Operational experience and lessons learned on influenza vaccination post studies Ombretta Palucci, Senior Director of Real World Strategy Lead Unit authorization safety © Copyright 2015 Quintiles

Enhanced surveillance of seasonal influenza vaccines under EMA guidance of April 2014 2

Interim guidance on enhanced safety surveillance for seasonal influenza vaccines in the EU (1) Objectives of enhanced safety surveillance • Detect a potential increase in reactogenicity and allergic events > intrinsic to the product (i.e. not due to a specific batch deviation or local programmatic issue) > in near real-time in the earliest vaccinated cohort • Establish a framework for enhanced surveillance that is feasible to implement every year http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/0 4/WC500165492.pdf Effective 15 April 2014 2014-15 Season a pilot year 3

Interim guidance on enhanced safety surveillance for seasonal influenza vaccines in the EU (2) Options for enhanced surveillance 1. Active surveillance (PASS)- preferred Enroll vaccinees in routine clinical practice Data collection through web-based survey with telephone follow-up or other approaches > 2. Passive surveillance 1 > Estimate a reporting rate as surrogate for incidence rate of AEIs Numerator - facilitated near real-time vaccine-specific and batch-specific reporting of AEIs Denominator - reliable near-real time data on actual usage of the vaccine (not sales/ distribution data) - - 3. Data mining or other use of electronic health record data 1 > Noted to be of limited use in identifying the required adverse events of interest (AEIs) of reactogenicity and allergic events 1 Requires justification and agreement of competent authority. 4

Interim guidance on enhanced safety surveillance for seasonal influenza vaccines in the EU (3) Requirements for active and passive surveillance • Include at least 100 vaccinees in each age group: 6 months to 5 years, 6 to 12 years, 13 to 18 years, ≥ 18 years-65 years and > 65 years Patients followed-up at 7 days post-immunisation for the stated AEIs (or up to 14 days for live attenuated vaccine) Need to be able to detect a change in the frequency and/or severity of AEIs compared to current product specific information or trial results in first year, and in future years using previous year’s experience as expected • • Based on selection of early/high use region, patient numbers should be achievable within one month 5

Operational experience and lessons learned on influenza vaccination post authorization safety studies 6

Operational Challenges Strategies to increase probability of success Challenges Lesson Learned • Vaccine availability Start of vaccination campaign (start date, age group recommendation) Vaccination coverage • Internal and External data mining Feasibility Close collaboration with Sponsor • Country Selection • Summer period Regulatory Environment ICF Site Contract • Regulatory Intelligence Database for Observational Studies Early submission Age specific ICF/assent form Observational site contract template • Study Set-up • Country specific vaccination site setting Site representativeness to fulfill different age cohort Site Interest Site Resources • Early engagement Fair market compensation Leverage existing site influenza network Diversify site setting (pediatricians, boarding schools) Involve sponsor’s affiliates to share a list of sites using the vaccine Identify back-up sites • • • Site Recruitment • 7

Operational Challenges Strategies to increase probability of success Challenges Lesson Learned • Subject pathway Fulfill all age cohorts Questionnaire completion • Provide study material (e.g. subject welcome package) Provide subject token of appreciation when possible and approved by EC Use multiple technologies (i.e. paper, web, phone) to enhance questionnaire completion Active follow-up of non responders (sending of reminders, follow-up calls, etc.) Age strata recruitment tracking and monitoring through automatic EDC reports • • Subject Recruitment and Follow-up • • • Real time data collection Real time data cleaning Real time reporting • EDC platform fast to set-up and easy to use e-PRO functionality Patient Contact Management System module Customized reports Remote risk based monitoring Technology 8

Case Study 9

Case Study: Active Surveillance Influenza Vaccine (1) Influenza season 2014-15 & 2015-16 Purpose • Under new draft EMA guidance for vaccine enhanced active surveillance, conduct a pilot PASS to collect participant self-reported reactogenicity data, supplemented by HCP data on the details of vaccination, and any medically attended Adverse Events (MAEs) in the seven-day period after influenza vaccination in a given year Study design • Observational prospective cohort study, with site based data collection and participant data collection regarding MAEs through internet survey • Single EU country Objectives • To characterise the reactogenicity (local, systemic and allergic reactions) within seven days after each influenza vaccination in participants routinely indicated for influenza vaccination in specified age groups. • To assess the frequency and severity of MAEs with initial symptom onset within seven days after each 10

Case Study: Active Surveillance Influenza Vaccine (2) Influenza season 2014-15 & 2015-16 Influenza Vaccine (2) Challenge Solution • Seasonal disease context • Strict and short timelines to set-up the study • Fast Subjects recruitment • Summary Safety Report at 30 days from the first doses of the product being used • Regulatory intelligence to speed up start-up • Team expertise in Vaccines and observational studies • Efficient Site selection to identify highly performing sites • Right EDC system to allow for fast set-up and intuitive use (limited training to users needed) • Close collaboration with the Sponsor and the local affiliates • Relevant Site training and close collaboration • Direct to Subject Follow-up • Remote risk-based monitoring fit for purpose Result Pilot for Full PASS (2014-15) • 10 Active Sites • FPI Oct14 • > 260 Subjects in approx. 5 weeks enrolment • 70% of subjects provided post-enrolment safety data Full PASS (2015-16) • 12 Active Sites • FPI Sep15 • > 400 Subjects in approx. 3 weeks enrolment • > 82% of subjects provided post-enrolment safety data Lessons Learned • Early study set-up together with pre-agreed site specific recruitment numbers accelerates recruitment • Setting differentiation increase recruitment in the pediatric cohort • Hands on site training increases timely data entry, e-diary compliance and data quality • Reminder calls increase subject compliance . 11

Conclusion 12

Conclusion Collaboration While challenging due to time constraints of data collection within the vaccination campaign season, execution of successful enhanced safety surveillance consistent with EMA guidance is possible with: Collaboration 13

Thank you 14