The World Health Organization (WHO) Program for International Drug Monitoring and Its Database

1. The World Health Organization (WHO) Program for International Drug Monitoring and Its Database Pippa Antonio, B.Sc. Life Sciences Research Office, Bethesda, MD 20814

2. Rationale behind its development • Need for collaboration on an international scale • To identify rare adverse reactions not previously seen through clinical trials • Length of study • Participant selection • Co-morbid conditions • Concomitant medications

3. Historical Development of the WHO Drug Monitoring Program (1) • 1968– Pilot Drug Monitoring Program began by WHO • 1970– Pilot project evaluated and methods accepted • 1978–Cooperative agreement between WHO and the Swedish government. • Policy making decisions retained by WHO at HQ in Geneva • Database maintenance and operation moves to Uppsala

4. Historical Development of the WHO Drug Monitoring Program (2) • 1978-83–Reports now filed by date of adverse event and not by date report made • 1982– Adverse Reaction Newsletter This is a yearly review of signals (From the beginning of 2000 it was incorporated into the WHO Pharmaceuticals Newsletter) • 1985– New Critical Terms list developed

5. Historical Development of the WHO Drug Monitoring Program (3) • 1985-1990-- Developed a procedure for release of data to 3rd parties • 1990– Medical Director added to the UMC • 1993 1st International Training Course, Uppsala (5 courses 1993-1999)

6. Historical Development of the WHO Drug Monitoring Program (4) • 1995– Start of Herbals monitoring project Pilot study using data mining technique • 1996– Uppsala Reports • 1998– Vigimed email server • 1999– Pilot study from 1995 was accepted and fully implemented.

7. Countries participating in the WHO International Drug Monitoring Program to Date Official Member Countries Associate Member Countries www.who-umc.org/whoprog.html

8. Top 10 Reporting Countries in WHO Database (Period 1968-1997) CountryYear of Entry% of Total Reports Germany 1968 20.0 France 1986 16.5 USA 1968 11.9 UK 1968 11.1 Australia 1968 9.0 Spain 1984 6.6 Canada 1968 6.2 Sweden 1968 4.5 Netherlands 1968 1.6 Denmark 1968 1.4 Japan 1972 1.4 Ireland 1968 1.4 Edwards, et al., 2002 Farah, et al., 2000 (Applies only to herbals)

9. WHO Definitions • ADVERSE REACTION • WHO Technical Report No 498 (1972); 'A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function.' • SIGNAL • Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information. http://www.who-umc.org/

10. Patient Patient Patient Patient Patient Patient Patient Health Care Provider Health Care Provider Health Care Provider Health Care Provider Health Care Provider 70 National Pharmacovigilance Centers 70 National Pharmacovigilance Centers 70 National Pharmacovigilance Centers WHO Collaborating Center for International Drug Monitoring (Uppsala Monitoring Center) Quarterly generation of signals sent to independent experts for evaluation Information Flow Towards a “Signal” Output Temporary (24 month) signal follow up list SIGNAL report Permanent Log (history) file

11. Monitoring of Herbals In the WHO database there are presently 11,716 suspected herbal case reports.The most commonly reported critical terms and reported reactions are: www.who-umc.org/projects.ht Top 10 Critical Terms Top 10 Reported Reactions

12. Bayesian Confidence Propagation Neural Network (BCPNN) • Where: • Px = The probability of a specific drug being listed on a case report • Py = The probability of a specific adverse event being listed on a case report • Pxy = The probability that a specific drug-adverse reaction combination is • listed on a case report • Thus the Information Component (IC) value is based on: • The number of case reports with drug C (Cx) • The number of case reports with ADR Y (Cy) • The number of reports with the specific combination (Cxy) • The total number of reports • Lindquist, et. al. 2000

13. Signal Output • Examples of signals highlighted by BCPNN, identified by the panel and then circulated in the 4th quarter of 1997: • FINESTERIDE Breast Neoplasm • RIFABUTIN Corneal Ulceration • FENFLURAMINE Abortion http://www.netcompetence.se/seminarier/umc/

14. What’s New? • Data Management: • New Vigibase on-line software management tool for pharmacovigilance centers • Publications: • “Expecting the Worst - Crisis Management” • “Dialogue in Pharmacovigilance” - more effective communications • Online Tools: • Ground-breaking Collaboration in Drug Safety Data • Standardized Terminologies: • Web enabled multi-dictionary browsing and encoding tool • ICD- WHO ART Project – bringing together terminologies

15. References • Bate, A., et al., Eur J Clin Pharmacol (1998) 54:315-21 • Bate, A., Eur J Clin Pharmacol (2002) 58: 483-490 • Bate, A., et al., Drug Safety. 2002; 25(6); 393-397 • Edwards, I.R., et al., Pharmacovigilance. (2002) 169-182, 291-300 • Farah, M., et al., Pharmacoepidemiology & Drug Safety (2000) 9:105-112 • Linquist, M., et al. Drug Safety. 2000 Dec 23 (6);533-542 • Linquist, M., et al., J Rheu 2001;28-5;1180-1187 • Olsson, S., Drug Safety 1998 Jul;19(1);1-10