WHO Collaborating Centre for International Drug …...• adverse reaction profiles IBUPROFEN - ADR profile 0 1000 2000 3000 4000 5000 6000 7000 8000 Appl site Cardiovasc Foetal Liver-bil

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WHO Collaborating Centre for International Drug Monitoring

the Uppsala Monitoring Centre

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WHO Drug Monitoring ProgrammeFounding Members 1968

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WHO Collaborating Centrethe Uppsala Monitoring Centre

• established as a foundation 1978• based on agreement Sweden - WHO• international administrative board• WHO Headquarters responsible for policy

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Flow of information

NATIONAL CENTRES

WHO COLLABORATING

CENTREWHO HQ

MEDICAL PRACTICE

MANUFACTURERS

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0

50000

100000

150000

200000

250000

Num

ber o

f Rep

orts

1968 1972 1976 1980 1984 1988 1992 1996 2000Year (Based on Onset Date)

WHO Database 2002.07.27Number of Reports by Year

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Submitting ADR Reports to WHO

• diskette requiring pc only• diskette produced by national computer

system• computer network (FTP/e-mail)• Vigibase on-line

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Submitting ADR Reports to WHO

• ICH - E2b format• WHO agreed format

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Staff

– Medical Director– 3 senior pharmacists– 1 administrative manager– 11pharmaceutical officers– 3 R&D scientists– 4 IT specialists– 3 project coordinators– 3 sales and marketing– 2 assistants

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Functions 1

• Signal detection– Identification of previously unknown drug

reactions

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New Signalling ProcedureWhat should be achieved?

• Signals should not be missed• Signals should be found early• ‘False’ signals should be kept to a

minimum

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Why use a Bayesian neural network?

• An automated procedure with a power to consider all combinations– drug - ADR– drug - indication - age - ADR

• All combinations are considered in an unbiased manner

• Strong associations are highlighted for clinical assessment

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Signal detection using a neural network approach

• If the Posterior probability > Prior probability– The drug ADR combination is present more

often than expected– This is represented by a high value of

Information Component (IC)

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Information Component (IC)

• Definition– IC=log2 (Posterior Probability/ Prior

Probability)

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-2

-1

0

1

2

3

4

5

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79:1 81:1 83:1 85:1 87:1 89:1 91:1 93:1 95:1

Time(year)

Captopril - Coughing

IC

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-6

-4

-2

0

2

4

6

8

71 74 77 80 83 86 89 92 95 98year

Practolol, ATC C07AB - Peritonitis

PractololATC C07AB

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Procedure for signal analysis

Signals

Clinical evaluation

AssociationsQuantitative

threshold

Combinations

Drug safety data

Quantitative informationStatistical measurements Signal

document

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Panel of signal reviewers

• 38 clinical and ADR experts• voluntary consultants recruited globally

– assess associations in specialist area for clinical significance

– write assessment report for SIGNAL

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Functions 2

• Signal strengthening– Annual Type-A document– Search requests– Web-based search programme

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Functions 3• adverse reaction profiles

IBUPROFEN - ADR profile

0 1000 2000 3000 4000 5000 6000 7000 8000

Appl site

Cardiovasc

Foetal

Liver-bil

Neoplasms

Repro

Skin

Vision

Syst

em O

rgan

Cla

ss

No of reports

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Functions 4

• Comparing national experiences

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International Differences

• Examples– metamizole blood cells– nitrofurantoin respiratory neurological– mianserin blood cells– flucloxacillin liver

Apparent or Real?

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International Differences(Quantitative and Qualitative)• disease prevalence• genetic• social• cultural• healthcare systems• health professional practices• indication for, and use of medicines• pharmaceutical formulations• drug monitoring practices

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Functions 5

• identification of risk factors

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Potential Risk Factors• other drugs• sex / gender• age• genetic constitution• dosage• duration of treatment• route of administration• indication

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Functions 6

• Combining ADR figures with other data – drug utilization statistics– population statistics

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UMC - a communication centre

• WHO Pharmaceuticals Newsletter

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UMC - a communication centre

• WHO Pharmaceuticals Newsletter• Uppsala Reports

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UMC - a communication centre

• WHO Pharmaceuticals Newsletter• Uppsala Reports

• Internet home page http://www.who-umc.org

• Vigimed e-mail discussion group

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Pharmacovigilance Training

• Training course – Uppsala, Canberra– 2 weeks– 25 participants– 8th course May 2003

• Internet-based training• Regional and local activities

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UMC involvement in local activities 1998 - 2002

• 1998 – Norway, China, Portugal, Malaysia, Morocco, India

• 1999 – Philippines, Venezuela, Mexico, South Africa

• 2000 – India, China, Kuwait, Romania, Uruguay

• 2001 – Oman, Russia, Ghana, Fiji, Singapore, Vietnam

• 2002– Cuba, Chile, Morocco, Malaysia, Cyprus

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Technical support

• documentation of established systems

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Technical support

• literature coverage

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Technical support

• literature coverage

• guidelines

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Technical support

• literature coverage• guidelines• terminologies

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Terminologies

• WHO Adverse Reaction Terminology• WHO Drug Dictionary• ATC Classification• ICD Classification

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Technical support

• literature coverage• guidelines• terminologies• software development

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Software for National CentresVigibase on-line

SearchAnalysis

E2B

Vigibase

DrRCNC

E2B

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UMC Functions

• Harmonisation

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Definitions established within the WHO Programme

– Adverse reaction– Adverse event– Side effect– Signal– Serious reaction– Causality:

• certain • probable/likely • possible • unlikely • conditional/unclassifiable • unassessable

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Worldwide network of knowledge and competence

• Annual meeting of representatives of National Centres

• Working relations with relevant organizations – CIOMS, ISoP, ISPE, DIA, IPCS, HAI, IFPMA, etc

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Research and development

• Methods for signal identification and analysis– data-mining approach to signal analysis

• Improved monitoring of traditional medicines– collaboration with Royal Botanical Gardens, Kew,

UK

• Good communications practice in pharmacovigilance; collaboration with: – University of Verona– EQUUS– CIOMS

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Ideas in Planning Phase

• Single international database for industry reports

• Phenotype/genotype testing of affected subjects

• Chemical structure/clinical safety relationship

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Data available to non-members

• by request to WHO Collaborating Centre• summary figures from all countries• case reports by consent (automatic

from 50 countries)• Caveat document

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Requirements for joining the WHO Programme

• programme for collection of spontaneous ADR reports established

• a National Centre designated by Ministry of Health

• technical competence to fulfil WHO reporting requirements

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Process for joining WHO Programme11. Ministry of Health (or

equivalent) designates National Centre

Ministry of Health

25National Centre

2. Ministry of Health sends formal application to WHO-HQ, Geneva

33. National Centre sends sample reports to the UMC

the UMC4. UMC notifies WHO-HQ

that reports are compatible

5. WHO-HQ advises Ministry of Health of admittance to the

WHO-HQGeneva 4

Programme

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Thank you for your attention!