FluMist Quadrivalent: Package Insert and Label Information (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

FluMist Quadrivalent has not been evaluated for its carcinogenic or mutagenic potential or its potential to impair fertility.

14 CLINICAL STUDIES

The effectiveness of FluMist Quadrivalent is based on data demonstrating the clinical efficacy of FluMist in children and the effectiveness of FluMist in adults, and a comparison of post vaccination geometric mean titers (GMTs) of hemagglutination inhibition (HI) antibodies between individuals receiving FluMist and FluMist Quadrivalent. The clinical experience with FluMist is relevant to FluMist Quadrivalent because both vaccines are manufactured using the same process and have overlapping compositions [see Description (11)].

14.1 Efficacy Studies of FluMist in Children and Adolescents

A multi-national, randomized, double-blind, active-controlled trial (MI-CP111) was performed to assess the efficacy of FluMist compared to an intramuscularly administered, inactivated Influenza Virus Vaccine manufactured by Sanofi Pasteur Inc. (active control) in children 6 months to less than 5 years of age during the 2004-2005 influenza season. A total number of 3916 children without severe asthma, without use of bronchodilator or steroids, and without wheezing within the prior 6 weeks were randomized to FluMist and 3936 were randomized to active control. Children who previously received any influenza vaccine received a single dose of study vaccine, while those who never previously received an influenza vaccination (or had an unknown history of influenza vaccination) received two doses. Participants were then followed through the influenza season to identify illness caused by influenza virus. As the primary endpoint, culture-confirmed modified CDC-ILI (CDC-defined influenza-like illness) was defined as a positive culture for a wild-type influenza virus associated within ±7 days of modified CDC-ILI. Modified CDC-ILI was defined as fever (temperature ≥ 100°F oral or equivalent) with cough, sore throat, or runny nose/nasal congestion on the same or consecutive days.

In the primary efficacy analysis, FluMist demonstrated a 44.5% (95% CI: 22.4, 60.6) reduction in influenza rate compared to active control as measured by culture-confirmed modified CDC-ILI caused by wild-type strains antigenically similar to those contained in the vaccine. See Table 6 for a description of the results by strain and antigenic similarity.

Table 6: Comparative Efficacy Against Culture-Confirmed Modified CDC-ILI * Caused by Wild-Type Strains (Study MI-CP111)
*
Modified CDC-ILI was defined as fever (temperature ≥ 100°F oral or equivalent) plus cough, sore throat, or runny nose/nasal congestion on the same or consecutive days.
In children 6 months through 5 years of age
NCT00128167; see www.clinicaltrials.gov
§
Inactivated Influenza Virus Vaccine manufactured by Sanofi Pasteur Inc., administered intramuscularly.
Reduction in rate was adjusted for country, age, prior influenza vaccination status, and wheezing history status.

FluMist

Active Control §

N

# of Cases

Rate (cases/N)

N

# of Cases

Rate (cases/N)

% Reduction in Rate for FluMist

95% CI

Matched Strains

All strains

3916

53

1.4%

3936

93

2.4%

44.5%

22.4, 60.6

A/H1N1

3916

3

0.1%

3936

27

0.7%

89.2%

67.7, 97.4

A/H3N2

3916

0

0.0%

3936

0

0.0%

B

3916

50

1.3%

3936

67

1.7%

27.3%

-4.8, 49.9

Mismatched Strains

All strains

3916

102

2.6%

3936

245

6.2%

58.2%

47.4, 67.0

A/H1N1

3916

0

0.0%

3936

0

0.0%

A/H3N2

3916

37

0.9%

3936

178

4.5%

79.2%

70.6, 85.7

B

3916

66

1.7%

3936

71

1.8%

6.3%

-31.6, 33.3

Regardless of Match

All strains

3916

153

3.9%

3936

338

8.6%

54.9%

45.4, 62.9

A/H1N1

3916

3

0.1%

3936

27

0.7%

89.2%

67.7, 97.4

A/H3N2

3916

37

0.9%

3936

178

4.5%

79.2%

70.6, 85.7

B

3916

115

2.9%

3936

136

3.5%

16.1%

-7.7, 34.7

ATP Population.

