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

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FluMist® age extensionFive years & younger

May 16, 2007

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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

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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

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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

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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

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MICP111Protocol definitions

Modified CDC ILI • Fever (38˚C equivalent)

and• Cough, sore throat, or runny nose/nasal

congestion.

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MICP 111Protocol definitions

Qualifying symptoms for obtaining nasal swab during influenza surveillance period:

• New onset of one or more:– fever ≥ 38C, 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

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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”)

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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

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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)

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MICP111 resultsPopulations for analysis

FluMist TIV

ITT population, N 4243 4232

Excluded from ATP pop, N (%) 327 (8) 296 (7)

Reasons for exclusion: N

No vaccine 34 36

Incorrect number of doses 238 190

Two active or two placebo 11 6

Only intranasal vaccine 1 1

Unknown identification of vaccine

15 16

Incorrect volume 7 29

No surveillance contact 19 17

Antiflu medication within 14 days 2 1

ATP population, N 3916 3936

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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

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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

FluMist3916

TIV3936

A.D.%

R.E.%

95% C.I.Cases N Rate % Cases N

Rate %

All 53 1.4 93 2.4 1.0 45 22, 61 A/H1 3 0.1 27 0.7 0.6 89 68, 97 A/H3 0 0 0 0 -- -- -- B 50 1.3 67 1.7 0.4 27 -5, 50

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Strain

FluMist3916

TIV3936

A.D.%

R.E.%

95%C.ICases N

Rate % Cases N Rate %

All 102 2.6 245 6.2 3.6 58 47, 67 A/H1 0 0 0 0 -- -- -- A/H3 37 0.9 178 4.5 3.6 79 71, 86 B 66 1.7 71 1.8 0.1 6 -32, 33

MICP 111Primary endpoint, antigenically dissimilar strains

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Strain

FluMist3916

TIV3936 A.D.

%R.E.%

95%C.I.Cases N Rate % Cases N Rate %

All 153 3.9 338 8.6 4.7 55 45, 63 A/H1 3 0.1 27 0.7 0.6 89 68, 97 A/H3 37 0.9 178 4.5 3.6 79 71, 86 B 115 2.9 136 3.5 0.6 16 -8, 35

MICP 111 Primary endpoint, all strains

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FluMist TIV A.D.%

R.E%

95% C.I.

N Cases N

Rate %

N Cases N

Rate %

Prior flu vaccination

Y 929 18 1.9 937 29 3.1 1.2 39 -9, 67N 2987 35 1.2 2999 64 2.1 0.9 47 20, 67

Protocol defined wheeze history

Y 246 8 3.3 216 9 4.2 0.9 24 -104, 72N 3670 45 1.2 3720 84 2.3 1.1 47 24, 63

Gender

M 2008 24 1.2 2017 43 2.1 0.9 50 17, 70F 1908 29 1.5 1919 50 2.6 1.1 45 13, 66

Race/ethnicity

Wh/NH 3168 49 1.5 3184 80 2.5 1.0 40 15, 58Non-

white748 4 0.5 752 13 1.7 0.3 65 -5, 90

MICP111 Subgroup efficacy analysis

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Strain

FluMist1918

TIV1926

A.D.%

R.E.%

95% C.I.Cases N

Rate % Cases N

Rate %

AS, All 22 1.1 33 1.7 0.6 35 -12, 62 A/H1 0 0 0 0 A/H3 0 0 0 0 B 22 1.1 33 1.7AD, All 31 1.6 98 5.1 3.5 68 53, 79 A/H1 0 0 0 0 A/H3 12 0.6 84 4.4 B 19 0.9 16 0.8All, All 52 2.6 132 6.9 4.3 62 48, 73 A/H1 0 0 0 0 A/H3 12 0.6 84 4.4 B 41 2.1 49 2.5

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

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Age group/Strain

FluMist TIVA.D.%

R.E.%

95%C.I.

