FluMist ® age extension Five years & younger May 16, 2007

1. FluMist® age extension Five years & younger May 16, 2007

2. FDA presentation Efficacy: Therese Cvetkovich, M.D. Medical Officer CBER/OVRR/DVRPA Safety: Melisse Baylor, M.D. Medical Officer CBER/OVRR/DVRPA Statistical: Sang Ahnn, Ph.D. Statistical Reviewer CBER/OBE/DB/VEB/VEB

3. FluMist efficacy supplement Efficacy and safety • MICP 111: Culture confirmed endpoint, TIV control, relative efficacy and safety, 6m-59m • D153-P501: Culture confirmed endpoint, placebo controlled, efficacy and safety in 12m-35 m. • AV006:Culture confirmed endpoint, placebo controlled, efficacy and safety 15m -71m, two years of data (reviewed in original BLA) Immunogenicity • Study AV018: concurrent administration of MMR and V with FluMist

4. MICP 111 • Randomized 1:1 • Double blinded • Safety and relative efficacy of FluMist against TIV 6 to 59 months of age • Stratified by • Age • 6-23m and 24-59m based on then current ACIP recommendations for yearly influenza vaccination • 24-35m and 36-59m based upon TIV dosing recommendation • Prior influenza vaccination • Country/geographic area • Wheezing history as defined in the protocol

5. MICP111Protocol definitions • Primary endpoint: relative efficacy of FluMist compared to TIV against culture confirmed influenza illness • Influenza illness: • culture confirmed modified CDC-ILI, • caused by community-acquired wild-type strains antigenically similar to those contained in the vaccine • occurred during the influenza surveillance period and at least 14 days after the last required vaccination

6. MICP111Protocol definitions Modified CDC ILI • Fever (38˚C equivalent) and • Cough, sore throat, or runny nose/nasal congestion.

7. MICP 111Protocol definitions Qualifying symptoms for obtaining nasal swab during influenza surveillance period: • New onset of one or more: • fever ≥ 38C, any wheezing, shortness of breath, pulmonary congestion, pneumonia, ear infection • New onset of two or more: • runny nose, sore throat, cough, myalgia, chills, headache, irritability, decreased activity, vomiting

8. MICP 111Analysis populations As treated population (ATP):Analysis of primary endpoint • Randomized subjects who: • ≥ 1 surveillance contact on or after November 1, 2004 and 14 days after the final vaccination • Did not experience a major protocol violation • Analyzed according to the active study vaccination received at dose 1 (“as-treated”) Major protocol violation: one likely to affect the clinical observations or response to vaccination of the subject. Intent to treat (ITT) • All randomized subjects • Analyzed regardless of active study vaccine given (“as-randomized”)

9. MICP 111Results • 220 investigators (108 US, 15 Asia, 97 Europe/Middle East) • 49% US, 6% Asia, 45% Europe/ME • Initiated October 20, 2004, completed August 31, 2005 • First dose Oct. 20-29, 2004 • Second dose Nov. 04 to Jan. 05 • 2004-05 formulation: both vaccines • One dose if previously vaccinated; two doses if not

10. MICP 111Results: population demographics • 48% 6 – 23 m • 22% prior flu vaccination (one dose group) • 6% positive wheezing history (protocol definition) • 80% white, non-Hispanic, 4% Black, 6% Hispanic, 7% Asian • 51% male • 5% underlying disease: mostly chronic lung disease (asthma)

11. MICP111 resultsPopulations for analysis

12. MICP 111TIV availability 2004-2005 • 6 – 35 months: 0.25 mL • 36- 59 months: 0.5 mL • 0.25 mL dose only available in US and Asia • Therefore, enrollment in US and Asia restricted to infants/children 6-35 m

13. MICP 111Primary endpoint: Positive influenza culture for strains antigenically related to those contained in the vaccine plus modified CDC ILI, 14 days or more after last vaccination (ATP); from applicant’s analyses

14. MICP 111Primary endpoint, antigenically dissimilar strains

15. MICP 111 Primary endpoint, all strains

16. MICP111 Subgroup efficacy analysis

17. MICP 111: Primary endpoint, US population(only 6 – 35m)

18. MICP 111 Primary endpoint, subgroup 6- 23 and 24- 59 months, all strains

19. MICP 111 Efficacy conclusions • Large adequate and well-controlled study • Active control: relative efficacy • Multiple geographic sites • Objective clinical endpoint • Prevented culture-confirmed CDC ILI • Efficacy against A strains; similar (79%) and dissimilar (89%); • B strains: Similar and dissimilar: 16% • Adequate power in both prespecified age subgroups

20. D153-P501Design • Phase 3 randomized double-blinded study • Multiple countries in Asia between September 30, 2000 and May 31, 2003 • Healthy 12- 36 month old children • Primary efficacy endpoint: culture confirmed ILI during the first influenza season

21. D153 P501Primary endpoint: culture confirmed ILI due to antigenically similar influenza strains

22. D153 P 501 Culture confirmed ILI due to any wild type influenza strain

23. AV006Study Design Phase 3, randomized (2:1), placebo controlled • Conducted over two years, 1996 – 97 and 1997 – 98. • Population: 15-71 months of age • Primary endpoint: culture-confirmed influenza illness due to wild-type virus subtypes antigenically similar to the strains contained in the vaccine.