A randomized, double-blind, saline placebo-controlled trial (D153-P501) was performed to evaluate the efficacy of FluMist in children 12 through 35 months of age without high-risk medical conditions against culture-confirmed influenza illness. This study was performed in Asia over two successive seasons (2000-2001 and 2001-2002). The primary endpoint of the trial was the prevention of culture-confirmed influenza illness due to antigenically matched wild-type influenza. Respiratory illness that prompted an influenza culture was defined as at least one of the following: fever (≥ 100.4°F rectal or ≥ 99.5°F axillary), wheezing, shortness of breath, pulmonary congestion, pneumonia, or otitis media; or two of the following: runny nose/nasal congestion, sore throat, cough, muscle aches, chills, headache, irritability, decreased activity, or vomiting. A total of 3174 children were randomized 3:2 (vaccine:placebo) to receive 2 doses of study vaccine or placebo at least 28 days apart in Year 1. See Table 7 for a description of the results.

During the second year of Study D153-P501, for children who received two doses in Year 1 and one dose in Year 2, FluMist demonstrated 84.3% (95% CI: 70.1, 92.4) efficacy against culture-confirmed influenza illness due to antigenically matched wild-type influenza.

Study AV006 was a second multi-center, randomized, double-blind, AF-SPG placebo-controlled trial performed in U.S. children without high-risk medical conditions to evaluate the efficacy of FluMist against culture-confirmed influenza over two successive seasons (1996-1997 and 1997-1998). The primary endpoint of the trial was the prevention of culture-confirmed influenza illness due to antigenically matched wild-type influenza in children who received two doses of vaccine in the first year and a single revaccination dose in the second year. Respiratory illness that prompted an influenza culture was defined as at least one of the following: fever (≥ 101°F rectal or oral; or ≥ 100.4°F axillary), wheezing, shortness of breath, pulmonary congestion, pneumonia, or otitis media; or two of the following: runny nose/nasal congestion, sore throat, cough, muscle aches, chills, headache, irritability, decreased activity, or vomiting. During the first year of the study, 1602 children 15 through 71 months of age were randomized 2:1 (vaccine:placebo). See Table 7 for a description of the results.

Table 7: Efficacy * of FluMist vs. Placebo Against Culture-Confirmed Influenza Illness Due to Antigenically Matched Wild-Type Strains (Studies D153-P501 & AV006, Year 1)
*
D153-P501 and AV006 data are for subjects who received two doses of study vaccine.
In children 12 through 35 months of age
In children 15 through 71 months of age
§
NCT00192244; see www.clinicaltrials.gov
NCT00192179; see www.clinicaltrials.gov
#
Number and percent of subjects in per-protocol efficacy analysis population with culture-confirmed influenza illness.
Þ
Number of subjects in per-protocol efficacy analysis population of each treatment group of each study for the “any strain” analysis.
ß
For D153-P501, influenza circulated through 12 months following vaccination.
à
Estimate includes A/H1N1 and A/H1N2 strains. Both were considered antigenically similar to the vaccine.

D153-P501 §

AV006

FluMist n # (%)

Placebo n # (%)

% Efficacy (95% CI)

FluMist n # (%)

Placebo n # (%)

% Efficacy (95% CI)

N Þ = 1653

N Þ = 1111

N Þ = 849

N Þ = 410

Any strain

56 (3.4%)

139 (12.5%)

72.9%ß(62.8, 80.5)

10 (1%)

73 (18%)

93.4%(87.5, 96.5)

A/H1N1

23 (1.4%)

81 (7.3%)

80.9%(69.4, 88.5)à

0

0

A/H3N2

4 (0.2%)

27 (2.4%)

90.0%(71.4, 97.5)

4 (0.5%)

48 (12%)

96.0%(89.4, 98.5)

B

29 (1.8%)

35 (3.2%)

44.3%(6.2, 67.2)

6 (0.7%)

31 (7%)

90.5%(78.0, 95.9)

During the second year of Study AV006, children remained in the same treatment group as in Year 1 and received a single dose of FluMist or placebo. During the second year, the primary circulating strain was the A/Sydney/05/97 H3N2 strain, which was antigenically dissimilar from the H3N2 strain represented in the vaccine, A/Wuhan/359/95; FluMist demonstrated 87.0% (95% CI: 77.0, 92.6) efficacy against culture-confirmed influenza illness.

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