# Presentation: 674719

## FluMist® age extension

- Five years & younger
- May 16, 2007

## 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

## 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

## 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

## 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

## MICP111Protocol definitions

- Modified CDC ILI
- Fever (38 ̊C equivalent)
- 		and
- Cough, sore throat, or runny nose/nasal congestion.

## 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

## 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”)

## 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

## 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)

## MICP111 resultsPopulations 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 |

## 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

## 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 % |  |  |  |
| 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 |

## MICP 111Primary endpoint, antigenically dissimilar strains

| 

Strain | FluMist
3916 |  | TIV
3936 |  | 

A.D.
% | 

R.E.
% | 

95%C.I |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | Cases 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

## MICP 111 Primary endpoint, all strains

| 

Strain | FluMist
3916 |  | TIV
3936 |  | 
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 |

## MICP111 Subgroup efficacy analysis

|  | 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, 67 |
| N | 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, 72 |
| N | 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, 70 |
| F | 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, 58 |
| Non-white | 748 | 4 | 0.5 | 752 | 13 | 1.7 | 0.3 | 65 | -5, 90 |

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

| 

Strain | FluMist
1918 |  | TIV
1926 |  | 

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 | 1.7 |  |  |  |
| AD, 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 | 0.8 |  |  |  |
| All, 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)

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

| Age group/
Strain | FluMist |  |  | TIV |  |  | 
A.D.
% | 
R.E.
% | 
95%
C.I. |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | N | Cases
 N | Rate % | N | Cases
N | 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, 68 |
| 24-59m | 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 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

## 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

## D153 P501Primary endpoint:  culture confirmed ILI due to antigenically similar influenza strains

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

|  | FluMist
1653 |  | Placebo
1111 |  | 
A.D.
 %  | 
Efficacy % | 
95% CI |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | Cases 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 |

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

|  | CAIV-T
1653 |  | Placebo
1111 |  | 
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

## 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.

## AV006Efficacy 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 |

## AV006Efficacy Year 2

|  | 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

## 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

## 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, MD
- Medical Officer
- DVRPA, OVRR, CBER
- VRBPAC
- May 16, 2007

## 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

## 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

## 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

## 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%)

## Adverse Events in the 28 Days Post-Vaccination

## MI-CP111: Significant New Medical Conditions

|  | FluMist | TIV |
| --- | --- | --- |
| Asthma | 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 |

## 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

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

## 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

## 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%) |

## 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%) |

## 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%) |

## 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 |

## 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

## Numbers and Percentages of All Wheezing Events by Age

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

|  | FluMist |  |  |  | TIV |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Age 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 | 30
31% | 60
37% | 23
28% | 13
36% | 27
34% | 27
26% | 23
24.5% | 8
17% |
| Severe | 3 
3% | 7
4% | 0 | 1
3% | 1
1% | 2
2% | 0 | 0 |
| # Events Resulting in Hospitalization | 2
2% | 5
3% | 0 | 1
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% |

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

|  | After 1st Dose |  | After 2nd Dose |  |
| --- | --- | --- | --- | --- |
|  | FluMist
N=4179 | TIV
N=4173 | FluMist
N=3002 | TIV
N=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 |

## 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

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

|  | + Hx Any Wheezing | No Hx Any
Wheezing |
| --- | --- | --- |
| # 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%) |

## 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 Severity |  |  |  |  |  |  |
| Mild | 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%) |

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

|  | FluMist |  | TIV |  |
| --- | --- | --- | --- | --- |
|  | # Subjects | Subjects w/ Wheezing Event | # 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%) |

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

|  | FluMist |  | TIV |  |
| --- | --- | --- | --- | --- |
|  | # Subjects | Subjects w/ Wheezing Event | # Subjects | Subjects w/ Wheezing Event |
| 6-23 Months of Age |  |  |  |  |
| Pos History | 332 | 77 (23%) | 295 |  42 (14%) |
| Neg History | 1660 | 120 (7%) | 1680 |  99 (6%) |
| 24-35 Months of Age |  |  |  |  |
| Pos History | 323 | 34 (10.5%) | 337 | 36 (11%) |
| Neg History | 1049 | 33 (3%) | 1042 | 36 (3%) |
| ≥ 36 Months of Age |  |  |  |  |
| Pos History | 249 | 19 (8%) | 236 | 23 (10%) |
| Neg History | 566 | 9 (2%) | 583 | 13 (2%) |

## 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 |
| 24-35
Months | 12 | 24 | 34* | 13 | 26 | 35* |
| 36-59
Months | 1 | 11 | 12 | 9 | 12 | 21 |

- *some subjects with hospitalizations in both time periods

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

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

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

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

|  | 6-23 Months |  | 24-35 Months |  | ≥ 36 Months |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | FluMist
N=1992 | TIV
N=1975 | FluMist
N=1372 | TIV
N=1379 | FluMist
N=815 | TIV
N=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% |

## 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 |

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

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

|  | FluMist | TIV |
| --- | --- | --- |
| Number of Events | 58 | 61 |
| Number of Subjects | 58 | 59 |
| Severity (# of Events) |  |  |
| Mild | 17 (29%) | 24 (39%) |
| Moderate | 38 (66%) | 36 (59%) |
| Severe | 3 (5%) | 1 (2%) |
| # Subjects Hospitalized | 15 (26%) | 11 (19%) |

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

| Age | FluMist Arm
N=167 | TIV Arm
N=166 |
| --- | --- | --- |
| 6-11 Months | 15 | 8 |
| 12-23 Months | 23 | 21 |
| 24-35 Months | 17 | 20 |
| ≥ 36 Months | 3 | 10 |

## 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

## 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

## 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