N Cases N

Rate %

N CasesN

Rate%

6-23m 1834 1852 AS 23 1.3 32 1.7 0.4 29 -21, 59 AD 35 1.9 98 5.3 3.4 64 47, 76 All 59 3.2 133 7.2 4.0 56 40, 6824-59m 2082 2084 AS 30 1.4 61 2.9 1.6 53 27, 70 AD 67 3.2 147 7.1 3.9 54 39 66 All 94 4.5 205 9.8 5.3 54 42, 65

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

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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

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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

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D153 P501Primary endpoint: culture confirmed ILI due to

antigenically similar influenza strains

FluMist1653

Placebo1111 A.D.

% Efficacy

%95% CICases N Rate % Cases N Rate %

All strains 56 3.4 139 13 9.1 73 63, 81

A/H1 23 1.4 81 7.3 5.9 81 69, 89

A/H3 4 0.2 27 2.4 2.2 90 71, 98

B 29 1.8 35 3.2 1.4 44 6, 67

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CAIV-T1653

Placebo1111 A.D.

% Efficacy

%95% CI

Cases N Rate % Cases N Rate %

All strains 81 4.9 182 16.4 11.5 70 61, 77

A/H1 23 1.4 82 7.4 6.0 81 70, 89

A/H3 14 0.8 60 5.4 4.6 84 72, 92

B 44 2.7 52 4.7 2.0 43 13, 75

D153 P 501 Culture confirmed ILI due to any wild type

influenza strain

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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.

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AV006Efficacy Year 1

FluMist Placebo Efficacy 95% CI

Number Cases % Number Cases %

Any strain 1070 14 1 532 94 18 93 87, 96

H3N2 1070 7 0.7 532 63 12 95 88, 97

B 1070 7 0.7 532 37 7 91 80, 96

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FluMist Placebo Efficacy 95% CI

Strain Number Cases % Number Cases %

All 917 15 2 441 56 13 87 78, 93

A/Sydney 917 15 2 441 51 12 86 75, 92

AV006Efficacy Year 2

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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

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Overall FluMist efficacy conclusions

• Efficacy against culture confirmed ILI

• Three years of data– Different community acquired influenza

strains, antigenically similar and antigenically dissimilar

FDA Clinical Analysis of FluMist Safety

Melisse Baylor, MDMedical Officer

DVRPA, OVRR, CBER

VRBPACMay 16, 2007

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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

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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

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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

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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%)

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Adverse Events in the 28 Days Post-Vaccination

TWO DOSE GROUP

TWO DOSE GROUP

ONE DOSE GROUP

After 1st Dose After 2nd Dose

FluMist TIV FluMist TIV FluMist TIV Subjects with ≥1 AE

33% 32% 34% 34% 27% 27%

AOM 7% 7% 8% 8% 7% 9% Diarrhea 7% 6% 6% 7.5% 5% 5% Teething 2% 3% 4% 5% 2% 3% Wheezing 2% 2% 3% 2.5% 2% 2% Rash 2.5% 2% 1% 3% 1% 1% Conjunctivitis 1% 1% 2% 2% 2% 2% Bronchitis 1% 2% 2% 1% 2% 2% Sinusitis 2% 1.5% 1% 1% <1% <1% Infectious croup

2% 1% 1% 1% 1% 1%

Gastroenteritis 1% 1% 1% 1% 1% 1% Sneezing 2% 1% 1% 1% <1% <1% Diaper dermatitis

<1% <1% 1% 1% <1% <1%

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MI-CP111: Significant New Medical Conditions

FluMist TIVAsthma 36 (0.9%) 24 (0.6%)Bronchospasm 9 (0.2%) 7 (0.2%)

Allergic rhinitis 3 (0.1%) 1 (<0.1%)

Food allergy 2 (<0.1%) 2 (<0.1%)

Gastroesophageal reflux 0 4 (0.1%)

