WHO Collaborating Centre for International Drug Monitoring the Uppsala Monitoring Centre

WHO Drug Monitoring Programme Founding Members 1968

WHO Collaborating Centre the Uppsala Monitoring Centre

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

WHO International Drug Monitoring Programme 2004

Flow of information

Medical practice National Centres Manufacturers WHO Headquarters WHO Collaborating Centre (UMC)

Wider scope of pharmacovigilance

• Adverse reactions – Type A – Type B • Lack of effect – counterfeiting – resistance – interaction • Quality problem • Dependence and abuse • Poisoning • Medical error

PHARMACOVIGILANCE

WHO definition

The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problem

Expansion of WHO Drug Monitoring Programme

• Database enriched – not only problems seen in industrialized countries – Drugs against tropical diseases – Better monitoring of traditional medicines – Another kind of co-morbidity – Effects of malnutrition

Developments in ICH Countries

• Strong focus on regulatory requirements/actions – Serious, unlabelled reactions to new drugs – Public health perspective in the background – Risk management • Industry stewardship has major role • Standardized format for exchange of case information (E2b) – MedDRA

Cumulative Number of Reports per Year in Vigibase April 2004

3 500 000 3 000 000 2 500 000 2 000 000 1 500 000 1 000 000 500 000 0 1967 1969 1971 1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003

Year

NLD 2% THA 2% SWE 3% ESP 3% FRA 4% AUS 5% CAN 5% DEU 6% TOP 10 COUNTRIES OTHERS 11% GBR 13% USA 46%

Submitting ADR Reports to WHO

• Vigibase online (Internet) • CD produced by national computer system • computer network (FTP/e-mail)

Submitting ADR Reports to WHO

• ICH - E2b format • WHO agreed format

Staff

– medical director – pharmacists – biomedical scientists – IT specialists – sales and marketing – administrative – total approx 40 persons

Functions 1

• Signal detection – Identification of previously unknown drug reactions

Signalling Procedure

What should be achieved?

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

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

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)

Information Component (IC)

• Definition – IC=log 2 (Posterior Probability/ Prior Probability)

Captopril - Coughing 2 1 0 4 3 6 5 -1 IC -2 79:1 81:1 83:1 85:1 87:1 89:1 91:1 93:1 95:1 Time(year)

Practolol, ATC C07AB - Peritonitis 8 6 4 2 0 -2 -4 -6 71 74 77 80 83 86 year Practolol ATC C07AB 89 92 95 98

Signal Detection & Follow-up

Combinations

.db (reported quarterly) Vigibas e Quarterly analysis BCPNN National Centres

Combinations database - example

Signal Detection & Follow-up

Combinations

.db (reported quarterly)

Triage (filter)

Quarterly analysis BCPNN Vigibas e National Centres

The triage procedure

• IC-2std>0 • Substantial increase in IC from last quarter • New drugs • Serious reactions (Critical terms) • Reports from >2 countries • Special interest reactions • Not in literature

Signal Detection & Follow-up

Combinations

.db (reported quarterly)

Triage (filter)

Quarterly analysis BCPNN Vigibas e Pharma Company Yes

Review panel

No SIGNAL Follow-up National Centres

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

Functions

2

• Signal strengthening – Web-based search programme – Search requests

Functions

3

• adverse reaction profiles

IBUPROFEN - ADR profile

Vision Skin Repro Neoplasms Liver-bil Foetal Cardiovasc Appl site 0 1000 2000 3000 4000 5000

No of reports

6000 7000 8000

Functions

4

• Comparing national experiences

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

Functions

5

• identification of risk factors

Potential Risk Factors

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

Functions 6

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

UMC - a communication centre

• WHO Pharmaceuticals Newsletter

12

UMC - a communication centre

• WHO Pharmaceuticals Newsletter • Uppsala Reports

Uppsala Reports

UMC - a communication centre

• WHO Pharmaceuticals Newsletter • Uppsala Reports • Internet home page http://www.who-umc.org

• Vigimed e-mail discussion group

Pharmacovigilance Training

• Training course – Uppsala, Canberra – 2 weeks – 25 participants – 9th course November 2004 • Regional and local activities

