1. 1 Vaccines and Related Biologic Products Advisory Committee (VRBPAC) May 16, 2007 FluMist ® Influenza Virus Vaccine Live, Intranasal Safety and Effectiveness of FluMist in a Pediatric Population Less than 59 Months of Age R. Douglas Pratt, MD, MPH Chief, Clinical Trials Branch DVRPA/OVRRCBER/FDA

2. 2 Background Overview Current Label Indication and Warnings Review VRBPAC #1: July 26, 2001 Review VRBPAC #2: Dec 17, 2002 FluMist ® Licensure June 17, 2003 FluMist ® Liquid: Licensed Jan 5, 2007 Review of Post-Marketing Vaccine Adverse Event Reports (VAERS) Proposed Label Indication Preview Questions to the Committee

3. 3 FluMist : Current Label INDICATION FluMist ® is indicated for active immunization of healthy children and adolescents, 5-17 years of age, and healthy adults, 18-49 years of age, against disease caused by influenza types A and B contained in the vaccine.

4. 4 FluMist : Current Label WARNINGS –The safety of FluMist in individuals with asthma or reactive airways disease has not been established. FluMist should not be administered to individuals with a history of asthma or reactive airways disease. –The safety of FluMist in individuals with underlying medical conditions that may predispose them to severe disease following wild-type influenza infection has not been established.

5. 5 FluMist VRBPAC # 1 July 26, 2001 Proposed Use: For ages 1-64 yrs Committee Vote: –Effectiveness was demonstrated across the age range –Safety, was not demonstrated Concerns included cases of pneumonia, wheezing in children No information about vaccine co-administration in second year of life (e.g., MMR+V) Main safety study (AV019) ongoing at time

6. 6 Safety Study AV019 9,689 children 1-17 years of age enrolled Randomized 2:1 (FluMist:Placebo) Conducted at N California Kaiser Permanente Medically Attended Events (MAE) evaluated –Electronic database queried for: Clinic visits, ER visits, Hospitalizations Data Collection Period: 42 days after dose Main finding: Asthma/Wheezing in children younger than 5 yrs of age

7. 7 AV019 - Number of 18-35 Month Old Subjects and Increased Relative Risk (90% CI) for Asthma Events in All Settings Combined

8. 8 AV019 – Relative Risk for Asthma Events Post-Dose 1 by Age in 6-Month Increments* (Selected Ages)

9. 9 FluMist VRBPAC # 2 December 17, 2002 Proposed Use: Healthy persons age 5-64 yrs Completed Study 019 safety data presented Committee was asked to discuss and vote on the adequacy of safety and effectiveness data by age groups: 5-17 years 18-49 years 50-64 years

10. 10 VRBPAC # 2 December 17, 2002 (cont.) Committee Vote Effectiveness: –Demonstrated for ages 5-49 years Not effective in age group > 50 years Safety: –Demonstrated for healthy persons age 5-64 yrs

11. 11 FluMist : Post Marketing Studies Licensed June 17, 2003 MedImmune agreed to: Conduct an open-label multi-year clinical safety trial in 60,000 FluMist recipients, 20,000 in each of the following age groups: 5-8 years 9-17 years 18-49 years. Safety outcomes to include asthma/wheezing; all medically attended adverse events (MAEs), serious adverse events (SAEs), including deaths; and rare events potentially related to wild-type influenza virus infection. Final Study Report anticipated in 2011.

