# Presentation: 803351

## FluMist®Influenza Virus Vaccine Live, Intranasal

***MedImmune***
***Gaithersburg, Maryland***

**Edward Connor, M.D.**** **
***Executive VP, Clinical Development***
***Chief Medical Officer***

## Sponsor Team

**Sponsor Project Team**
**Robert Walker, M.D.**** **
**     ***FluMist Project Director*** **
**George Kemble, Ph.D.**
*       **Head of Research, MedImmune Vaccines*
**Iksung Cho, MS**
*       **Head of Biostatistics*
**Micki Hultquist, MS**
*       **FluMist Project Lead Statistician*

**External Investigators/Advisors**
**Robert Belshe, M.D.**
**        ***Professor, Internal Medicine/Infectious Disease*
*	**Director, Center for Vaccine Development*
*	**Saint Louis University School of Medicine*
**Kathryn Edwards, M.D.**
**       ***Professor of Pediatrics**Vice Chair for Clinical Research in Pediatrics**Director of Pediatric Clinical Research **Division of Pediatric Infectious Diseases*
**	***Vanderbilt University School of Medicine*
**Dereck Weycker, Ph.D.**
**       ***Policy Analysis, Inc.*
**Janet Wittes, Ph.D.**
**        ***Statistics Collaborative, Inc.*
**Pamela Zeitlin, M.D., Ph.D.**
**       ***Professor of Pediatrics and Physiology*
*	**Director, Pediatric Respiratory Sciences*
*	**Johns Hopkins University School of Medicine*

## Sponsor Presentation

**Introduction and Overview**
**Data on efficacy of FluMist in children <5 years of age**
**Data on safety of FluMist in children <5 years of age**
**Post-marketing studies**
**Conclusions**

## Influenza and Vaccination

**Influenza is the leading cause of vaccine-preventable mortality and morbidity in the U.S.**
**Vaccination is the primary method for preventing illness and severe complications related to influenza**
**Antigenic mismatch between vaccines and circulating strains is common and complicates influenza prevention**

## Influenza in Children

**Rates of influenza infection are highest among children**
- Hospitalization rates among young children similar to elderly
- Significant burden of outpatient clinic visits and ER visits
**Annual vaccination is recommended for all children 6-59 months of age in the U.S.**
**Trivalent inactivated vaccine (TIV) is the only currently licensed product for children <5 years of age**
- Single manufacturer for children <4 years of age

*Thompson et al, J Am Med Assoc  289:179, 2003 *
*Poehling et al, N Engl J Med 355:31, 2006*
*ACIP Recommendations:  MMWR  55:RR-10, 2006 *
*AAP Recommendations:  Pediatrics 119: 846, 2007*
*AAFP Practice Guidelines:  Am Fam Phys 74:665, 2006*

## Live, cold-adapted, temperature-sensitive, attenuated influenza virus vaccine
Trivalent (A/H1N1, A/H3N2, B)
107 FFU of each strain per dose
Dose: 0.2 mL intranasal spray (0.1 mL per nostril)
Storage: 2-8oC (refrigerator)
Contains no preservatives (e.g., no thimerosal)

**Trivalent (A/H1N1, A/H3N2, B)**
**10****7**** FFU of each strain per dose**
**Dose: 0.2 mL intranasal spray (0.1 mL per nostril)**
**Storage: 2-8oC (refrigerator)**
**Contains no preservatives (e.g., no thimerosal)**

**FluMist****® ****Product Characteristics**

## FluMist® Regulatory Milestones

**2003**
- FluMist (frozen) approved for healthy individuals 5 to 49 years of age
**2003-2007**
- Commercial product available
**January 2007**
- Refrigerated FluMist approved for healthy individuals 5 to 49 years of age

## FluMist® Post Licensure Safety (5-49 years of age)

**Approximately 7M doses have been distributed for commercial use from 2003 to 2007**
**No new safety signals have been identified since licensure**
- VAERS data from first 2 seasons1
- Post-marketing safety study (N = 45,000) 2002-20062