Drug hypersensitivity 2 (<0.1%) 1 (<0.1%)

Acute otitis media 2 (<0.1%) 1 (<0.1%)

Drug eruption 2 (<0.1%) 1 (<0.1%)

Eczema 1 (<0.1%) 2 (<0.1%)

Autism 2 (<0.1%) 0

Vesicoureteric reflux 0 2 (<0.1%)

Anemia 2 (<0.1%) 0

Hypersensitivity 2 (<0.1%) 0

Chronic otitis media 2 (<0.1%) 0

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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

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

VaccinationAfter 1st Dose After 2nd Dose FluMist N=4179

TIV N=4173

FluMist N=3002

TIV N=3034

Pneumonia 7 (0.2%) 6 (0.1%) 8 (0.3%) 4 (0.1%) Gastroenteritis 4 (0.1%) 4 (0.1%) 6 (0.2%) 5 (0.2%) Bronchiolitis 2 (<0.1%) 1

(<0.1%) 2 (0.1%) 2 (0.1%)

Acute otitis media 2 (<0.1%) 0 0 2 (0.1%) Upper respiratory tract infection

2 (<0.1%) 1 (<0.1%)

0 1 (<0.1%)

Febrile seizures 0 2 (<0.1%)

1 (<0.1%) 1 (<0.1%)

Wheezing 2 (<0.1%) 2 (<0.1%)

0 0

Infectious croup 0 0 0 2 (0.1%)

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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

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History of AsthmaSafety Population

FluMist ArmN=4179

TIV ArmN=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%)

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

FluMist TIV#Subjects 292

(6.99%)249 (5.97%)

Gender: female/male 134/158 107/142

Race:Asian 17 14

Black 19 8

Hispanic 32 23

Other 3 2

White/Non-Hispanic 221 (76%) 202 (81%)

Age: mean, median 20.4, 18.5 22.6, 20

# of Subjects with hx of wheezing per protocol 49 (17%) 42 (17%)

# of Subjects with any hx of wheezing 130 (45%) 101 (41%)

# of Subjects who did not receive dose #2 33 (11%) 19 (7.5%)

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

FluMist TIV#Events 379 323

Asthma 37 (10%) 17 (5%)

Bronchiolitis 67 (18%) 52 (16%)

Bronchospasm 13 (3%) 13 (4%)

Wheezing 262 (69%) 241 (75%)

# of Events after dose 1 / dose 2 224/155 184/139

Day of onset: mean, median 19.4, 18 18.6, 16

Severity: (#events/#subjects)Mild 242 (64%) 234 (72%)

Moderate 126 (33%) 85 (26%)Severe 11 (3%) 3 (1%)

# Events resulting in hospitalizations 8 (2%) 6 (2%)

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Number of All Wheezing Events by Day of Onset

Total Asthma Bronchiolitis Bronchospasm Wheezing

FluMist (N=905)0-2 Days 29 (3.2%) 0 7 1 21

3-10 Days 84 (9.3%) 11 15 2 56

11-21 Days 108 (12%) 9 25 5 69

22-42 Days 158 (17.4%) 17 20 5 116

>42 Days 526 (58.1%) 37 75 16 398

TIV (N=872)0-2 Days 27 (3.1%) 2 3 1 21

3-10 Days 79 (9.0%) 3 9 3 64

11-21 Days 86 (9.9%) 1 21 2 62

22-42 Days 131 (15.0%) 11 19 7 94

> 42 Days 549 (62.9%) 55 84 10 400

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Duration in Days of All Wheezing Events in 42 Days Post-Vaccination

FluMist TIV

Mean Median Range Mean Median Range

Asthma 22.96 11.0 1-180 12.2 13.0 5-22

Bronchiolitis 9.8 8.0 2-48 8.79 7.0 2-39

Bronchospasm 8.0 6.0 1-29 9.17 6.0 4-22

Wheezing 6.63 4.0 1-67 6.32 4.0 1-133

Missing Data: 8% of FluMist events and 9% of TIV events

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Numbers and Percentages of All Wheezing Events by Age