12. 12 FluMist Liquid Formulation Approved Jan 2007--replaced frozen formulation Storage at 2-8 °C for 18 weeks, but not beyond June 30 of given influenza season Smaller volume (0.2 mL) Change supported by: –Potency through dating period –Clinical data in children and adults, age 5-49 years, demonstrating an immunologic bridge (non-inferiority) to frozen formulation

13. 13 FluMist Adverse Events Reported to the Vaccine Adverse Event Reporting System (VAERS) As of February 28, 2007

14. 14 Adverse Event Reports to VAERS After FluMist By Age Group* Age groupAll reports N% 6-23 months10.1 2-4 years141.9 5-17 years26635.8 18-49 years37049.7 ≥ 50 years263.5 Unknown679.0 Total744100 * Reports received as of February 28, 2007

15. 15 VAERS Reports: Main Outcomes of Interest by Age Group Age group All reports Asthma/ Wheezing PneumoniaBronchitisPossible Anaphyl- axis GBSBell’s palsy N(%) * N N N N N 6-23 mos1 † 0(0)0 0 0 0 0 2-4 yrs14 ‡ 0(0)0 0 0 0 0 5-17 yrs26616(6.0)7(2.6)2(0.8)5(1.9)0(0)4(1.5) 18-49 yrs3705(1.4)5 3(0.8)8(2.2)5(1.4)4(1.1) ≥ 50 yrs260(0)1(3.8)1 0(0)1(3.8)1 Unknown671(1.5)2(3.0)2 0(0)1(1.5)0(0) Total74422(3.0)15(2.0)8(1.1)13(1.7)7(0.9)9(1.2) * Percentage of total reports in the corresponding age group † Includes vaccine administration error (n=1) ‡ Includes vaccine failure (n=1), rhinitis (n=2), secondary transmission (n=2), rash/other allergic (n=2), abdominal/GI (n=1), seizures (n=1), and vaccine administration error (n=5)

16. 16 VAERS Reports of Asthma/Wheezing by Age Group and Chronic Condition Age group All Reports Asthma/Wheezing TotalPre-existing chronic condition AsthmaOther chronic None 6-23 mos10000 2-4 years140000 5-17 years26616709 18-49 years3705302 ≥ 50 years260000 Unknown671001 Total7442210012

17. 17 VAERS Limitations VAERS is a voluntary, passive surveillance system –Risk of underreporting or reporting bias –Possibly incomplete, unreliable data Outcomes requiring timely laboratory confirmation should be investigated in settings other than VAERS

18. 18 FluMist : Proposed Label Proposed INDICATION FluMist ® is indicated for the active immunization of individuals 1-49 years of age against influenza disease caused by influenza virus types A and B contained in the vaccine.

19. 19 FluMist VRBPAC #3 May 16, 2007 Data from additional clinical studies were submitted in the license supplement that are intended to support use of FluMist in children < 5 years of age. The main study of efficacy and safety in children < 5 years of age was: MI-CP111: Comparative Efficacy and Safety of Liquid FluMist vs TIV in Children 6-59 months of age

20. 20 Clinical Study MI-CP111: Design Randomized (1:1), controlled and comparative, FluMist vs. TIV Double-blind: placebos for intramuscular and intranasal routes Enrollment stratified by age, country, previous influenza vaccination and history of ≥ 3 wheezing illnesses Exclusions for history of severe asthma or recent wheezing Efficacy: –Relative efficacy (vs. TIV) for culture-confirmed modified CDC-ILI influenza as primary efficacy outcome Safety: –Study defined “Medically Significant Wheezing (MSW)” as primary safety outcome 8,475 children enrolled (4,117 US)

21. 21 Questions for the Committee 1.Do the data demonstrate the efficacy of FluMist for prevention of influenza illness in the following: a.In the applicant's proposed population, i.e., children age 12-59 months without history of wheeze? b.Children in the age strata 6 – 23 months? c.Children in the age strata 24 – 59 months?

22. 22 Questions for the Committee (continued) 2.Do the safety data demonstrate that the benefits will exceed the risks of FluMist for use in: a. The applicant’s proposed population, i.e., children age 12-59 months without history of wheeze? b.Children in the age strata 6 – 23 months, regardless of wheezing history? c. Children in age strata 24- 59 months, regardless of wheezing history?

23. 23 Questions for the Committee (continued) 3.If approved for children less than 5 years of age, what additional post-marketing studies or surveillance activities would you recommend?