Adverse Events Following Licensure of Measles, Mumps, Rubella and Varicella Vaccine (ProQuad*) September 2005- March 2008 Hector S. Izurieta, MD, MPH Division of Epidemiology/OBE/CBER Food and Drug Administration * Trade Mark used for identification purposes only

On Behalf of: VAERS Study Team: Wei Hua, Patrick O’Connor, Emily Woo, Soju Chang, Robert Ball and Miles Braun (FDA) Penina Haber, Mona Marin, Karen Broder, Elaine Miller and John Iskander (CDC)

VSD Study Team Northern California Kaiser Permanente Nicola Klein, MD, PhD Roger Baxter, MD Ned Lewis, MPH Bruce Fireman, MS Paula Ray, MPH Liisa Lyons Pat Ross Harvard Pilgrim Tracy Lieu, MD, MPH Katherine Yih, PhD, MPH Ruihua Yin, MS Sharon Greene, PhD, MPH Martin Kulldorff, PhD CDC Eric Weintraub James Baggs, PhD Julianne Gee, MPH John Iskander, MD, MPH Karen Broder, MD

Merck Phase 4 Observational Cohort Study Team* Patricia Saddier, MD PhD, Merck Research Laboratories Steve Jacobsen, MD PhD, Southern California Kaiser Permanente (Principal Investigator)

Background

ProQuad (MMRV) Licensure Measles, mumps, rubella and varicella vaccine live The antigens are those used for MMR and Varicella vaccines Contains higher dose of varicella virus FDA Licensure, September 6, 2005 Approved for children ages 12 months to 12 years ACIP recommended its use in 2006

Clinical trials 4497 children ages 12-23 months received first dose of MMRV Safety was compared to MMR + V Used 42 day risk period post-vaccination Systemic adverse events at significantly higher rate for MMRV than MMR+V: Fever (21.5 vs. 14.9%) Measles-like rash (3 vs. 2.1%) No sequelae, small number of febrile seizures Lower fever rate after 2nd dose of MMRV than after 1st dose

Post-Marketing Passive surveillance, Vaccine Adverse Event Reporting System (VAERS) Phase 4 observational study febrile seizures and general safety, days 5-12/ 0-30 >25,000 subjects Vaccine Safety Datalink (VSD) Rapid Cycle Analysis (RCA) study

Main Findings from the Vaccine Adverse Events Reporting System (VAERS)

VAERS Passive surveillance system for reporting vaccine adverse events (AEs) Voluntary Easy to report Nationwide reach Useful for: Signal detection Monitoring known reactions Identifying possible risk factors Vaccine lot surveillance

VAERS Limitations Usually can’t assess if vaccine caused reported event: Reported diagnoses often not verified Lack of consistent diagnostic criteria Wide range in data quality, under-reporting Inadequate denominator data No unvaccinated control group Outcomes requiring timely laboratory confirmation better investigated in settings other than VAERS

VAERS Quantitative Analysis Reporting rates vs. background rates Proportion of reports for one specific AE among total reports for the same vaccine “Data mining” - Identify events reported more commonly for one product than others Proportional Reporting Ratios (PRR) *Empirical Bayesian Geometric Mean (EBGM) , EB05 Data mining doesn’t account for medical knowledge or biases in reporting – Need expert judgment * Explore differences in proportionality of AE reports for a given vaccine compared to others using Empirical Bayesian methods

VAERS Search Criteria U.S. cases only Vaccinated since MMRV licensure (09.06.2005) Reports received during 09.06.2005 – 03.10.2008 Compares AE reports for MMRV vs. MMR+Varicella

Adverse Event Reports for MMRV Compared to MMR+Varicella   MMRV (All ages) % of All MMRV Reports MMR+ V % % of All MMR+V Reports All Reports 1,904 100 1,732 Serious 113 5 126 7.3 Deaths 0.26 9 0.52

Main Adverse Events of Interest: MMRV vs. MMR+Varicella Per 1,000 MMRV VAERS Reports MMR+V (#) Per 1,000 MMR+ V VAERS Reports Anaphylaxis 7 3.7 11 5.8 Urticaria 124 65.1 118 62.0 Ataxia 3 1.6 Convulsion 54 28.4 66 34.7 Meningitis 1 0.5 2 1.1 Encephalitis 4 2.1 Arthritis Thrombocytopenia

