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

2. 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)

3. 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

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

5. Background

6. 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

7. Clinical trials
4497 children ages 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

8. 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

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

10. 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

11. 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

12. 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

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

14. 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

15. 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

16. 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

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

18. 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 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

19. Relative Risk (RR) & Attributable Risk (AR) First Dose 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)

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

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

22. 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

23. 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

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

25. Temporal Distribution of Seizures After Simultaneous MMR and Varicella Vaccination
Number of Seizures
( , ~90,000 vaccine visits)

26. 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

27. 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

28. 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.

29. 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

30. 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

31. 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

32. 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.

33. 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

34. Fin

35. Backup Slides

36. 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

37. 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

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

39. 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 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)

40. 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

41. 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

42. 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

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

44. 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

45. 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

46. 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.