Vaccine Safety and effectiveness need for linked immunization information systems

Transcription

1 Vaccine Safety and effectiveness need for linked immunization information systems Prof. dr. Miriam Sturkenboom, Erasmus University Medical Center, The Netherlands

2 Outline How to monitor vaccine safety /effectiveness? Why do we need vaccination information systems? What is the potential in Europe, example from VAESCO? What are the ethical issues regarding use of IIS in vaccine safety studies?

3 Postmarketing assessment of safety/effectiveness Concerns about vaccine safety has led in the past to crises in public perception of vaccine safety decreases in vaccination coverage, resurgence of communicable diseases Monitoring of vaccine safety should be part of any vaccination programme/strategy Efficacy data limited: additional effectiveness data necessary against comparators

4 Methods for vaccine safety monitoring Monitoring safety (signal detection /failure) Spontaneous reporting of adverse events following immunization (national/international) -> no direct need for immunization registries, possibly to verify exposure in cases Observed vs expected analyses Required: background incidence rates, vaccination coverage, spontaneous reports -> direct need for data on coverage (especially in target groups) Rapid cycle analysis (VSD): -> direct need for immunization registries

5 Study types for hypothesis testing studies (safety and effectiveness) Quantification and verification: assessment of absolute risk and relative risk (Self controlled case series) Case control Cohort design Increasing needs in amount of information All need linked: Vaccine exposure Outcomes Co-variates

6 Self controlled case series Self controlled case series: information on case only during period of follow-up Yields a measure of association only: no absolute risk

7 Case control Case control: uses cases and controls and assesses exposure in certain risk window prior to index date Yields a measure of association only: no absolute risk

8 Cohort Follow-up of dynamic cohort Cohort: need to characterize exposure, outcomes, follow-up and co-variates on entire population Each day of follow-up needs to be assigned to exposure/covariate status Yields a measure of association and also absolute risk

9 Cohort example ORIGINAL ARTICLE A Population-Based Study of Measles, Mumps, and Rubella Vaccination and Autism Kreesten Meldgaard Madsen, M.D., Anders Hviid, M.Sc., Mogens Vestergaard, M.D., Diana Schendel, Ph.D., Jan Wohlfahrt, M.Sc., Poul Thorsen, M.D., Jørn Olsen, M.D., and Mads Melbye, M.D. N Engl J Med 2002; 347: We conducted a retrospective cohort study of all children born in Denmark from January 1991 through December The cohort was selected on the basis of data from the Danish Civil Registration System, which assigns a unique identification number to every live-born infant and new resident in Denmark. MMR-vaccination status was obtained from the Danish National Board of Health. Information on the children's autism status was obtained from the Danish Psychiatric Central Register, which contains information on all diagnoses received by patients in psychiatric hospitals and outpatient clinics in Denmark. We obtained information on potential confounders from the Danish Medical Birth Registry, the National Hospital Registry, and Statistics Denmark.

10 Need for objective information Immunization information registries useful for each design in vaccine safety /effectivenss studies Allow for objective and rapid assessment of each individual s - vaccination timing - vaccination type - vaccination dose - concomitant vaccinations - prior vaccinations In EUROPE: data are available but scattered /fragmented - Public health agencies (local, regional, national: child hood vaccinations) - General practitioners (influenza, some childhood..) - Employers - Travel clinics Exposure and outcome data reside with different groups (linkage difficult)

11 Because of computerized health care we may have great potential for linkage of registries if we take concerted action Hospitalizations (discharge) Population and eligibility period Outpatient prescriptions Death registry Ambulatory visits and procedures Linkage on unique patient identifiers may be subject to special approvals in various countries Cancer registry Birth registry Vaccination registry

12 What do we mean with health care databases? We do not mean the databases with spontaneous reports! Medical record databases from GPs Claims (Administrative databases/insurances) linked to registries On well defined populations (millions) Used very successfully in quantification of safety and effectiveness in drugs / influenza vaccination

13 Example of cohort study using GP database Effectiveness of influenza vaccination Figure. Hazard Ratios for Mortality by Individual Vaccination States, Stratified by Population Mortality risk is shown by the number of successive vaccinations, ie, first, second, third, fourth, fifth, more than 6, interruption of vaccination (stop), or restart. Voordouw, A. C. G. et al. JAMA 2004;292: Copyright restrictions may apply.