*1** Izurieta et al, J Am Med Assoc  294:2720, 2005 *
*2 **Baxter et al, PAS 2007*

## FluMist® Rationale for Lower Age Limit in Initial Approval 

**MedImmune did not seek an indication in children <5 years **
**Wheezing signal in placebo-controlled safety study **
**Further data needed to understand the signal**

*Bergen et al, Pediatr Infect Dis J  23:138, 2004 *
*Belshe et al, Clin Infect Dis  39:920, 2004*

| Age (mo) | Outcome | Incidence |  | Relative Risk(90% CI) |
| --- | --- | --- | --- | --- |
|  |  | FluMist
N=2032  | Placebo
N=1025 |  |
| 12–59 | Asthma | 0.69% | 0.20% | 3.53(1.10, 15.66) |
| 12–59 | Asthma +Wheezing | 1.23% | 0.78% | 1.58(0.82, 3.20) |

**Study AV019 Post Hoc Analysis of Diagnostic Codes**

## FluMist® Background for Expansion of Indicated Population

**Two published studies suggested better efficacy of FluMist compared to TIV in children**
- 6-71 mos with recurrent RTI (N=2187)1 & 6-17 yrs with asthma (N=2229)2
- 53% & 35% fewer cases of influenza (predominantly matched B)
- No safety signals identified
- Open-label, not conducted under US IND
**IND studies of efficacy and safety of FluMist in children **_**<**_**59 months of age**
- Study AV006 (NIH CRADA with Aviron)
- Study D153-P501 (Wyeth)
- Study MI-CP111

*1** Ashkenazi et al, Pediatr Infect Dis J  25:870, 2006 *
*2** Fleming et al, Pediatr Infect Dis J  25:860, 2006 *

## FluMist® Principal Findings for Children <5 years (IND Studies)

**Efficacy**
- High levels of efficacy against influenza
- Significantly higher efficacy compared to TIV in MI-CP111
- Cross-protection against mismatched A/H3N2, including better cross-protection compared to TIV in MI-CP111
**Safety**
- Further evaluation is needed in children 6-11 months of age and in children 12-59 months with a history of wheeze/asthma
- For children without a history of wheeze/asthma
- Safety established in children 24-59 months of age
- Risk-benefit warrants availability for children 12-23 months of age

## FluMist® Proposed Expanded Indicated Population

-     ***Children 12 to 59 months of age without a history of wheeze/asthma***

## EfficacyFluMist® in Children <5 Years of Age

**High levels of efficacy against influenza**
**Significantly higher efficacy compared to TIV in MI-CP111**
**Cross-protection against mismatched A/H3N2, including better cross-protection compared to TIV in MI-CP111**

## Studies AV006 and D153-P501Placebo-Controlled Efficacy Studies

*1** Belshe et al. N Engl J Med. 338:1405-1412, 1998*
*2** Belshe et al. J Pediatr. 136:168-175, 2000*
*3** Tam et al. Pediatr Infect Dis J. In press.*

|  | AV0061,2 | D153-P5013 |
| --- | --- | --- |
| N | 1,602 | 3,174 |
| Years/Location | 1996-98, US | 2000-02, Asia (8 countries) |
| Design | Randomized (2:1), DB | Randomized (3:2), DB |
| Age at entry | 15-71 months | 12-35 months |
| Year 1 strains | Matched A/H3N2, B | Matched A/H1N1, A/H3N2, B |
| Year 2 strains | Mismatched A/H3N2 | Matched A/H3N2 |

**Two placebo-controlled studies assessed efficacy vs. all    three influenza subtypes, including mismatched A/H3N2**

## FluMist® Efficacy in Vaccine-naïve Children Year One Efficacy by Strain (Matched)

**Study D153-P501****2**

**93.4%**

**96.0%**

**90.5%**

**72.9%**

**80.9%**

**90.0%**

**44.3%**

**Study AV006****1**

**Influenza Strain**

*1 **Belshe et al. N Engl J Med. 338:1405-1412, 1998*
*2** Tam et al. Pediatr Infect Dis J. In press.*

