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WHO Collaborating Centre for International Drug Monitoring the Uppsala Monitoring Centre 1 WHO Drug Monitoring Programme Founding Members 1968 2 3 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 4 Flow of information MEDICAL PRACTICE NATIONAL CENTRES MANUFACTURERS WHO COLLABORATING CENTRE WHO HQ 5 WHO Database 2002.07.27 Number of Reports by Year 250000 Number of Reports 200000 150000 100000 50000 0 1968 1972 1976 1980 1984 1988 Year (Based on Onset Date) 6 1992 1996 2000 Submitting ADR Reports to WHO • diskette requiring pc only • diskette produced by national computer system • computer network (FTP/e-mail) • Vigibase on-line 7 Submitting ADR Reports to WHO • ICH - E2b format • WHO agreed format 8 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 9 Functions 1 • Signal detection – Identification of previously unknown drug reactions 10 New Signalling Procedure What should be achieved? • Signals should not be missed • Signals should be found early • ‘False’ signals should be kept to a minimum 11 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 12 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) 13 Information Component (IC) • Definition – IC=log2 (Posterior Probability/ Prior Probability) 14 Captopril - Coughing 6 5 4 3 2 1 0 -1 IC -2 79:1 81:1 83:1 85:1 87:1 89:1 91:1 93:1 95:1 Time(year) 15 Practolol, ATC C07AB - Peritonitis 8 6 4 2 0 -2 -4 Practolol ATC C07AB -6 71 74 77 80 83 86 year 16 89 92 95 98 Procedure for signal analysis Quantitative threshold Associations Clinical evaluation Signals Combinations Quantitative information Statistical measurements Signal document Drug safety data 17 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 18 19 Functions 2 • Signal strengthening – Annual Type-A document – Search requests – Web-based search programme 20 Functions 3 • adverse reaction profiles IBUPROFEN - ADR profile System Organ Class Vision Skin Repro Neoplasms Liver-bil Foetal Cardiovasc Appl site 0 1000 2000 3000 4000 5000 No of reports 21 6000 7000 8000 Functions 4 • Comparing national experiences 22 International Differences • Examples – metamizole – nitrofurantoin – mianserin – flucloxacillin blood cells respiratory neurological blood cells liver Apparent or Real? 23 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 24 Functions 5 • identification of risk factors 25 Potential Risk Factors • • • • • • • • other drugs sex / gender age genetic constitution dosage duration of treatment route of administration indication 26 Functions 6 • Combining ADR figures with other data – drug utilization statistics – population statistics 27 UMC - a communication centre • WHO Pharmaceuticals Newsletter 28 29 12 UMC - a communication centre • WHO Pharmaceuticals Newsletter • Uppsala Reports 30 31 UMC - a communication centre • WHO Pharmaceuticals Newsletter • Uppsala Reports • Internet home page http://www.who-umc.org • Vigimed e-mail discussion group 32 Pharmacovigilance Training • Training course – Uppsala, Canberra – 2 weeks – 25 participants – 8th course May 2003 • Internet-based training • Regional and local activities 33 34 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 35 Technical support • documentation of established systems 36 37 Technical support • literature coverage 38 39 Technical support • literature coverage • guidelines 40 41 42 43 44 Technical support • literature coverage • guidelines • terminologies 45 Terminologies • • • • WHO Adverse Reaction Terminology WHO Drug Dictionary ATC Classification ICD Classification 46 Technical support • • • • literature coverage guidelines terminologies software development 47 Software for National Centres Vigibase on-line Search Analysis E2B Dr RC NC Vigibase E2B 48 UMC Functions • Harmonisation 49 Definitions established within the WHO Programme – – – – – – Adverse reaction Adverse event Side effect Signal Serious reaction Causality: • • • • • • certain probable/likely possible unlikely conditional/unclassifiable unassessable 50 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 51 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 52 53 54 55 Ideas in Planning Phase • Single international database for industry reports • Phenotype/genotype testing of affected subjects • Chemical structure/clinical safety relationship 56 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 57 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 58 Process for joining WHO Programme 1. Ministry of Health (or equivalent) designates National Centre 2. Ministry of Health sends formal application to WHOHQ, Geneva 1 Ministry of Health 2 5 National Centre 3 3. National Centre sends sample reports to the UMC the UMC 4. UMC notifies WHO-HQ that reports are compatible WHO-HQ Geneva 5. WHO-HQ advises Ministry of Health of admittance to the Programme 59 4 Thank you for your attention! 60