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David Coulter

Summary of content

What is a signal? Recognising a signal What can be achieved by you? Clinical assessment of individual

events Clinical review of collated events Principles of signal detection Ta

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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

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Definition 2

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

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Recognising a signal

Signal identification

Record

Collate

Look!!

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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

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Recognition of a signal 2 You don’t need to do data mining

(BCPNN), or proportional reporting ratios (PRR), or disproportionality analysis to identify signals

Careful clinical assessment of your own events data is the quickest and most satisfying way.

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Recognition of a signal 3

Routine clinical appraisal facilitates the earliest possible generation of hypotheses

Automated signal detection good for testing hypotheses identifying missed signals still needs clinical confirmation

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Recognition of a signal 4

Clinical review the quickest method

careful informed systematic standardised clinical review In your centre

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What can be achieved –by you?

What can be achieved?Example: IMMP -omeprazole

Hyponatraemia Dry mouth Taste disturbance Interstitial nephritis Polydypsia / polyuria Polymyositis

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Omeprazole

Hepatitis Angioedema / urticaria Bone marrow depression Carcinoid tumour Gastric polyps Diarrhoea

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Omeprazole

Hallucinations Amnesia / confusion Headache Myalgia Gynaecomastia / galactorrhoea

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Omeprazole

Paraesthesia Pruritus Rash Extrapyramidal symptoms Blood dyscrasias

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Clinical assessment of individual events

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COX-2 inhibitors and disturbance of vision

Example 1

M 78 Shoulder pain Rofecoxib 50 mg once Woke next morning with

no vision right eye 6/18 left eye

Recovered next day

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Example 1

M 81 Osteoarthritis knee Celecoxib 100mg daily Central loss of vision Onset after each morning dose,

recovering after a few hours No recurrence after withdrawal

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Example 1

These 2 case reports can be called the INDEX CASES

Contain good information close time relationship positive dechallenge one had rechallenge

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Example 1

Now we look for information that may strengthen the signal:

Other case reports WHO database (Vigibase) Literature Mechanism

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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 ?

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Example 1WHO reports

Celecoxib Blindness 12 Temporary blindness 4 Vision abnormal 181

Rofecoxib Blindness 22 Temporary blindness 5 Vision abnormal 167

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Example 1Literature search

One case report with celecoxib Orange spots in both visual fields. (Lund

& Neiman, 2001) No reports with rofecoxib Visual field defects have been

reported rarely with the traditional NSAIDs

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Example 1Mechanism

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

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Example 1Conclusion

Two good index cases Several supporting cases Supporting cases in WHO database Similar reports for related drugs A plausible mechanism Only one similar report in the

literature We have a signal!

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Clinical review of collated events

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COX-2 inhibitors and prothrombotic disorders

Demo

Cluster of events

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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

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5

0

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Acciden

ts

Alimen

tary

Autonomic

Circulat

ory

Endocrine/M

etabolic ENT

Eyes

Haemato

logica

l

Hepato

biliary

Immun

ological

Infectio

ns

Musculosk

eletal

Neoplas

ms

Neuro

logical

Psych

iatric

Respira

tory

Skin

Urogen

ital

System Organ Class

% o

f Tot

al In

cide

nts

CelecoxibRofecoxib

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Prothrombotic eventsSummary of findings No difference in rates of IHD / stroke

between rofecoxib & celecoxib Higher rate of prothrombotic events

than comparators Shorter time to onset of death than

comparators Differences in death rates due to

prothrombotis events Higher rate of cardiac dysrythmias

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Principles of signal detection

Remember

Treatment dates -starting date & ending

Date of onset of event Was the patient on the drug when

the event began? Calculate onset time Effect of dechallenge / rechallenge

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Signal assessment

Other questions Could the problems be caused by a

disease? The disease being treated A co-morbid condition

Could the problems be caused by another drug?

Are the events caused by related drugs? Is it relevant or important?

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Look for non-random features Gender Age Duration to onset

Survival / life table analysis

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Non-random features

Differences in means Patients with reaction v patients in cohort t-test

Differences in rates RR with CI

Survival or life table analysis Clustering around a certain duration Differences between medicines

Multiple logistic regression

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Collate reports clinically

By Clinical Category (CC) Then in clinically related groups

Anatomical functional change Clinical sub-group

Primary event term Secondary event term

Motto:Sort & see & pursue

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Identifying early signals

Report your signals to: your advisory committee &/or

regulatory authority local health practitioners the Uppsala Monitoring Centre local ADR bulletin medical journal

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Signal identification

Record

Collate

Look!!

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Thank You

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Merci

beaucoup