**Efficacy estimates are for matched strains, the studies’ primary endpoint**

**Efficacy (%) with 95% CI**

## FluMist® Efficacy in Previously Vaccinated Children: Year Two Efficacy by Strain

**Efficacy (%) with 95% CI**

**Influenza Strain**

**87.0%**

**86.7%**

**84.3%**

**86.3%**

**AV006 estimates are for all strains because 94% of strains were mismatched**
**D153-P501 estimates are for matched strains**

**Study D153-P501****2**

**Study AV006****1**

*1 **Belshe et al. N Engl J Med. 338:1405-1412, 1998*
*2** Tam et al. Pediatr Infect Dis J. In press.*

## Study MI-CP111Pivotal Comparative Trial in Children <5 Years of Age

**Pivotal trial to evaluate safety and efficacy of FluMist compared to TIV**
**Allows assessment of the benefits and risks of both vaccines in children 6-59 months of age**

*Belshe et al, N Engl J Med  356:685, 2007*

## Study MI-CP111Design

**Randomized, double-blind, TIV-controlled, multinational **
**Children 6-59 months of age (N=8,475)**
- Excluded only recent wheezing, history of severe asthma, immunocompromised
**Stratification factors**
- Age (6-23, 24-35, 36-59 months), country, previous influenza vaccination, and history of _>_3 wheezing illnesses
- Stratification of 24-35 months to balance children receiving different TIV licensed dosages (children <3 years receive 0.25 mL)
- Pre-specified analyses for children 6-23 months and 24-59 months
- Enrollment of children 6-23 months was increased to enable robust subgroup analysis

*Belshe et al, N Engl J Med  356:685, 2007*

## Study MI-CP111Design

**Primary efficacy endpoint was *****culture-confirmed modified CDC influenza-like illness (mCDC-ILI)***** against matched strains**
- Increased temperature (100oF oral or equivalent) plus cough, sore throat or *runny nose/nasal congestion* on same or consecutive days
- Symptoms must be within +/- 7 days of positive culture
**According to protocol (ATP) and intent-to-treat (ITT) analyses**

*Belshe et al, N Engl J Med  356:685, 2007*

## Study MI-CP111Baseline Characteristics 

|  | TIV 
N=4232 | FluMist 
N=4243 |
| --- | --- | --- |
| Mean Age (mos) | 25.6 | 25.7 |
| Male | 51.4% | 51.3% |
| White, Non-Hispanic | 80.4% | 80.2% |
| Previously vaccinated | 22.5% | 22.3% |
| Prior wheeze history
   Any
   3 or more | 
20.7%
  5.7% | 
21.7%
  6.5% |

**ITT Population**

**Baseline characteristics were balanced between the treatment groups**

## Study MI-CP111Follow-up of Subjects

|  | TIV 
N=4232 | FluMist 
N=4243 |
| --- | --- | --- |
| Median duration of follow-up, days (range) | 219 (0-224) | 219 (0-224) |
| 2 Dose group who received Dose 2 | 94.3% | 92.8% |
| Nasal swabs collected (per child) | 10,335 (2.4) | 10,142 (2.4) |
| Of cultures taken, proportion within 24 hours of symptoms | 87% | 85% |

**ITT Population**

**Follow-up was also balanced between the treatment groups**

## Study MI-CP111Influenza Strains in the General Population, 2004-2005

|  |  | Proportion of Strains |  |
| --- | --- | --- | --- |
| Subtype | Strain | U.S. | Europe |
| A/H1N1 | A/New Caledonia/20/99-like |   1% | 19% |
| A/H3N2 | A/Wyoming/3/2003-like | 15% |   2% |
|  | A/California/7/2004-like | 51% | 59% |
| B | B/Yamagata/16/88 lineage* | 25% | 11% |
|  | B/Victoria/02/87 lineage |   9% |   8% |

- No strain-specific data available for Asia
*Mismatched strains shown in blue italics; *
- *matched and* mismatched *B/Yamagata strains circulated

- Source: U.S. Centers for Disease Control and Prevention, European Influenza Surveillance Scheme (EISS)

