Sukhminder K. Sandhu, PhD, MPH, MS LCDR, USPHS FDA/CBER/OBE/DE/AEB

1. Update on Surveillance for Guillain-Barré Syndrome after Vaccination with Pandemic Influenza A/H1N1 2009-containing Vaccines, 2009–2011 VRBPACNovember 16, 2011 Sukhminder K. Sandhu, PhD, MPH, MS LCDR, USPHS FDA/CBER/OBE/DE/AEB 1

2. Background • As part of pandemic preparedness, the following systems conducted enhanced safety monitoring for pandemic influenza A/H1N1 2009-containing vaccines* • http://www.hhs.gov/nvpo/nvac/reports/vsrawg_repot_may2010.html; dose numbers updated by respective systems. • † Preliminary number of doses for current 2011–12 season. 2

3. Background (cont’d) Surveillance methods were applied to detect Guillain-Barré Syndrome (GBS) after pandemic influenza A/H1N1 2009 vaccination GBS was associated with the 1976–77 swine influenza vaccine1,2 Elevated relative risk of 7.60 within 6 weeks after vaccination, attributable risk of 8.8 cases per million vaccinations Highest risk 2–3 weeks after vaccination Assessments of subsequent influenza vaccines have not found as high of a risk, with the highest attributable risk on the order of 1–2 cases per million vaccinations3 In 2009, enhanced safety monitoring began for pandemic influenza A/H1N1 2009 vaccine 2010–11 and 2011–12 trivalent vaccines have the same 3 strains, including the pandemic influenza A/H1N1 2009 strain ¹Am J Epidemiol. 1979;110:105-123. ²Am J Epidemiol. 1991;133:940-51. ³N Engl J Med. 1998;339:1797-1802. 3

4. Objective To provide a brief update on GBS after vaccination with pandemic influenza A/H1N1 2009-containing vaccines from 2009–10 to 2011–12 influenza seasons 4

5. End of Season Analysis Methods Influenza A/H1N1 2009-containing vaccines, 2009–2011 GBS case definition 2009-Chart-confirmed GBS cases using Brighton level case definitions 2010 and 2011-No chart review, GBS cases defined using ICD-9-CM data only Exposed window Up to 42 days post-vaccination with pandemic influenza A/H1N1 2009-containing vaccines Comparator Historical GBS rates among seasonal influenza vaccinated individuals Unexposed time periods Risk Interval Self-controlled Case-centered Unvaccinated persons 5

6. End of Season Results Influenza A/H1N1 2009 Monovalent Vaccine, 2009–10* • High degree of variability in the RR suggests that chance or uncontrolled confounding could contribute to the findings • An HHS funded meta-analysis is in process. * Slides adapted from Presentation by Dr. Claudia Vellozzi at ICPE 2011; † P-value < 0.05 6

7. CMS Near Real-time Surveillance MethodsInfluenza A/H1N1 2009-containing Vaccines, 2010–2011 • Updating Sequential Probability Ratio Test (USPRT) accounts for repeated testing and delay in claims • Primary Analysis • 0–42 day risk window • All influenza A/H1N1 2009-containing vaccines • All ages • Secondary Analyses: Variation of risk windows, age groups and vaccine types • Signal defined as an observed GBS rate higher than critical limit • Critical limit is a threshold defining rates that are statistically higher than that expected based on prior 5 influenza seasons

8. CMS Near Real-time Surveillance Results Influenza A/H1N1 2009-containing Vaccines, 2010–11 Secondary (7–21 days) Analysis Signaled (No chart reviews, ICD-9 data only, Inpatient setting only) Secondary analysis signaled when observed rate surpassed critical rate

9. CMS Near Real-time Surveillance Results Influenza A/H1N1 2009-containing Vaccines, 2010–11 Primary (0–42 days) Analysis Signaled (No chart reviews, ICD-9 data only, Inpatient setting only) Primary analysis signaled when observed rate surpassed critical rate

10. CMS Near Real-time Surveillance Results Influenza A/H1N1 2009-containing Vaccines, 2010–11 Primary (0–42 days) and Secondary (7–21 days) Analyses (No chart reviews, ICD-9 data only, Inpatient setting only)