24. AV006Efficacy Year 1

25. AV006Efficacy Year 2

26. Efficacy conclusions • AV006: • Adequate and well-controlled study • Objective clinical endpoint • Two years • Efficacy against culture confirmed ILI • A strains • similar 95% -dissimilar 86% • B strain: similar 91% • D153P501 • Adequate and well controlled study • Placebo controlled: absolute efficacy • Objective clinical endpoint • Efficacy against similar and dissimilar w-t influenza strains

27. Overall FluMist efficacy conclusions • Efficacy against culture confirmed ILI • Three years of data • Different community acquired influenza strains, antigenically similar and antigenically dissimilar

28. FDA Clinical Analysis of FluMist Safety Melisse Baylor, MD Medical Officer DVRPA, OVRR, CBER VRBPAC May 16, 2007

29. FDA Safety Review • Studies: • MI-CP111 • D153-P501 • AV006 • Study MI-CP111: • Reactogenicity Events and Adverse Events • Significant New Medical Conditions • Serious AEs and Deaths • Analysis of Wheezing • Analysis of Hospitalizations

30. Study MI-CP111: Exclusion Criteria • Excluded children with: • History of severe asthma • Medically diagnosed wheezing in 42 days prior to study entry • Bronchodilator or steroid use in 42 days prior to study entry

31. Safety Monitoring in MI-CP111 • Reactogenicity Events – 42 days • fever, runny/stuffy nose, sore throat, cough, wheezing, vomiting, headache, muscle aches, chills, decreased activity, irritability, abdominal pain, decreased appetite, injection site signs/symptoms • Adverse Events – 42 days • Medically significant wheezing – 42 days • Significant New Medical Conditions – 180 days • Serious AEs – 180 days

32. Reactogenicity Events • Reactogenicity events more common in FluMist recipients than TIV recipients • After the first dose: 69% vs 63% • After the second dose: 55% vs 51% • Reactogenicity events reported more frequently in FluMist recipients than TIV recipients • Runny / stuffy nose: 57% vs 46% after 1st dose • Low grade fever: 15% vs 12% after 1st dose • In subgroup of subjects <24 months of age • Higher frequency of all REs (75% of FluMist recipients and 67% of TIV recipients) • Cough also more common in FluMist recipients (32%) than in TIV recipients (30%)

33. Adverse Events in the 28 Days Post-Vaccination

34. MI-CP111: Significant New Medical Conditions

35. Serious Adverse Events • 2 Deaths – • One each study arm • Both accidental - neither vaccine related • Serious AEs • In 180 days post-vaccination: 3.3% of subjects in FluMist arm and 3.1% in TIV arm • In 42 days post-vaccination: 1.3% of subjects in FluMist arm and 1.3% in TIV arm • In 10 days post-vaccination: 0.3% of subjects in FluMist arm and 0.4% in TIV arm

36. Serious Adverse Events Reported in ≥ 1 Study Subjects in 6 Weeks Post-Vaccination

37. Definitions of Wheezing • Medically significant wheezing: Applicant definition for wheezing on examination plus one of the following: signs of respiratory distress (↑ respiratory rate, retractions, dyspnea), hypoxemia (oxygen saturation < 95%), or new prescription for daily bronchodilator • Primary definition used by Applicant in safety analysis • All Wheezing: Applicant definition for the preferred terms asthma, bronchiolitis, bronchospasm, and wheezing; • Secondary safety endpoint for Applicant • Primary definition used by clinical reviewer

38. History of AsthmaSafety Population

39. Analysis of All Wheezing Events(Within 42 Days After Last Vaccination)

40. Analysis of All Wheezing Events (42 Days Post-Vaccination) (Cont.)

41. Number of All Wheezing Events by Day of Onset

42. Duration in Days of All Wheezing Events in 42 Days Post-Vaccination Missing Data: 8% of FluMist events and 9% of TIV events

43. Numbers and Percentages of All Wheezing Events by Age

44. Severity of All Wheezing Events in 42 Days Post-Vaccination by Age

45. All Wheezing: Serious Adverse Events (42 Days Post-Vaccination)

46. Additional Analyses • Increased wheezing and bronchiolitis in males compared to females in both arms • No difference in wheezing by race/ethnicity • Little difference in wheezing by country of origin • Upper and Lower respiratory tract events • Increased number of events of pulmonary congestion and sinusitis in FluMist arm • Few events of respiratory distress, hypoxia, and tachypnea

47. Any History of Wheezing and All Wheezing Events within 42 Days: FluMist Arm

48. Any History of Wheezing and All Wheezing Events by Age: FluMist Arm

49. Number and Percentage of Subjects with Any Wheezing Event within 42 Days by History of Wheezing

50. Number and Percentage of Subjects with Any Wheezing Event within 42 Days by History of Wheezing