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

2. 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. 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. 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. 5 MICP111 Protocol 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. 6 MICP111 Protocol definitions Modified CDC ILI Fever (38˚C equivalent) and Cough, sore throat, or runny nose/nasal congestion.

7. 7 MICP 111 Protocol 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. 8 MICP 111 Analysis 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. 9 MICP 111 Results 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. 10 MICP 111 Results: 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. 11 MICP111 results Populations for analysis FluMistTIV ITT population, N42434232 Excluded from ATP pop, N (%)327 (8)296 (7) Reasons for exclusion: N No vaccine3436 Incorrect number of doses238190 Two active or two placebo116 Only intranasal vaccine11 Unknown identification of vaccine 1516 Incorrect volume729 No surveillance contact1917 Antiflu medication within 14 days21 ATP population, N39163936

12. 12 MICP 111 TIV 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. 13 MICP 111 Primary 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 Strain FluMist 3916 TIV 3936 A.D. % R.E. % 95% C.I. Cases N Rate % Cases N Rate % All531.4932.41.04522, 61 A/H130.1270.70.68968, 97 A/H30000-- B501.3671.70.427-5, 50

14. 14 Strain FluMist 3916 TIV 3936 A.D. % R.E. % 95%C.I Cases N Rate %Cases NRate % All1022.62456.23.65847, 67 A/H10000-- A/H3370.91784.53.67971, 86 B661.7711.80.16-32, 33 MICP 111 Primary endpoint, antigenically dissimilar strains

15. 15 Strain FluMist 3916 TIV 3936A.D. % R.E. % 95% C.I. Cases NRate %Cases NRate % All1533.93388.64.75545, 63 A/H130.1270.70.68968, 97 A/H3370.91784.53.67971, 86 B1152.91363.50.616-8, 35 MICP 111 Primary endpoint, all strains

16. 16 FluMistTIVA.D. % R.E % 95% C.I. NCases N Rate % NCases N Rate % Prior flu vaccination Y929181.9937293.11.239-9, 67 N2987351.22999642.10.94720, 67 Protocol defined wheeze history Y24683.321694.20.924-104, 72 N3670451.23720842.31.14724, 63 Gender M2008241.22017432.10.95017, 70 F1908291.51919502.61.14513, 66 Race/ethnicity Wh/NH3168491.53184802.51.04015, 58 Non- white 74840.5752131.70.365-5, 90 MICP111 Subgroup efficacy analysis

17. 17 Strain FluMist 1918 TIV 1926 A.D. % R.E. % 95% C.I. Cases N Rate %Cases N Rate % AS, All221.1331.70.635-12, 62 A/H10000 A/H30000 B221.1331.7 AD, All311.6985.13.56853, 79 A/H10000 A/H3120.6844.4 B190.9160.8 All, All522.61326.94.36248, 73 A/H10000 A/H3120.6844.4 B412.1492.5 MICP 111: Primary endpoint, US population (only 6 – 35m)

18. 18 Age group/ Strain FluMistTIV A.D. % R.E. % 95% C.I. N Cases N Rate % N Cases N Rate % 6-23m18341852 AS231.3321.70.429-21, 59 AD351.9985.33.46447, 76 All593.21337.24.05640, 68 24-59m20822084 AS301.4612.91.65327, 70 AD673.21477.13.95439 66 All944.52059.85.35442, 65 MICP 111 Primary endpoint, subgroup 6- 23 and 24- 59 months, all strains

19. 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. 20 D153-P501 Design 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. 21 D153 P501 Primary endpoint: culture confirmed ILI due to antigenically similar influenza strains FluMist 1653 Placebo 1111A.D. % Efficacy % 95% CI Cases NRate %Cases NRate % All strains563.4139139.17363, 81 A/H1231.4817.35.98169, 89 A/H340.2272.42.29071, 98 B291.8353.21.4446, 67