11. CMS End of Season ResultsInfluenza A/H1N1 2009-containing Vaccines, 2010–11 • CMS (no chart reviews, ICD-9 data only, inpatient setting only) • Cohort analysis (historical comparator of prior 5 influenza seasons) • 15,333,318 vaccinated beneficiaries • Observed: 97 cases (6.33 cases per million person-periods*) • Expected: 78 cases (5.07 cases per million person-periods*) • RR = 1.25 • Association statistically significant • Risk interval analysis (Weeks 1–6 vs. Weeks 9–14) • 15,086,159 vaccinated beneficiaries • Weeks 1–6: 95 cases (6.3 cases per million person-periods*) • Weeks 9–14: 71 cases (4.7 cases per million person-periods*) • RR = 1.3, 95% CI = 0.98–1.8 • Association NOT statistically significant * Per million person-periods. A person counted for the entire 42 days contributes 1 person-period.

12. VSD End of Season ResultsInfluenza A/H1N1 2009-containing Vaccines, 2010–11 • VSD (no chart reviews, ICD-9 data only, Days 1–42, first event in year from any setting)* • 2,826,287 TIV doses administered • Observed: 26 cases (9.2 cases per million doses) • Expected: 22.6 cases (8.0 cases per million doses) • RR = 1.2 • No signal detected * Courtesy of VSD/ISO/CDC

13. CMS & VSD Near Real-time Surveillance Preliminary Results Influenza A/H1N1 2009-containing Vaccines, 2011–12 • CMS • Actively conducting surveillance for GBS post-influenza vaccination since August 06, 2011 • As of November 04, 2011, a total of 9,014,787 doses observed • 15 recorded post-vaccination GBS cases • No signal for GBS • VSD* • 1.5 million TIV doses administered • No signal for GBS * Courtesy of VSD/ISO/CDC

14. Limitations Due to rarity of GBS, incidence estimates are unstable and dependent on weeks selected for risk and/or comparator windows Potential confounders Secular trends in GBS Influenza infection seasonality Other infections Use of administrative claims data Possible misclassification of outcome GBS defined by ICD-9-CM diagnosis code Possible misclassification of onset date Admission date used as surrogate for onset date 14

15. Conclusions The 1976 swine influenza vaccine was associated with an increased frequency of Guillain-Barré syndrome. Evidence for a causal relationship with subsequent vaccines prepared from other influenza viruses is unclear, but if influenza vaccines pose a risk, it is probably slightly more than 1 additional case per 1,000,000 vaccinees. Analyses in some, but not all, surveillance systems used in the 2009-2010 season suggest that the risk may have exceeded that seen in recent influenza seasons This risk was likely considerably smaller than the risk of GBS after the 1976 swine influenza vaccine. The lack of consistent statistically significant results within and across systems and years suggests that the findings noted could be due to chance or confounders The pandemic influenza A/H1N1 2009 monovalent vaccine data are contributing to a meta-analysis coordinated by the HHS National Vaccine Program Office. The analyses are ongoing and once completed, will allow us to better define risk, taking into account all systems. Analyses from surveillance systems used in the 2010-2011 season suggest a risk closer to that seen after previous seasonal influenza vaccines. In addition, in the current influenza season, FDA and CDC have not detected a safety signal for Guillain-Barré syndrome after 10,500,000 vaccinations in the Centers for Medicare and Medicaid Services and Vaccine Safety Datalink systems. 15

16. CMS Jeffery A. Kelman, MD, MMSc Christopher Worrall FDA Robert Ball, MD, MPH, ScM Dale Burwen, MD Theresa Finn, PhD Wei Hua, MD PhD MS MHS Hector Izurieta, MD, MPH Philip Krause, MD David Martin, MD, MPH Laura Polakowski, MD, MSPH Craig Zinderman, MD, MPH NVPO Daniel Salmon, PhD, MPH Acumen, LLC Armen Avagyan Jay Donde Riley Franks Bruno Garcia Jonathan Gibbs Garner Kropp Thomas MaCurdy, PhD CDC Claudia Vellozzi, MD, MPH Eric Weintraub, MPH DoD Patrick Garman, PharmD, PhD VA Francesca Cunningham, PharmD Kwan Hur, PhD Acknowledgements 16