VAERS Data Mining:* Significant EBO5 Scores by Age Group For children aged <1 year: medication error For children ages 1-<2 years Rash (morbiliform, others) Abnormal chest X-Ray Tonic-clonic movements For individuals aged >6 years: Injection site reactions of various types Body temperature increase * Compares MMRV with all other vaccines

Main Findings from Merck’s Phase 4 Observational Cohort Study* *Extracted from Dr. Patricia Saddier’s February 27, 2008 ACIP presentation

Pre-specified Study Objectives Primary Objective – To study the risk of febrile seizures after MMRV compared with MMR+V given as separate injections Incidence and relative risk 5-12 days after first dose Among children 12-60 months of age Other time windows include 0-4 and 0-30 days Secondary Objective - General safety Children 12 months-12 years of age 1st or 2nd dose 0-30 day time period →General safety evaluation: No safety signal in interim results

Relative Risk (RR) & Attributable Risk (AR) First Dose - 12-60 Months of Age Interim Results: Confirmed Febrile Seizures Days MMRV (N = 14,263) MMR + V (N =14,263) RR (95% CI) AR Rate/1000 (95% CI) Cases Rate /1000 5-12 7 0.5 3 0.2 2.3 (0.6, 9.0) 0.3 (-0.2, 0.8) 5-30 10 0.7 14 1.0 0.7 (0.3, 1.6) -0.3 (-1.0, 0.4) 0-30 19 1.3 0.7 (0.4, 1.5) -0.4 (-1.2, 0.5)

Confirmed Febrile Seizures by Day of Onset Rate/1000 – MMRV and MMR+V

Findings from VSD Study * Extracted from Dr. Nicola Klein’s February 27, 2008 ACIP presentation

Participating Vaccine Safety Datalink Sites Group Health Cooperative Northwest Kaiser Permanente Health Partners Harvard Marshfield Clinic No. CA Kaiser Permanente Kaiser Permanente Colorado CDC = Infants, children, adolescents under 18 = All ages

Overview of MMRV Study Age: 12-23 months Outcomes monitored: Ataxia - Thrombocytopenia Seizures - Arthritis Meningitis and encephalitis - Allergic reactions 42 days of post vaccination monitoring, initially using rapid cycle analysis (RCA) for signal detection For RCA, expected rates of seizures, ataxia, and allergic reactions calculated based on historical rates

Temporal distribution of seizures after MMRV vaccination Number of Seizures Days Post-MMRV Vaccine (2/06-9/07, after 47,137 vaccine visits)

Temporal Distribution of Seizures After Simultaneous MMR and Varicella Vaccination Number of Seizures (2004-2005, ~90,000 vaccine visits)

Unadjusted Rates of Seizures 7-10 Days Post-Vaccination MMRV 9.6/10,000 MMR + V 4.9/10,000 MMR alone 3.5/10,000 Varicella alone 1.5/10,000 Number of seizure/10,000 visits * V= varicella vaccine

Logistic Regression Analysis: Risk of seizure 7-10 days Post-Vaccination using Chart Verified Febrile Seizures Odds ratio* 95% Confidence Interval P-value MMRV versus MMR + V 2.3 1.6, 3.2 <0.0001 *Adjusted for age and influenza season. N for MMRV = 43,353, MMR + V = 314,599

Risk Difference during 7-10 Days Post-Vaccination Window Attributable Risk for MMRV compared to MMR + varicella vaccines. 5.2/10,000 (95% CI 2.2, 8.1) For every 10,000 children who receive MMRV instead of separate MMR + varicella vaccines, there will be approximately 5 additional seizures 7-10 days after vaccination.