**High proportion of mismatched A/H3N2 circulated as well as some mismatched B and alternate lineage B**

## Study MI-CP111All Culture-Confirmed Modified CDC-ILI

**Culture-confirmed Modified CDC-ILI Caused by **
**Any Wild-type Strain (Matched and Mismatched)**

**01 NOV 04**

**01 DEC 04**

**01 JAN 05**

**01 FEB 05**

**01 MAR 05**

**01 APR 05**

**01 MAY 05**

**Percent**

**10.0**
**9.5**
**9.0**
**8.5**
**8.0**
**7.5**
**7.0**
**6.5**
**6.0**
**5.5**
**5.0**
**4.5**
**4.0**
**3.5**
**3.0**
**2.5**
**2.0**
**1.5**
**1.0**
**0.5**
**0.0**

**FluMist**

**1****st**** immunizations**
**completed by 10/29/04**

**TIV**

**Study MI-CP111****All Culture-Confirmed Modified CDC-ILI**

**338 cases**

**153 cases**

## Study MI-CP111 Efficacy Comparison: Primary and Secondary Endpoints – ATP and ITT

**TIV**

**FluMist**

**Comparative Efficacy Against Culture-confirmed Modified CDC-ILI**

**58.2%**
**(*****P*****<0.001)**

**0.7**

**2.6**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**Matched Strains**

**Mismatched Strains**

**Matched Strains**

**Mismatched Strains**

**Attack Rate (%)**

**No. of Cases**

**93**

**53**

**102**

**245**

**55**

**100**

**111**

**TIV N=4232, FluMist N=4243**

**ATP**

**ITT**

**44.5%**
**(*****P*****<0.001)**

**2.4**

**1.4**

**6.2**

**56.6%**
**(*****P*****<0.001)**

**0.7**

**2.6**

**46.0%**
**(*****P*****<0.001)**

**2.4**

**1.3**

**6.0**

**TIV N=3936, FluMist N=3916**

**255**

**Solid bars = matched**
**Hatched bars = mismatched**

## Study MI-CP111 Efficacy Comparison by Strain

**TIV (N=3936)**

**FluMist (N=3916)**

**Comparative Efficacy Against Culture-confirmed Modified CDC-ILI (ATP Population)**

**54.9%**
**(*****P*****<0.001)**

**89.2%**
**(*****P*****<0.001)**

**79.2%**
**(*****P*****<0.001)**

**16.1%**
**(*****P*****=NS)**

**8.6**

**0.7**

**4.5**

**3.5**

**3.9**

**0.1**

**0.9**

**2.9**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**All Strains**

**H1N1**

**H3N2**

**B**

**Attack Rate (%)**

**Strain**

**No. of Cases**

**338**

**153**

**3**

**27**

**37**

**178**

**115**

**136**

**10**

**Solid bars = matched**
**Hatched bars = mismatched**

## Study MI-CP111 Efficacy Comparison by Age: Matched Strains

**29.1%**
**(*****P*****=NS)**

**52.5%**
**(*****P*****<0.001)**

**1.7**

**2.9**

**1.3**

**1.4**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**6-23 mos**

**Attack Rate (%)**

**32**

**23**

**10**

**24-59 mos**

**61**

**30**

**Comparative Efficacy Against Culture-confirmed Modified CDC-ILI (ATP Population)**

**Age Group**

**No. of Cases**

**TIV **N=1852, 6-23 mos
-           N=2084, 24-59 mos

**FluMist **N=1834, 6-23 mos
-                 N=2082, 24-59 mos

## Study MI-CP111 Efficacy Comparison by Age: All Strains

**55.7%**
**(*****P*****<0.001)**

**54.4%**
**(*****P*****<0.001)**

**7.2**

**9.8**

**3.2**

**4.5**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**6-23 mos**

**Attack Rate (%)**

**133**

**59**

**10**

**24-59 mos**

**205**

**94**

**TIV **N=1852, 6-23 mos
-           N=2084, 24-59 mos

**FluMist **N=1834, 6-23 mos
-                 N=2082, 24-59 mos