22. 22 CAIV-T 1653 Placebo 1111A.D. % Efficacy % 95% CI Cases NRate %Cases NRate % All strains814.918216.411.57061, 77 A/H1231.4827.46.08170, 89 A/H3140.8605.44.68472, 92 B442.7524.72.04313, 75 D153 P 501 Culture confirmed ILI due to any wild type influenza strain

23. 23 AV006 Study 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. 24 AV006 Efficacy Year 1 FluMistPlaceboEfficacy95% CI NumberCases%NumberCases% Any strain107014153294189387, 96 H3N2107070.753263129588, 97 B107070.75323779180, 96

25. 25 FluMistPlaceboEfficacy95% CI StrainNumberCases%NumberCases% All91715244156138778, 93 A/Sydney91715244151128675, 92 AV006 Efficacy Year 2

26. 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. 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. 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. 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. 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. 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 1 st 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. 33 Adverse Events in the 28 Days Post-Vaccination

34. 34 MI-CP111: Significant New Medical Conditions FluMistTIV Asthma36 (0.9%)24 (0.6%) Bronchospasm9 (0.2%)7 (0.2%) Allergic rhinitis3 (0.1%)1 (<0.1%) Food allergy2 (<0.1%) Gastroesophageal reflux04 (0.1%) Drug hypersensitivity2 (<0.1%)1 (<0.1%) Acute otitis media2 (<0.1%)1 (<0.1%) Drug eruption2 (<0.1%)1 (<0.1%) Eczema1 (<0.1%)2 (<0.1%) Autism2 (<0.1%)0 Vesicoureteric reflux02 (<0.1%) Anemia2 (<0.1%)0 Hypersensitivity2 (<0.1%)0 Chronic otitis media2 (<0.1%)0

35. 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. 36 Serious Adverse Events Reported in ≥ 1 Study Subjects in 6 Weeks Post- Vaccination

37. 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. 38 History of Asthma Safety Population FluMist Arm N=4179 TIV Arm N=4173 Per Protocol History of Wheezing: History of ≥ 3 wheezing episode requiring medical follow-up or hospitalization 271 (6.5%)239 (5.7%) Total number with any history of wheezing: by parent/guardian, health care provider, or both 904 (23%)868 (21%)

39. 39 Analysis of All Wheezing Events (Within 42 Days After Last Vaccination) FluMistTIV #Subjects292 (6.99%) 249 (5.97%) Gender: female/male134/158107/142 Race: Asian1714 Black198 Hispanic3223 Other32 White/Non-Hispanic221 (76%)202 (81%) Age: mean, median20.4, 18.522.6, 20 # of Subjects with hx of wheezing per protocol49 (17%)42 (17%) # of Subjects with any hx of wheezing130 (45%)101 (41%) # of Subjects who did not receive dose #233 (11%)19 (7.5%)

40. 40 Analysis of All Wheezing Events (42 Days Post-Vaccination) (Cont.) FluMistTIV #Events379323 Asthma37 (10%)17 (5%) Bronchiolitis67 (18%)52 (16%) Bronchospasm13 (3%)13 (4%) Wheezing262 (69%)241 (75%) # of Events after dose 1 / dose 2224/155184/139 Day of onset: mean, median19.4, 1818.6, 16 Severity: (#events/#subjects) Mild242 (64%)234 (72%) Moderate126 (33%)85 (26%) Severe11 (3%)3 (1%) # Events resulting in hospitalizations8 (2%)6 (2%)

41. 41 Number of All Wheezing Events by Day of Onset TotalAsthmaBronchiolitisBronchospasmWheezing FluMist (N=905) 0-2 Days29 (3.2%)07121 3-10 Days84 (9.3%)1115256 11-21 Days108 (12%)925569 22-42 Days158 (17.4%)17205116 >42 Days526 (58.1%)377516398 TIV (N=872) 0-2 Days27 (3.1%)23121 3-10 Days79 (9.0%)39364 11-21 Days86 (9.9%)121262 22-42 Days131 (15.0%)1119794 > 42 Days549 (62.9%)558410400