6-11 Mos

12-23 Mos

24-35 Mos

≥ 36 Mos

FluMist # Subjects with Wheezing 73 124 67 28 % of All Wheezing Subjects 25% 42% 23% 10% % of Subjects in Age Range from Entire Study Population

11% 9% 5% 3%

TIV # Subjects with Wheezing 62 79 72 36 % of All Wheezing Subjects 25% 32% 29% 14% % of Subjects in Age Range from Entire Study Population

9% 6% 5% 4%

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

FluMist TIVAge in Months 6-11 12-23 24-35 ≥ 36 6-11 12-23 24-35 ≥ 36

# Events 97 163 83 36 80 102 94 47

Severity:Mild 64

66%96

59%60

72%22

61%51

64%73

72%71

75.5%39

83%

Moderate 3031%

6037%

2328%

1336%

2734%

2726%

2324.5%

817%

Severe 3 3%

74%

0 13%

11%

22%

0 0

# Events Resulting in Hospitalization

22%

53%

0 13%

22.5%

22%

12%

11%

# Subjects w/ no dose #2

8 10%

15 11.5%

4 6%

6 21%

8 13%

45%

3 4%

4 10.5%

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

After 1st Dose After 2nd Dose

FluMistN=4179

TIVN=4173

FluMistN=3002

TIVN=3034

Asthma 1 (<0.1%) 0 0 0

Bronchiolitis 2 (<0.1%) 1 (<0.1%) 2 (0.1%) 2 (0.1%)

Bronchospasm 1 (<0.1%) 1 (<0.1%) 0 0

Wheezing 3 (<0.1%) 2 (<0.1%) 0 0

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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

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

+ Hx Any Wheezing

No Hx AnyWheezing

# Subjects 130 162

Type of Events (% of Events)Asthma 21 (12%) 16 (8%)

Bronchiolitis 19 (11%) 48 (24%)

Bronchospasm 5 (3%) 8 (4%)

Wheezing 132 (75%) 130 (64%)

# of Events by Severity (% of Events)

Mild 104 (59%) 138 (68%)

Moderate 69 (39%) 57 (28%)

Severe 4 (2%) 7 (3%)

# Subjects Hospitalized 2 (1.5%) 4 (2%)

# Subjects: No dose #2 16 (12%) 17 (10%)

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

6-23 months 24-35 Months ≥36 Months

+ Hx Neg Hx + Hx Neg Hx + Hx Neg Hx

# Subjects 77 120 34 33 19 9

# Events 110 150 41 42 26 10

# Events by SeverityMild 65 (59%) 95 (63%) 25 (61%) 35 (83%) 14 (54%) 8 (80%)

Moderate 41 (37%) 49 (33%) 16 (39%) 7 (17%) 12 (46%) 1 (10%)

Severe 4 (4%) 6 (4%) 4 (5%) 0 0 1 (10%)

# Subj. Hospitalized 2 (2.5%) 3 (2.5%) 0 0 0 1 (11%)

# Subj.: No dose #2 10 (13%) 9 (7.5%) 2 (6%) 2 (6%) 4 (21%) 2 (22%)

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

History of Wheezing

FluMist TIV

# Subjects Subjects w/ Wheezing Event


Pos History Any Wheezing

904 130 (14%) 868 101 (12%)

Neg History Any Wheezing

3275 162 (5%) 3305 148 (4%)

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

History of Wheezing FluMist TIV



6-23 Months of AgePos History 332 77 (23%) 295 42 (14%)

Neg History 1660 120 (7%) 1680 99 (6%)

24-35 Months of AgePos History 323 34 (10.5%) 337 36 (11%)

Neg History 1049 33 (3%) 1042 36 (3%)

