1. 1 Proposed Pharmacovigilance Plan for H5N1 Influenza Virus Vaccine Patrick Caubel, MD, PhD Head of Pharmacovigilance North America February 27, 2007

2. 2 Background Planning for the prospect of pandemic influenza is one of the most effective steps to mitigate the impacts of such an event Vaccination remains a critical defense against pandemic influenza Vaccine safety monitoring is necessary Part of a comprehensive public health surveillance program

3. 3 Pharmacovigilance Plan Objectives Detect, evaluate and minimize risks due to the pandemic influenza vaccine Contributes to the benefit-risk evaluation in a pandemic situation Agree beforehand on: Objectives for postmarketing safety surveillance Collaborative plan with key stakeholders Put in place an adequate system tailored to a pandemic situation to allow adequate responses

4. 4 Pharmacovigilance (PV) Planning PV activities have to be designed considering the following: 1. Limited clinical data available 2. High volume of safety data anticipated within a short time frame 3. Increased public anxiety with AEs (adverse events) reported, regardless of causality 4. Limited personnel in industry and regulatory agencies 5. Possible disruption of pharmacovigilance systems Need for an on-going safety signal detection and evaluation Feasibility and effectiveness of the proposed actions/ measures need to be tested prior to the pandemic

5. 5 Pre-pandemic: Standard PV Practices Applicable in pre-pandemic period: Spontaneous reporting Aggregate reports at defined time intervals Signal detection and analysis Safety surveillance studies (possible cohort study in first responders) Passive collection of vaccine failure reports Objective: Develop a better understanding of vaccine safety profile that could impact pandemic safety monitoring

6. 6 Pandemic: Proposed PV Practices Applicable in pandemic situation: Spontaneous reporting with a focus on special AEs Simplified aggregate reports Real time signal detection and analysis Safety surveillance studies (in early recipients after pandemic is declared) Passive collection of vaccine failure reports Objective: Allocation of available resources on tasks critical for understanding the evolving benefit-risk profile in a pandemic situation

7. 7 Spontaneous Reporting: Data Collection Spontaneous reporting will remain the basis for safety evaluation One common simplified and targeted collection form could be used by all parties when the vaccination process begins Healthcare professionals and patients should be encouraged to report primarily serious adverse events, life-threatening events, adverse events of special interest (AESI), and deaths

8. 8 Spontaneous Reporting: Adverse Events of Special Interest All parties must consider a list of adverse events of special interest (AESI) for which a common case definition will be used in order to ensure harmonized safety assessment EMEA has proposed a list of AESI for pandemic vaccine surveillance

9. 9 Spontaneous Reporting: Safety Database Rapid and open communication and information sharing between sanofi pasteur, other vaccine manufacturers and Authorities/Public Health Services (FDA, CDC, state and local authorities) is essential Electronic communication should be established prior to the pandemic period One single safety database dedicated to flu pandemic vaccines could be used and shared by all parties (VAERS database)

10. 10 Aggregate Reports Periodic Safety Update Reports (PSURs) are prepared at defined time intervals; however, during the pandemic period due to limited resources, preparation and submission of PSURs may not be feasible Options: Simplified PSURs Focusing on serious adverse events, deaths, life-threatening events, and AESI can be prepared. PSURs prepared on an ad-hoc basis upon request from Health Authority An aggregated PSUR will be submitted when the pandemic is declared finished

11. 11 Signal Detection and Analysis Crude inspection of single cases or line-listings not adequate Quantitative and automated data-mining methods should be considered (e.g. proportional reporting ratios, Bayesian methods) Modification of standard methods may be required (stratifications, use of appropriate comparator) May detect increase in incidence of AESI and support detection of unexpected AEs Should be tested with seasonal flu vaccines

12. 12 Monitoring for Vaccine Effectiveness There is no vaccine that is 100% effective Vaccine failure evaluation done through pharmacovigilance monitoring should not be used to assess vaccine effectiveness

13. 13 Safety Surveillance Studies Safety profile will remain unknown in numerous populations prior to vaccination campaign Consideration should be given to initiating cohort studies either prior to the pandemic (first responders, critical workers) or after the pandemic is declared (early recipients) Case-control studies using large population-based databases (e.g. Vaccine Safety Data Link) may be useful for rare serious AEs Should be coordinated by national and international public health agencies

14. 14 Summary Streamlining and prioritization are essential for early detection and communication of potential risks Pharmacovigilance plan and information-sharing system could be tested and harmonized during the forthcoming and subsequent flu seasons Proposed pharmacovigilance actions are part of an evolving plan to be refined with key stakeholders, together with roles and responsibilities Sanofi pasteur is committed to global pandemic preparedness

15. 15 Conclusion Safety of our vaccines are of paramount importance for sanofi pasteur. Sanofi pasteur is prepared to work with the Government on efficient methods of collecting safety and effectiveness data.