UMC involvement in local activities 2000 -2004

• 2000 – India, China, Kuwait, Romania, Uruguay • 2001 – Oman, Russia, Ghana, Fiji, Singapore, Vietnam • 2002 – Cuba, Chile, Morocco, Cyprus • 2003 – Serbia, Zambia, Saudi-Arabia, Ghana, India • 2004 – Hong Kong, China, Brazil,

Pharmacovigilance and Public Health Programmes

• New medicines for tropical diseases – Artimisinine derivatives against malaria – HIV/AIDS – Vaccination Programmes – etc • Global Fund • ’3 x 5’ initiative by WHO • Challenges for data collection • Need for pharmacovigilance training

Technical support

• literature coverage

Technical support

• literature coverage • guidelines

Dr RC NC Software for National Centres Vigibase on-line

E2B

Search Analysis Vigibase

UMC Functions

• Harmonisation

Definitions established within the WHO Programme

– Adverse reaction – Adverse event – Side effect – Signal – Serious reaction – Causality: » certain » probable/likely » possible » unlikely » conditional/unclassifiable » unassessable

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

Projects

• Methods for signal identification and analysis – data-mining approach to signal analysis • Improved monitoring of traditional medicines – collaboration with Royal Botanical Gardens, Kew, UK, Dept Systematic Botany, Uppsala • Good communications practice in pharmacovigilance; collaboration with: – University of Verona – EQUUS – CIOMS

Common name Problems in Herbal Pharmacovigilance Botanical name Chemical relation

Chinese, Asian Ginseng American Ginseng Tienchi Ginseng Siberian Ginseng Russian Ginseng Brazilian Ginseng Wild red Am. Ginseng Alaskan Ginseng Wild Ginseng Ayurvedic Ginseng Ginseng of the Andes’

Panax ginseng

Meyer

Panax quinquefolius

L.

Panax pseudoginseng Eletherococcus senticosus Acanthopanax

Maxim.

senticosus

Harms.

Rumex hymenosepalus Pfaffia paniculata Echinopanax

Wall.

Torr.

(Mart.) Kunze Standard Similar Similar Different Different Different . Different Different

horridum

(Sm.) Decne.)

Aralia nudicaulis Lepidium meyenii

L.

Withania somnifera

(L.) Dunal Walpers Different Different Different

WHO herbal ADR database Valid scientific botanical names

• No internationally standardized and accepted classification of all botanical names of medicinal herbs exist.

• Therefore the UMC has created a list of preferred botanical names and their synonyms.

• The preferred names are...

...the complete Latin binomial name including the author.

...assigned in collaboration with Royal Botanical Gardens of Kew, London.

...specified with part and extract (in English) if given.

WHO herbal ADR database BOTANICAL PREFERRED NAME Valid scientific plant name_ID Part_ID Extract_ID SYNONYMS Latin name or common name HCN

WHO herbal ADR database Herbal Code Number (HCN)

• Similar to CASnumber used for chemical substances

- one unique number for each herbal substance - same number of digits

• But the HCN

- always begins with a ’9’ - developed by the UMC

• Possible to link all herbal substances of the same plant by linking the eg.

Valeriana officinalis

Valid scientific name ID

Valeriana officinalis root

Part ID (root)

90051 90051 90051 000 005 005 00 00 Valeriana officinalis root dry extract

Extract ID (dry extract)

90051 005 02 02

WHO herbal ADR database ADR REPORT SUBSTANCE Substance name CAS/HCN Literature source Source version BOTANICAL PREFERRED NAME Valid scientific plant name_ID Part_ID Extract_ID SYNONYMS ID HCN INGREDIENT ATC/HATC ATC code Official/Herbal ID ID ID MED.PROD.

Drug name Filenumber Manufacturer Country Source Source version Latin name or common name

Data available to non-members

• By request to WHO Collaborating Centre • To degree health professionals • Caveat document

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

Process for joining WHO Programme

1. Ministry of Health (or equivalent) designates National Centre 2.

Ministry of Health sends formal application to WHO HQ, Geneva 3.

National Centre sends sample reports to

the

UMC 4.

UMC notifies WHO-HQ that reports are compatible 5.

WHO-HQ advises Ministry of Health of admittance to the Programme 5 Ministry of Health WHO-HQ Geneva 2 4 1 National Centre the UMC 3