≥ 36 Months of AgePos History 249 19 (8%) 236 23 (10%)

Neg History 566 9 (2%) 583 13 (2%)

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Number of Hospitalizations by Age and Time Post-Vaccination

(0-180 Days After Last Vaccination)

FluMist TIV

Age ≤ 42 Days

> 42 Days

Total ≤ 42 Days

> 42 Days

Total

6-11 Months

15 27 42 9 9 18

12-<24 Months

17 25 42 16 29 45

24-35Months

12 24 34* 13 26 35*

36-59Months

1 11 12 9 12 21

*some subjects with hospitalizations in both time periods

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Hospitalizations by Age and Wheezing History for 180 Days After Last

VaccinationNo. of subjects with: FluMist FluMist TIV TIV + Hx Neg Hx +Hx Neg Hx 6-11 mos of age N=77 N=607 N=63 N=620 All-cause hosp 5 (6.5%) 37 (6.1%) 1 (1.6%) 17 (2.7%) Respiratory hosp 3 (3.9%) 19 (3.1%) 1 (1.6%) 7 (1.1%) 12-23 mos of age N=255 N=1053 N=232 N=1060 All-cause hosp 12 (4.7%) 30 (2.8%) 6 (2.6%) 39 (3.7%) Respiratory hosp 7 (2.7%) 16 (1.5%) 3 (1.3%) 18 (1.7%) 24-59 mos of age N=572 N=1615 N=573 N=1625 All-cause hosp 14 (2.4%) 32 (2.0%) 11 (1.9%) 45 (2.8%) Respiratory hosp 7 (1.2%) 14 (0.9%) 5 (0.9%) 20 (1.2%)

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54



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MI-CP111: Hospitalizations by Age and Diagnosis within 42 Days After Last

Vaccination6-23 Months 24-35 Months ≥ 36 Months

FluMistN=1992

TIVN=1975

FluMistN=1372

TIVN=1379

FluMistN=815

TIVN=819

# of Subjects 87 67 34 35 13 21

# of Events 108 81 41 43 14 22# Subjects w/

Respiratory Events

44 29 13 16 6 9

% Subjects w/ Resp. Events

2.2% 1.5% 0.9% 1.2% 0.8% 1.0%

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Hospitalizations in the First Two Weeks Post-Vaccination

6-11 Months 12-23 Months 24-35 Months ≥ 36 Months

FluMist

Pneumonia - 3 Pneumonia - 3 Pneumonia - 3 Bronchiolitis

Gastroenteritis - 2 Bronchiolitis Gastroenteritis - 2

AOM Asthma Herpangina

Wheezing Drug hypersens. Seizure

Periorb. cellulitis AOM/URTI

Pharyngitis

Anuria

TIV

Bronchiolitis – 2 Gastroenteritis - 2 Gastroenteritis Gastroenteritis

Gastroenteritis - 2 Viral infection - 2 Pneumonia Pneumonia

Pneumonia Wheezing Wheezing

Bronchiolitis Herpangina Croup

Sinusitis URTI

Febrile seizure Accidental injury-2

57

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

Months

0

2

4

6

8

10

12

14

16

18

N(A

GE)

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

CAI

V-T

TIV

6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

TRTSAFE within AGE

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MI-CP111: Adverse Events of Pneumonia in 42 Days Post-Vaccination

FluMist TIV

Number of Events 58 61Number of Subjects 58 59Severity (# of Events)

Mild 17 (29%) 24 (39%)Moderate 38 (66%) 36 (59%)

Severe 3 (5%) 1 (2%)# Subjects Hospitalized 15 (26%) 11 (19%)

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Number of Subjects with Pneumonia by Age within 42 Days of Vaccination

Age FluMist ArmN=167

TIV ArmN=166

6-11 Months 15 8

12-23 Months 23 21

24-35 Months 17 20

≥ 36 Months 3 10

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

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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

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

Documents

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