42. 42 Duration in Days of All Wheezing Events in 42 Days Post-Vaccination FluMistTIV MeanMedianRangeMeanMedianRange Asthma22.9611.01-18012.213.05-22 Bronchiolitis9.88.02-488.797.02-39 Bronchospasm8.06.01-299.176.04-22 Wheezing6.634.01-676.324.01-133 Missing Data: 8% of FluMist events and 9% of TIV events

43. 43 Numbers and Percentages of All Wheezing Events by Age

44. 44 Severity of All Wheezing Events in 42 Days Post-Vaccination by Age FluMistTIV Age in Months 6-1112-2324-35≥ 366-1112-2324-35≥ 36 # Events 971638336801029447 Severity: Mild 64 66% 96 59% 60 72% 22 61% 51 64% 73 72% 71 75.5% 39 83% Moderate 30 31% 60 37% 23 28% 13 36% 27 34% 27 26% 23 24.5% 8 17% Severe 3 3% 7 4% 01 3% 1 1% 2 2% 00 # Events Resulting in Hospitalization 2 2% 5 3% 01 3% 2 2.5% 2 2% 1 2% 1 1% # Subjects w/ no dose #2 8 10% 15 11.5% 4 6% 6 21% 8 13% 4 5% 3 4% 4 10.5%

45. 45 All Wheezing: Serious Adverse Events (42 Days Post-Vaccination) After 1 st DoseAfter 2 nd Dose FluMist N=4179 TIV N=4173 FluMist N=3002 TIV N=3034 Asthma1 (<0.1%)000 Bronchiolitis2 (<0.1%)1 (<0.1%)2 (0.1%) Bronchospasm1 (<0.1%) 00 Wheezing3 (<0.1%)2 (<0.1%)00

46. 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. 47 Any History of Wheezing and All Wheezing Events within 42 Days: FluMist Arm + Hx Any Wheezing No Hx Any Wheezing # Subjects130162 Type of Events (% of Events) Asthma21 (12%)16 (8%) Bronchiolitis19 (11%)48 (24%) Bronchospasm5 (3%)8 (4%) Wheezing132 (75%)130 (64%) # of Events by Severity (% of Events) Mild104 (59%)138 (68%) Moderate69 (39%)57 (28%) Severe4 (2%)7 (3%) # Subjects Hospitalized2 (1.5%)4 (2%) # Subjects: No dose #216 (12%)17 (10%)

48. 48 Any History of Wheezing and All Wheezing Events by Age: FluMist Arm 6-23 months24-35 Months≥36 Months + HxNeg Hx+ HxNeg Hx+ HxNeg Hx # Subjects771203433199 # Events11015041422610 # Events by Severity Mild65 (59%)95 (63%)25 (61%)35 (83%)14 (54%)8 (80%) Moderate41 (37%)49 (33%)16 (39%)7 (17%)12 (46%)1 (10%) Severe4 (4%)6 (4%)4 (5%)001 (10%) # Subj. Hospitalized2 (2.5%)3 (2.5%)0001 (11%) # Subj.: No dose #210 (13%)9 (7.5%)2 (6%) 4 (21%)2 (22%)

49. 49 Number and Percentage of Subjects with Any Wheezing Event within 42 Days by History of Wheezing FluMistTIV # SubjectsSubjects w/ Wheezing Event # SubjectsSubjects w/ Wheezing Event Pos History Any Wheezing 904 130 (14%)868101 (12%) Neg History Any Wheezing 3275162 (5%)3305148 (4%)