**Age Group**

**No. of Cases**

**Solid bars = matched**
**Hatched bars = mismatched**

**Comparative Efficacy Against Culture-confirmed Modified CDC-ILI (ATP Population)**

## Study MI-CP111Other Efficacy Endpoints

**Illness associated with a positive culture for all strains regardless of match**

**45.9%**
**(*****P*****=0.046)**

**0.5**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**Symptomatic Influenza**

**LRI**

**AOM**

**Attack Rate (%)**

**No. of Cases**

**393**

**195**

**18**

**33**

**26**

**54**

**50.6%**
**(*****P*****<0.001)**

**10.0**

**5.0**

**0.8**

**50.6%**
**(*****P*****=0.003)**

**1.4**

**0.7**

**8**

**9**

**10**

**TIV (N=3936)**

**FluMist (N=3916)**

**Solid bars = matched**
**Hatched bars = mismatched**

## Overall Efficacy ConclusionsChildren <5 Years of Age

**High levels of efficacy against influenza**
**Significantly higher efficacy compared to TIV in MI-CP111**
**Cross-protection against mismatched A/H3N2, including better cross-protection compared to TIV in MI-CP111**

## SafetyFluMist in Children <5 Years of Age

**For children without a history of wheeze/asthma:**
**Safety established in children 24-59 months**
**Risk-benefit warrants availability for children 12-23 months**

## FluMist Safety in Children <5 Years

**Reactogenicity and Adverse Events**
**Mortality**
**Serious Adverse Events**
**Wheezing Outcomes **
**Risk-benefit Summary**

## Study MI-CP111: Reactogenicity

|  | Injection Site Reaction | Runny Nose/Nasal Congestion | Fever >100°F | Fever >101°F | Fever >102°F |
| --- | --- | --- | --- | --- | --- |
| TIV | 25% | 46% | 12% | 7% | 4% |
| FluMist | 21% | 57% | 15% | 8% | 4% |
|  | p<0.001 | p<0.001 | p<0.001 | NS | NS |

- Each child received both an intranasal spray and an intramuscular injection

**Percent of Children with Events Days 0–10**
**Two Dose Group, Post Dose 1**

## Study MI-CP111Adverse Events (AE) Through 28 Days

**Approximately 30% of children in both groups had **_**>**_**1 AE**
**Adverse events with difference >1% between groups:**
- Events higher with FluMist: sneezing (1.1%)
- Events higher with TIV: diarrhea (1.1%), AOM (1.5%), and rash (1.3%)
**Severe AE and related AE were balanced between treatment groups**
**A small number of children in each group did not receive a second vaccination because of an AE or RE**
- 27/3247 (0.8%) TIV, 37/3269 (1.1%) FluMist

## 2 deaths occurred on study, both were unrelated
1 FluMist: 1 year-old due to foreign body (toy) aspiration
1 TIV: 2 year-old due to a house fire

- 1 FluMist: 1 year-old due to foreign body (toy) aspiration
- 1 TIV: 2 year-old due to a house fire

**Study MI-CP111****Mortality**

## Overall SAE rates were similar: 3.1% TIV, 3.3% FluMist
94% of all SAEs were hospitalizations
Increased hospitalization rate with FluMist in 6-11 months

- 94% of all SAEs were hospitalizations
**Increased hospitalization rate with FluMist in 6-11 months**

**Study MI-CP111****SAE/Hospitalizations Through 180 Days Post Last Dose**

**Hospitalization Rates by Age**

- For all subjects

**p=0.002**

## Overall SAE rates were similar: 3.1% TIV, 3.3% FluMist
94% of all SAEs were hospitalizations
Increased hospitalization rate with FluMist in 6-11 months

- 94% of all SAEs were hospitalizations
**Increased hospitalization rate with FluMist in 6-11 months**

**Study MI-CP111****SAE/Hospitalizations Through 180 Days Post Last Dose**

## Study MI-CP111Hospitalizations in Children 6-11 Months of Age

|  | TIV | FluMist |
| --- | --- | --- |
| Lower Respiratory | 7 | 18 |
| Upper Respiratory | 3 | 7 |
| Gastrointestinal | 8 | 13 |
| Other Infectious | 2 | 7 |
| Other | 1 | 6 |
| Total | 21 | 51 |

