This document provides an introduction to causality assessment in determining if a vaccine has caused an adverse reaction in a patient. It discusses the evidence and methods used in causality assessment including biological hypotheses, individual case reports, and epidemiological studies. Challenges in vaccine causality assessment are also outlined due to complex vaccine composition and simultaneous administration. The document concludes by noting causality assessment is the first step to determine an appropriate response and can be difficult, requiring consideration of multiple clinical, biological and epidemiological factors in each case.

1. INTRODUCTION TO CAUSALITY ASSESSMENT

4. EVIDENCE FOR CAUSALITY Biologic hypothesis Individual cases Epidemiologic studies Uncontrolled observational studies Cohort Case control

6. SINGLE CASES/ UNCONTROLLED OBSERVATIONAL STUDIES Meyboom et al.: 1992 Pharmacological effects Previous knowledge Clinical characteristics Lab findings Data quality Likelihood/exclusion of other causes CAUSALITY Association (time, place ) Biological Plausibility Temporal association Geographically associated Local reactions Reproducibility Reliability Rx, risk factors, susceptibility, progamme error Confident diagnosis of lesion lab results favour causation

7. ADVERSE DRUG REACTION VS. ADVERSE EVENT Adverse drug reaction (event attributed to drug ) Adverse event All spontaneous reports Events not attributed to drug Diseases Other drugs Environment Diet Genetics Compliance Other factors Programmatic errors

9. Classify and compare (3) EPIDEMIOLOGIC STUDY: CASE-CONTROL STUDY // Begin Risk factor + Drug A Risk factor - No drug A Risk factor + drug A Risk factor - No drug A - Cases - People with disease or outcome - Controls - People without disease/outcome Past Present //

10. (3) EPIDEMIOLOGIC STUDY: COHORT STUDY Study population Free of disease Have outcome already (exclude) Risk factor + drug A Risk factor - No drug A Disease/outcome + Disease/outcome - Disease/outcome + Disease/outcome - // Present Future

11. EPIDEMIOLOGICAL STUDIES Case control studies Cohort studies Adverse event Yes No Total Vaccine Yes a b a+b No c d c+d Auriche M, Loupi E. Drug Safety 1993; 9 (3): 30-35 Risk ratio= Risk in vaccinated: A/A+B Risk in unvaccinated: C/C+D

13. Knowledge of the adverse drug effect (%) // Signal assessment Time Signal generation Strengthening Signal Signal DISCOVERY OF AN ADVERSE EFFECT Follow-up Meyboom RHB et al Drug Safety 1997;17(6):374-389 0 100 70 20 50 //

18. YOUR DECISION ON CAUSALITY WILL DETERMINE HOW YOU AND OTHERS WILL REACT ...