Summary (1): VAERS Proportion of serious reports and AEs of interest not higher for MMRV compared with MMR+Varicella Data mining results remarkable only for higher proportionality of tonic clonic movements for MMRV vs. others

Summary (2): Merck Observational Study Preliminary analysis found higher (non statistically significant) rates of confirmed febrile seizures for days 5-12 post-MMRV when compared with historical controls vaccinated with MMR and varicella at the same visit The study also evaluated risk for febrile seizures during days 0–30 after vaccination. This risk was not significantly different for MMRV compared to MMR + V

Summary (3): VSD Observational Study Preliminary analysis found higher (statistically significant) rates of febrile seizures for days 7-10 post-MMRV compared to MMR +V approximately one additional febrile seizure for every 2,000 children vaccinated with MMRV

Change in ACIP Recommendations, February 28, 2008 ACIP does not express a preference for use of MMRV over separate injections (i.e., MMR and varicella) ACIP also recommended establishing a work group to evaluate increased risk for febrile seizures after first dose of MMRV CDC, FDA, and ACIP will communicate updates and implement further necessary actions based on these evaluations.

Other Actions by FDA and CDC On February 28, 2008, FDA approved revised MMRV label that incorporates recent findings CDC and FDA posted information on the internet On March 14, 2008, CDC published MMWR update

Fin

Backup Slides

Clinical Trials Febrile Seizures – MMRV vs MMR+V* Vaccine N Days 0-42 Cases Rate per 1000 MMRV 5,731 13 2.3 8 1.4 MMR + V 1,997 4.0 5 2.5 * Presented by Dr. Saddier at February 27, 2008 ACIP

Post-licensure Study Rationale Higher rate of fever after MMRV than MMR+V in clinical trials To assess incidence of febrile seizure following MMRV To better assess general safety of MMRV in routine practice → Large-scale post-licensure observational study designed with FDA input * Presented by Dr. Saddier at February 27, 2008 ACIP

Main Findings from Merck’s Phase 4 Observational Cohort Study* *Extracted from Dr. Patricia Saddier’s February 27, 2008 ACIP presentation

Study Design & Population Post-licensure observational cohort study Conducted at Kaiser Permanente Southern California (KPSC) Target of 25,000 children for primary objective on Febrile Seizures 1st dose of ProQuad® between 12-60 months of age MMR- and varicella disease/vaccination negative children Febrile seizures confirmed by chart abstraction All results reviewed by external, independent study Safety Review Committee (SRC)

Primary Comparison Group Historical controls vaccinated concomitantly with MMR+V prior to availability of ProQuad® Matched on age, gender, date of vaccination, and dose sequence

Time Periods of Interest for Assessing Febrile Seizures Post-vaccination Days Rationale for Evaluation 0-4 Likely unrelated to MMR, V, or MMRV Possibly related to concomitant vaccines 5-12 Main period of increased fever with MMRV Primary period of interest for FS 5-30 / 0-30 Period of viral replication for all 4 components: Measles, Mumps, Rubella, Varicella

Merck Study Entire Population Preliminary Unvalidated, Unadjudicated Seizure Codes as of Feb 2008 Additional data recently received Neither validated nor adjudicated data Outpatient, ER, & hospital data Validated, adjudicated results expected July-Aug 2008 Days MMRV (N = 31,403) MMR + V (N = 31,403) Cases Rate /1000 5-12 47 1.5 28 0.9 5-30 86 2.7 73 2.3

Findings from VSD Study * Extracted from Dr. Nicola Klein’s February 27, 2008 ACIP presentation

VSD: MMRV Seizure Outcome Seizure definition: First instance coded for epilepsy or convulsion in the Emergency Department or in the inpatient setting 42 days of post vaccination monitoring (initially using RCA for signal detection MMRV usage began in VSD: January 2006 Data analysis began: late June 2007 Number of doses administered (01/08): >60,000

VSD: Chart Review Findings among Febrile Seizure Cases MMRV* (n=42) MMR + V (n=124) Hospitalized 4 (10%) 22 (18%) First seizure event 30 (71%) 86 (69%) Family history 8 (19%) 14 (11%) * Includes two cases with an ICD9 code for encephalitis

VSD: Risk of Seizure 0-42 Days* after MMRV Vaccination Compared to MMR + Varicella Vaccine Odds ratio* 95% Confidence Interval P-value MMRV versus MMR + V 1.32 1.05, 1.64 0.015 *Adjusted for age and influenza season. Attributable Risk for MMRV compared to MMR + varicella vaccines. 5.1/10,000 (95% CI 0.5, 9.7) N for MMRV = 43,406; MMR + V = 314,985 * Presented at ACIP by Dr. Nicola Klein: audience was cautioned that this result is not definitive as VSD is still investigating this particular window.