***FluMist***

***TIV***

**Days Following Randomization**

**Temporal Distribution of Hospitalizations**

**Hospitalization by Diagnosis**

## Study MI-CP111Additional Exploratory Safety Analysis

**Multiple additional factors were evaluated for association with safety parameters**
**Prior history of wheeze/asthma was prospectively collected and identified by either parent or investigator**
- 21% of children had a history of wheeze/asthma reported
- 85% by parent
- 15% by health care provider only
**Prior history of wheeze/asthma was associated with higher rates of hospitalization**

## Study MI-CP111Hospitalization by Age and History of Wheeze/Asthma, Through 180 Days Post Last Dose

**Without a history of wheezing (N=6580)**

**p=0.004**

**With a history of wheezing (N=1772)**

**p=0.039**

## Further evaluation is needed in children
6-11 months of age
12-59 months of age with a history of wheeze/asthma
No SAE/hospitalization increase in children 12-59 months of age without a history of wheeze/asthma

- 6-11 months of age
- 12-59 months of age with a history of wheeze/asthma
**No SAE/hospitalization increase in children 12-59 months of age without a history of wheeze/asthma**

**Study MI-CP111****SAE/Hospitalization Conclusions**** **

## Protocol-defined Medically Significant Wheezing (MSW)
Wheeze on physical examination plus at least one of the following: new daily bronchodilator use, respiratory distress or hypoxemia 
Parents instructed to have child evaluated by HCP for any respiratory illness including wheezing
Treatment left to physician discretion
Any wheeze
Not a pre-specified case definition in the protocol
Any wheeze event reported by parent or investigator 
Includes MSW and other wheeze events

- Wheeze on physical examination plus at least one of the following: new daily bronchodilator use, respiratory distress or hypoxemia
- Parents instructed to have child evaluated by HCP for any respiratory illness including wheezing
- Treatment left to physician discretion
**Any wheeze**
- Not a pre-specified case definition in the protocol
- Any wheeze event reported by parent or investigator
- Includes MSW and other wheeze events

**Study MI-CP111****Wheezing Outcomes**

**Pre-specified interval: randomization through 42 days post last dose**

## Study MI-CP111Wheezing Outcomes Through 42 Days Post Last Dose

**Study MI-CP111****Wheezing Outcomes Through 42 Days Post Last Dose**

**Children 24-59 Months**

**Children 6-23 Months**

**p=0.002**

- For all subjects regardless of history of wheeze/asthma

**p=0.002**

**Wheezing increased in children 6-23 months of age**
**No increase in children 24-59 months of age**

## Study MI-CP111Protocol-Defined Wheezing (MSW) within 42 Days Post Last Dose By Age at Study Entry

**Higher rates of wheezing in FluMist recipients through 23 months of age**

**Protocol-Defined Wheezing (MSW) Rates by Age**

- 6-23 Months

- 24-59 Months

## Study MI-CP111Severity of MSW* in Children <24 Months

**MSW occurred in 192 children**
**75 TIV, 117 FluMist**
**14 children were hospitalized for MSW**
- 4/75 TIV vs. 10/117 FluMist
- 3 in each group had a pathogen identified
- No ICU admission or mechanical ventilation because of MSW** **
**69% of TIV cases and 75% of FluMist cases had new daily bronchodilator use but no respiratory distress or hypoxemia**
**Rates of recurrent wheezing through 180 days post last dose**
- At least 1 additional episode: 21/75 (28%) TIV vs. 38/117 (32%) FluMist
- At least 2 additional episodes: 4/75 (5%) TIV vs. 5/117 (4%) FluMist