50. 50 Number and Percentage of Subjects with Any Wheezing Event within 42 Days by History of Wheezing FluMistTIV # SubjectsSubjects w/ Wheezing Event # SubjectsSubjects w/ Wheezing Event 6-23 Months of Age Pos History33277 (23%)295 42 (14%) Neg History1660120 (7%)1680 99 (6%) 24-35 Months of Age Pos History32334 (10.5%)33736 (11%) Neg History104933 (3%)104236 (3%) ≥ 36 Months of Age Pos History24919 (8%)23623 (10%) Neg History5669 (2%)58313 (2%)

51. 51 Number of Hospitalizations by Age and Time Post-Vaccination (0-180 Days After Last Vaccination) FluMistTIV Age≤ 42 Days > 42 Days Total≤ 42 Days > 42 Days Total 6-11 Months 1527429918 12-<24 Months 172542162945 24-35 Months 122434*132635* 36-59 Months 111129 21 *some subjects with hospitalizations in both time periods

52. 52 Hospitalizations by Age and Wheezing History for 180 Days After Last Vaccination

53. 53 Hospitalizations by Age and Wheezing History for 180 Days After Last Vaccination

54. 54 Hospitalizations by Age and Wheezing History for 180 Days After Last Vaccination

55. 55 MI-CP111: Hospitalizations by Age and Diagnosis within 42 Days After Last Vaccination 6-23 Months24-35 Months≥ 36 Months FluMist N=1992 TIV N=1975 FluMist N=1372 TIV N=1379 FluMist N=815 TIV N=819 # of Subjects876734351321 # of Events1088141431422 # Subjects w/ Respiratory Events 4429131669 % Subjects w/ Resp. Events 2.2%1.5%0.9%1.2%0.8%1.0%

56. 56 Hospitalizations in the First Two Weeks Post- Vaccination 6-11 Months12-23 Months24-35 Months≥ 36 Months FluMist Pneumonia - 3 Bronchiolitis Gastroenteritis - 2BronchiolitisGastroenteritis - 2 AOMAsthmaHerpangina WheezingDrug hypersens.Seizure Periorb. cellulitisAOM/URTI Pharyngitis Anuria TIV Bronchiolitis – 2Gastroenteritis - 2Gastroenteritis Gastroenteritis - 2Viral infection - 2Pneumonia Wheezing BronchiolitisHerpanginaCroup SinusitisURTI Febrile seizureAccidental injury-2

57. 57 Number of Hospitalizations by Age and Treatment Arm in Children <24 Months

58. 58 MI-CP111: Adverse Events of Pneumonia in 42 Days Post-Vaccination FluMistTIV Number of Events5861 Number of Subjects5859 Severity (# of Events) Mild17 (29%)24 (39%) Moderate38 (66%)36 (59%) Severe3 (5%)1 (2%) # Subjects Hospitalized15 (26%)11 (19%)

59. 59 Number of Subjects with Pneumonia by Age within 42 Days of Vaccination AgeFluMist Arm N=167 TIV Arm N=166 6-11 Months158 12-23 Months2321 24-35 Months1720 ≥ 36 Months310

60. 60 Study AV006 Study Design –Randomized, double-blind, placebo controlled –Enrolled children 15-71 months of age –Excluded children with hx of wheezing or bronchodilator use in prior 3 months Results: –FluMist – 816 subjects, Placebo-410 – No increase in respiratory events or asthma reported in FluMist recipients –7 hospitalizations in FluMist arm vs. 3 in Placebo arm

61. 61 Study D153-501 Study Design –Randomized, double-blind, placebo controlled –Enrolled children 12-35 months of age –Excluded children with hx of wheezing in prior 2 weeks –Followed AEs for 11 days post-vaccination Results: –FluMist – 1901 subjects, Placebo-1273 – No increase in bronchospasm, bronchiolitis, or pneumonia in FluMist recipients –No difference in hospitalizations between arms

62. 62 Summary FluMist was safe and effective in subjects 24 months of age and older In Study MI-CP111, in subjects <24 months of age, there were: –Increased hospitalizations –Increased severity of wheezing –Increased severity of respiratory events History of wheezing was poorly predictive of wheezing post-vaccination