alPsy

chiat

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ry

SkinUro

genita

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System Organ Class

% o

f Tot

al In

cide

nts

CelecoxibRofecoxib

Prothrombotic events

Summary of findingsNo difference in rates of IHD / stroke between rofecoxib & celecoxibHigher rate of prothrombotic events than comparatorsShorter time to onset of death than comparatorsDifferences in death rates due to prothrombotis eventsHigher rate of cardiac dysrythmias with celecoxib



Principles of signal detection

Remember

Treatment dates ‐starting date & endingDate of onset of eventWas the patient on the drug when the event began?Calculate onset timeEffect of dechallenge / rechallenge


Signal assessment

Other questionsCould the problems be caused by a disease?

The disease being treatedA co‐morbid condition

Could the problems be caused by another drug?Are the events caused by related drugs?Is it relevant or important?


Look for non‐random features

GenderAgeDuration to onset

Survival / life table analysis


Non‐random features

Differences in meansPatients with reaction v patients in cohortt‐test

Differences in ratesRR with CI

Survival or life table analysisClustering around a certain durationDifferences between medicines

Multiple logistic regression


Collate reports clinically

By Clinical Category (CC)Then in clinically related groups

Anatomical functional changeClinical sub‐group

Primary event termSecondary event term

Motto:

Sort & see & pursue27 Nov 2009Dar es Salaam 40

Identifying early signals

Report your signals to:your advisory committee &/or regulatory authoritylocal health practitionersthe Uppsala Monitoring Centrelocal ADR bulletinmedical journal


Signal identification

Record

Collate

Look!!


Thank You


Identifying early signals - WHO · 11/27/2009 · Physicians Desk Reference(PDR). ... Dar es...

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