14 Population based health care databases in EU UK: GPRD, THIN, QRESEAR CH, IMS: > 20 M Scotland: 5M NL: PHARMO/ IPCI 5M Nordic countries: > 25M DE: 12 M ES: BIFAP 2.5M IT: HSD, PEDIANET 2 MI IT ISSRs: 30M Only a few countries have vaccination registries linkable to outcome / population databases although in many countries immunization registries are available Registry/claims based Medical record (GP) Medical record (GP) and claims

15 Utility of (linked) vaccination registries VAESCO: H1N1v and GBS case control study Jeanne P Dieleman, Silvana Romio, Corinne S de Vries, Cormac Sammon, Nick Andrews, Anders Hviid, Henrik Svanström, Ditte Mølgaard-Nielsen, Christel Saussier, Anne Castot, Harald Heijbel, Lisen Arnheim Dahlström, Par Sparen, Jonas Hallgren, Mees Mosseveld, Nicoline van der Maas, Bart Jacobs, Kari Johansen, Piotr Kramarz, Daniel Weibel, Jan Bonhoeffer, Miriam CJM Sturkenboom for the VAESCO CONSORTIUM

16 What is VAESCO? Consortium of European partners academics, public health, regulators (currently 9 countries) Aims for high quality vaccine safety information based on concerted effort of European member states Funded by ECDC, coordinated by Brighton Collaboration

17 Objective of the study To assess the association between H1N1vvaccination and GBS in Europe (a priori safety concern) Look at type of vaccination Look at dose effects Open to all countries (independent of the availability of registries) to start capacity building

18 Designs

19 Data Sources: H1N1v-GBS Case-Control Reporting Network Database Study Selfcontrolled case series Reporting Network Database

20 Case /control definition Cases Guillain-Barré syndrome (GBS) and variants of GBS such as Miller-Fisher syndrome (MFS) Validated by Brighton collaboration definition Level 1-3 Or specialist diagnosis (letter available) and independent expert review of all case information independent of exposure (locally) Controls Community controls: 4-20, matched to the case on index date, age, sex and country (site)

21 Data entry standa remain lo

22 How to combine data and overcome ethical and data formatting issues: distributed model LOCAL SHARED A JAVA based script that harmonizes data formatting/ elaboration Script Database 1 Database 2 Database.. n Input Output Aggregated data pooling

23 How are data being pooled? Individual Casetype Caseid Exposure type 001xxxx D1+D2 001xxxx exp1 001xxxx D2 001xxxx D2+exp2 Jerboa Output Format Case control study Individual Exposure Interval length 001xxxxx D1+D Number of events Jerboa Output Format SCCS 001xxxxx D1+D2+D xxxxx D1+D xxxxx D1+D2+exp xxxxx D1+D

24 The VAESCO experience towards EVSD Countries with Record linkage: use of aggregated data often possible, linkage between vaccination registries and population /outcome data is an issue that delays rapid (prospective) safety studies despite the availability of data in Norway, Finland, Sweden, Iceland and in Denmark to some extent. Medical records: Medical record databases (from GPs) can be used after governance approval, but they do not capture all vaccines and are not nationwide: linkage to national immunization registries may need to be promoted (UK, NL, Spain, Italy.) Insurance based: insurance companies may capture some vaccination data and outcomes, not used to large extent and not linked to national immunization registries (Germany, Switzerland, France, Belgium ) Non-linked: Some countries have population based data, but not electronically and not linked to population or outcomes (Italy, France.)

25 Specific Ethical issues regarding processing of data All member states are signatories of the European Convention on Human Rights (ECHR) from the Council of Europe. According to article 8 of the ECHR people have, subject to certain restrictions, a fundamental right to respect for one's "private and family life, his home and his correspondence". This right is embedded into national legislation of most member states. Data privacy laws, however, vary widely across Europe. The European Commission (EC) realized that this diversity of national legislation impedes uniform data protection and the free flow of data within the EU zone. Therefore the EC drafted the Directive 95/46/EC on the protection of individuals with regard to the processing of personal data and on the free movement of such data ( Directive ) to harmonize data protection regulation within the EU Implementation was required in national law by 1998 Not a closed regulatory system and leaves open a certain scope for policy making at national level, certain minimum requirements must be complied with. This also applies to the processing of personal data for scientific purposes

26 Ethical issues Principle Directive: personal data may not be processed except under certain conditions. These conditions fall into three categories: legitimate purpose, transparency and proportionality Subject has the right to access data processed on him, thus there must be a registry for which purposes and by whom the data are processed. Database owners need to specify how they keep a registry (transparency). Consent is not necessary where the data have not been obtained from the data subject himself. In these cases Member States shall provide appropriate safeguards. Whenever data is collected from the subject himself, consent is necessary. Personal data should be processed adequately anonymously, and correctly and kept up to date and not stored longer than necessary. For safeguard and transparency reasons each database has own governance principles which may lead to additional hurdles EC directive currently being reviewed/updated : open for comments!

27 The VAESCO approach towards safety assessment All countries can participate in vaccine safety assessment but it is much easier with linked IIS Through pragmatic approach and showing the benefit of concerted action we would like to create awareness and proof of potential and needs, each country alone may be too small/weak. VAESCO one of the first to come with association between H1N1v and GBS so there are possibilities and there is even more potential

28 Thank you for your attention! THE VAESCO consortium Brighton Collaboration, ECDC, THL (Finland), SSI (DK), RIVM (NL), AFFSAPS (France), AIFA (Italy), SIMG (Italy), the Green Channel (Italy),Erasmus University (NL), Helath Protection Agency (UK), Bath University (UK), AEMPS/BIFAP (Spain), Paul Ehrlich Institute (Germany), Norwegian Institute of Public Health Swedish Institute for Infectious Disease Control.