- * Protocol-defined (MSW) within 42 days after last vaccination

## Study MI-CP111Severity of MSW* in Children 12-23 Months Without a History of Wheeze/Asthma

**Study MI-CP111****Severity of MSW* in Children 12-23 Months *****Without***** a History of Wheeze/Asthma**

**MSW occurred in 58 children**
**23 TIV, 35 FluMist**
**3 children were hospitalized for wheezing**
- 1/23 TIV, 2/35 FluMist
- 1 in each group had a pathogen identified
**74% of TIV cases and 86% of FluMist cases had new daily bronchodilator use but no respiratory distress or hypoxemia**
**Rates of recurrent wheezing through 180 days post last dose**
- At least 1 additional episode: 5/23 (22%) TIV vs. 5/35 (14%) FluMist
- At least 2 additional episodes: 1/23 (4%) TIV vs. 1/35 (3%) FluMist

- * Protocol-defined (MSW) within 42 days after last vaccination

## Wheezing is not increased in children >24 months of age
There appears to be an increase in wheezing in children 12-23 months of age without a prior history of wheeze/asthma

**There appears to be an increase in wheezing in children 12-23 months of age without a prior history of wheeze/asthma**

**Study MI-CP111****Wheezing Conclusions**** **

## Study MI-CP111Risk-Benefit Summary

**Assess overall risks/benefits of FluMist relative to TIV**
**Data display:**
**Rate differences (FluMist-TIV) per 1000 children**
**Safety endpoints from randomization through 42 & 180 days after last vaccination**
**Culture-confirmed modified CDC-ILI from randomization through 180 days after last vaccination based on all cases (matched and mismatched)**
**Summaries for 12-23 months and 24-59 months without a history of wheeze/asthma**

## Study MI-CP111 Event Rate Differences (FluMist-TIV) per 1000 Children with 95% CI in Children Without a History of Wheeze/Asthma

**Study MI-CP111**** ****Event Rate Differences (FluMist-TIV) *****per 1000 Children***** ****with 95% CI in Children Without a History of Wheeze/Asthma**

**Benefit**

**Risk**

**FluMist N=1615, TIV N=1625**

**24-59 Months**

**12-23 Months**

**FluMist N=1053, TIV N=1060**

**-8**

**7**

**4**

**-35**

**-3**

**12**

**18**

**-8**

**-3**

**1**

**-6**

**-49**

**-6**

**-8**

**Any**
**wheeze**

**MSW**

**Hosp**

**Any**
**wheeze**

**MSW**

**Hosp**

**mCDC-**
**ILI**

**Through**
**42 Days PLD**

**Through**
**180 Days PLD**

**Wheeze endpoints**

**Hospitalization**

**Culture-Confirmed Modified CDC-ILI**

## Safety Summary

**Reactogenicity of FluMist as expected **
**Further evaluation is needed in children **
- 6-11 months of age
- 12-59 months of age with a history of wheeze/asthma
**Based on risk-benefit profile for the 77% of children in        MI-CP111 who were 12-59 months *****without***** a history of wheeze/asthma**
- For children 24-59 months, significant benefit and no increase in wheezing or hospitalization
- For children 12-23 months, significant benefit but there appears to be a residual increase in wheeze within 42 days post-vaccination

## Proposed Post-marketing Initiatives

**Proposed observational safety study in children 12-59 months of age**
- Similar to ongoing post-marketing safety study in healthy children and adults 5-49 years of age
- Planned enrollment of at least 20,000 FluMist recipients
- Including assessment of hospitalizations and wheezing
**Passive surveillance**
**Education & outreach**
- Risks included in package insert
- Appropriate language in FluMist Vaccine Information Statement (VIS)
- Targeted outreach to healthcare practitioners and to parents/guardians of children vaccinated with FluMist

## Overall ConclusionsChildren <5 Years of Age

**Influenza causes significant morbidity in children on an annual basis**
**Influenza vaccine options are limited for young children **
**FluMist represents a highly efficacious vaccine in children <5 years**
- 73 to 93% efficacy in placebo-controlled studies
- 55% fewer cases of influenza illness than TIV in MI-CP111
- Significant cross-protection against *mismatched* A/H3N2, including better cross-protection compared to TIV
**Safety of FluMist established in children 24-59 months without a history of wheeze/asthma**
**FluMist risk-benefit profile in children 12-23 months without a history of wheeze/asthma also warrants vaccine licensing in this population **

## Slide 52