Update on the febrile seizure signal after influenza vaccine David Martin, MD, MPH Pharmacovigilance Branch Division of Epidemiology Office of Biostatistics and Epidemiology Center for Biologics Evaluation and Research February 25, 2011

2 Background Febrile seizures: seizures that occur in febrile children who do not have an intracranial infection, metabolic disturbance, or history of afebrile seizures 1,2 Affects 2-5% of young children in the United States 1 Usually occurs at ages 6-60 months Peak age months Australia suspended 2010 seasonal trivalent influenza vaccination for all children < 5 years old in April 2010 In the US, the CSL influenza vaccine (Afluria) is not recommended for children <9 years for the influenza season due to these findings 3 Enhanced monitoring for febrile seizures was conducted by FDA and CDC in the season 1 AAP. Pediatrics. 2008;121: Johnston M. Nelson Textbook of Pediatrics

3 Framework for Vaccine Safety Monitoring at the FDA Center for Biologics Evaluation and Research Signal detection Signal evaluation: hypothesis testing in a formal pharmacoepidemiologic study Active surveillance Signal validation Signal strengthening VAERS Safety data from clinical trials Other sources Periodic Reporting by sponsors In order to detect new unexpected safety signals, CBER medical officers rely on VAERS, safety data from clinical trials, periodic reporting by sponsors, and other sources such as the medical literature. These safety signals then become new outcomes of interest which are the subject of active surveillance activities. If the signals are strengthened and validated in these systems, then they can be tested in formal epidemiologic studies.

4 Product - event disproportionality in VAERS Statistic called Empirical Bayesian Geometric Mean (EBGM) quantifies disproportional reporting in the VAERS database FDA ranks influenza product brand name-event combinations by the lower 5% bound (EB05) of the confidence interval surrounding the EBGM More specific than EBGM Limitations of VAERS apply: EBGMs and EB05s do not demonstrate causality

5 Fluzone – febrile seizure signal FDA VAERS data mining signaled for the combination of Fluzone and the coding term febrile convulsion in December 2010 EB05>2 with no stratification of the database Signal strengthened in the 0-18 months age stratum Signal has persisted into January 2011 No interaction with other vaccines No other independent vaccine product - febrile convulsion findings to date FDA and CDC reviewed available VAERS data mining and VSD rapid cycle analysis findings FDA and VAERS public communication issued on January 20,

6 Signal strengthening in VSD Prospective surveillance for febrile seizures in Influenza RCA Signal identified Prospective surveillance for febrile seizures in Pneumococcal Conjugate RCA for PCV13 No signal Joint signal evaluation in Influenza and Pneumococcal RCA Signal with concomitant administration Grace Lee, ACIP presentation, 2/23/2011

7 Seizures Definition in Influenza RCA, Age group 6 months – 4 years 5 – 17 years ICD9 codes 780.3* Convulsions Setting Inpatient or ED only Time period Risk Window 0-1 days (based on findings from Australia) Comparison Window days First in 6 months 7 Grace Lee, ACIP presentation, 2/23/2011

8 Self-Controlled Rapid Cycle Analysis for 780.3* and TIV, 6-59 mo 8 Grace Lee, ACIP presentation, 2/23/2011 The VSD primary analysis signaled on December 26, 2010 when the log likelihood ratio crossed the critical value.

9 Concomitant Vaccines among Cases and Vaccinees 6-23 months, Seizure cases (N=20) The majority concomitantly received either PCV13 (75%) and/or DTaP- containing vaccines (65%) 11 children received both PCV13 and DTaP-containing vaccines Only 15% of seizure cases received TIV only (i.e. no concomitant vaccines given) TIV vaccinees (N=77,338) Fewer TIV vaccine recipients concomitantly received PCV13 (36%) and/or DTaP-containing vaccines (34%) 44% received TIV only Of note, many children received both PCV13 and DTaP simultaneously with TIV, but only PCV13 was new this season Grace Lee, ACIP presentation, 2/23/2011

10 Joint signal evaluation in Influenza and Pneumococcal RCA Design: Self-controlled Seizures definition harmonized for influenza and PCV13 protocols: Age group: 6-11mo; mo; mo ICD9 codes: 780.3* Setting: Inpt, ED Risk window: 0-1 d Comparison window: d First in 42 days Attributable risk estimated from self-controlled design Grace Lee, ACIP presentation, 2/23/2011

11 Joint febrile seizure evaluation findings in 12 – 23 month old children * +/- other non-TIV, non-PCV vaccines; assuming chart confirmation rate of 80% Case(0-1) Case(14-20) 240,08862,457210,06958,02314,25834,109Doses 08/ /1005/ /11 Grace Lee, ACIP presentation, 2/23/2011 Attributable risk 61 (95% CI: +13 to +109) per 100,000 doses ~1 in 1,640 vaccinees for febrile seizures on days 0-1 following vaccination noted for TIV + PCV13* vaccinees for month old children

12 Summary Biologic plausibility Whole-cell pertussis vaccines, measles-containing vaccines and 2010 Southern Hemisphere CSL TIV have been associated with an increased risk of febrile seizures DTaP was not associated with febrile seizures in a recent VSD analysis VAERS data mining Fluzone-febrile seizure signal VSD prospective Historical and Self Controlled Analyses Signal for 780.3* after TIV No signal for 780.3* after PCV 13 VSD Joint Analysis Signal for concomitant administration Attributable risk ~ 61 per 100,000 doses

13 Next Steps VSD investigation plans Case ascertainment will continue until the end of influenza season Chart review for all cases that received PCV13 and/or TIV on days 0-1 and will be completed, and attributable risk estimates will be updated based on chart review Role of other concomitant vaccines will be assessed ACIP Working Groups General Recommendations Working Group will consider additional information on febrile seizures following vaccination in coordination with other ACIP working groups as appropriate

14 Acknowledgements Frank DeStefano, MD, MPH CDC Immunization Safety Office Grace Lee, MD, MPH, Alison Tse, ScD & Hung-Fu Tseng, PhD, MPH on behalf of the Influenza and Pneumococcal Conjugate Vaccine RCA Working Groups Harvard Pilgrim Health Care Institute and Southern California Kaiser Permanente FDA CBER Pharmacovigilance Group

15 Joint FDA/CDC VAERS descriptive analysis: December 13, 2010 Forty-two febrile seizure cases after Fluzone All recovered Ten (24%) serious*; most hospitalized overnight and released Vaccination to onset interval Median: 10 hours Range: 3 hours to 10 days 86% occurred on the same day or day after administration Concomitant vaccination reported in 27 (64%) of cases. Medical history Family history of seizure in 7 (17%) cases Concurrent illness (URI or GI) in 6 (8%) of cases Temperature elevation: to 104°F No apparent geographic or product lot clustering * Regulatory definition: Any adverse experience occurring at any dose that results in any of the following outcomes: Death, a life-threatening adverse experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect.