Roundtable: Cutting edge safety systems A global perspective

1. Roundtable: Cutting edge safety systems A global perspective

2. Outline Background WHO Programme for International Drug Monitoring Overview Potential for strengthening vaccine pharmacovigilance WHO's Global Network for Post-marketing Surveillance of New Vaccines Selected country examples of new methodologies

3. Background Global impact of real or perceived safety concerns Challenges for ensuring effective safety monitoring systems in non-industrialized countries Relative lack of resources Communication, cultural and other local factors What would an ideal post licensure vaccine safety system be ��.. globally? How can we build more effective systems in non-industrialized countries?

4. WHO Programme for International Drug Monitoring Network of National Pharmacovigilance Centres, WHO HQ, and the WHO Collaborating Centre for International Drug Monitoring (the Uppsala Monitoring Centre (UMC)) Established in 1968 and at UMC since 1978 Jan 2007: 82 member countries (+ 17 associate members) Approx. 3.7 million case reports in database Only approx. 10% of database relates to vaccine reports (82% of vaccine reports from 3 countries) � M Letourneau, 2005; publication pending

5. Functions of the WHO Programme Identification and analysis of new adverse reaction signals WHO database as reference source for signal strengthening and ad hoc investigations. Information exchange between WHO and National Centres (Vigimed) Periodical newsletters, guidelines etc. in PhV and risk management Tools for management of clinical information (WHO Drug Dictionary and the WHO Adverse Reaction Terminology; WHO-ART to MedDRA mapping) Training and consultancy support to National Centres Software for case report management (VigiFlow) Annual meetings for representatives of National Centres Methodological research

6. Steps in UMC signalling Global reporting (from National Centres) of safety data to UMC Quarterly analysis of data using a Bayesian Confidence Propagation Neural Network (BCPNN) method Generates Combinations Database (all Drug-ADR combinations) Triage algorithms applied to prioritize associations of interest (potential signals) for review by clinical "signal reviewers" based on an Information Component (IC) value; unexpected drug-ADR pairs based on special terms of interest Signal review (including review of literature) Publication in Signal document Additional pattern recognition to generate hypotheses for further study (e.g., specific events or ADR risk factors)

7. 7 UMC: Signal Detection & Follow-up

8. Improving vaccine safety monitoring through the WHO Programme for International Drug Monitoring WHO consultation on improving global AEFI monitoring (9-10 Jan 2006) http://www.who.int/wer/2006/wer8127.pdf Improving AEFI reporting to UMC understanding determinants for AEFI reporting Improving UMC resources and methods for reporting and analysis of vaccine safety data Improving advocacy and communication Linkages with international vaccine safety groups/experts

9. Global Network for Post-marketing Surveillance of New Vaccines To support WHO vaccine prequalification system (supply by UN agencies) with safety data in post-marketing phase Objectives: Ensure standardised approach to monitoring serious adverse events Identify/address potential safety signals in timely manner Ensure adequate safety information to support vaccination policy and recommendations may include recommendations for more controlled studies

10. Global PMS Network: Surveillance methods Start with 10-12 countries Core/standard PMS guidelines adaptation to local resources and systems improve use of standardised terminology and case definitions (e.g., Brighton Collaboration) Case detection public AND private sector stimulated passive system (based on existing systems) active sentinel surveillance for selected events and vaccines monitoring in campaign settings (e.g., JE) Strengthen data analysis, investigation & causality assessment for serious AEs reporting to UMC to enhance signal detection

11. Proposed functional structure

12. A new way to monitor vaccine safety in South Australia

13. First pilot study in Australia to evaluate  ? technical feasibility ? effectiveness ? acceptability of linking Commonwealth and State health records to monitor vaccine safety. We received HSRIP funding in 2004We received HSRIP funding in 2004

19. We received HSRIP funding in 2004We received HSRIP funding in 2004

20. Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute Istituto Superiore di Sanit� Italy

21. Italian Hera study: safety of hexavalent vaccine 2003: signal of possible association between hexavalent product and sudden unexpected deaths raised in Germany Hexavalent vaccines widely used in Italy since 2001 Coverage in Italy for three doses (ICONA 2003, on a sample of 4,602 children from the 2001 birth cohort; Ciofi degli Atti, 2005) >78% by 12th month; >95% by 24th month Case series method used to evaluate risk of death due to unknown or ill defined causes during the first two years of life following vaccination

22. Objectives To evaluate whether the incidence density of unexpected deaths during the first two years of life is higher in periods of time close to vaccine administration (i.e. vaccinations are associated with an increased short term risk of SIDS-SUD)  To compare the incidence density following the administration of one of the two available hexavalent vaccines, and to compare hexavalent vaccines with products previously used in Italy

23. Study design and analysis Five annual cohorts of newborns in Italy (> 500,000 newborns per year); 1 Jan 1999 - 31 Dec 2003 Only vaccinated cases included in analysis For each case, the observation period following each vaccine dose was divided into: Three risk periods following vaccination were considered: 0-1; 0-7; and 0-14 days Control period between the 14th day and the subsequent vaccination or death Confounding factors adjusted by age (=80; 81-100; 101-120; 121-180; 181-360; >360 days)

24. Computation of person-time during at risk- and control-periods

25. Conclusions No increased risk for 0-1 days following vaccination by dose for 2nd year of life For the risk periods 0-7 and 0-14 days most RR estimates were slightly greater than 1 with non-significant confidence intervals At 14 days both hexavalent vaccines had the same estimated risk The RRs concerning concomitant administration of six antigens do not differ from the estimates of the two hexavalent products Manuscript in preparation for publication

26. How can we ensure "ideal post licensure vaccine safety systems" in the WHO Programme? Improving reporting by National Centres to UMC and use of UMC resources and methods for reporting and analysis of vaccine safety data Networks of non-industrialized countries for post-marketing surveillance (incl. data linkage, epidemiological studies etc.) Linkages with international vaccine safety groups and experts Capitalize on experiences from advanced monitoring systems Subgroup of Global Advisory Committee on Vaccine Safety established in Jun 06 to advise on global AEFI monitoring CIOMS/WHO Working Group on Vaccine Pharmacovigilance

27. Acknowledgements the Uppsala Monitoring Centre/WHO Programme for International Drug Monitoring Mike Gold, Sarah Dugdale et al (South Australia Vaccine Safety Study) Stefania Salmaso et al (Istituto Superiore di Sanit�, Italy)