# Presentation: 207437

## FluMistfor children < 5 years of ageSTATISTICAL DISCUSSION of SAFETY based on MI-CP111

- Sang H. Ahnn, Ph.D.
- CBER/FDA
**VRBPAC**
**May 16, 2007**
**Gaithersburg, MD**

**Notes:**
I will focus my presentation on the safety issues in MI-CP111 which is the main study to support this licensure.

## MI-CP111

- A multi-center, double-blind, randomized study to compare the efficacy and safety of FluMist vs. TIV.
- 8,475 (4,117 in the U.S.) subjects randomized (1:1 ratio) to either FluMist or TIV, stratified by:
- 	~** age** (6-23 months, 24-35 months, 36-59 months)
- 	~ **prior influenza vaccination** (yes/no)
- 	~ **wheezing history status** (≥ 3 wheezing illnesses 	requiring medical follow-up or hospitalization: yes/no)
- 	~ **country**.

## MI-CP111

- MI-CP111 was performed in children 6-59 months of age, including those with a history of wheezing or asthma.
- Children with medically-diagnosed or treated wheezing within 42 days before enrollment or with history of severe asthma were excluded
- The applicant is seeking an indication extension of FluMist for children 12-59 months of age, excluding those children with a history of wheezing or asthma.

- Exclusion criterion: Subjects with medically-diagnosed or treated wheezing within 42 days before enrollment or with history of severe asthma were excluded from the study
- Stratum (for randomization): Subjects with ≥ 3 wheezing illnesses requiring medical follow-up or hospitalization is a pre-specified subgroup within which subjects were randomized
- Post hoc subgroup: Subjects with a history of wheezing is a post-hoc, non-randomized subgroup

**Three uses of Wheezing History **
**in MI-CP111**

**Notes:**
Wheezing history variable were used in three different ways

## MI-CP111 Safety Results (Safety population)

|  | FluMist |  | TIV |  |   |
| --- | --- | --- | --- | --- | --- |
| Age (months) | N | # of Subjects with Medically Significant Wheezing  | N | # of Subjects with Medically Significant Wheezing   | Relative Risk 
of FluMist compared to TIV
(95% CI) |
| 6 ~59 | 4179 | 163 (3.9%) | 4173 | 131 (3.1%) | 1.24 (0.99, 1.56) |
| 6-23 | 1992 | 117 (5.9%) | 1975 | 75 (3.8%) | 1.55 (1.17, 2.05) |
| 24-35 | 1372 | 33 (2.4%) | 1379 | 32 (2.3%) | 1.04 (0.64, 1.67) |
| 36-59 | 815 | 13 (1.6%) | 819 | 24 (2.9%) | 0.54 (0.28, 1.05) |

- _Relative Risk of FluMist to TIV_
- Based on Medically Significant Wheezing* (MSW)

- *Occurring through 42 days after vaccination

**Notes:**
MSW was a pre-specified safety endpoint of primary concern.
RR for the whole study population is 
Especially in 6-23 age group, RR is 

## MI-CP111 Safety Results on Safety population

|  | FluMist |  | TIV |  |   |
| --- | --- | --- | --- | --- | --- |
| 
Age (months) | 

N | # of Subjects with Medically Significant Wheezing Hospitalization  | 

N | # of Subjects with Medically Significant Wheezing
Hospitalization  | 
Relative Risk 
of FluMist Compared to TIV
(95% CI) |
| 6 ~59 | 4179 | 12 (0.29%) | 4173 | 8 (0.19%) | 1.50 (0.63, 3.56) |
| 6-23 | 1992 | 10 (0.50%) | 1975 | 4 (0.20%) | 2.48 (0.82, 7.46) |
| 24-35 | 1372 | 1 (0.07%) | 1379 | 2 (0.15%) | 0.50 (0.07, 3.83) |
| 36-59 | 815 | 1 (0.12%) | 819 | 2 (0.24%) | 0.50 (0.07, 3.83) |

**MI-CP111 Safety Results on Safety population**
- _Relative Risk of FluMist to TIV_
- Based on Medically Significant Wheezing-related Hospitalization*

- *Medically significant wheezing (MSW) –related hospitalizations comprise hospitalizations within 7 days after MSW, provided that the MSW event occurred within 42 days after vaccination

**Notes:**
Definition of MSW-related hospitalization
This study is not powered to differences in hospitalization rate between the two groups, since the hospitalization rate is very low as you see here.

## Exclusion of 6-11 Month-olds

- 	The applicant stated “In children 6-11 months of age, rates of medically significant wheezing and rates of hospitalizations were higher in FluMist vs. TIV recipients.”  This result is the basis for the applicant excluding the 6-11 month subgroup from the sought indication.

## MI-CP111 Safety Results (Safety population)

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

Age (months) | 

N | # of Subjects with Medically Significant Wheezing  | 

N | # of Subjects with Medically Significant Wheezing   | Relative Risk 
of FluMist compared to TIV
(95% CI) |
| 6-23 | 1992 | 117 (5.9%) | 1975 | 75 (3.8%) | 1.55 (1.17, 2.05) |
| 6-11 | 684 | 47 (6.9%) | 683 | 29 (4.2%) | 1.62 (1.04, 2.53) |
| 12-23 | 1308 | 70 (5.4%) | 1292 | 46 (3.6%) | 1.50 (1.05, 2.16) |

**MI-CP111 Safety Results (Safety population)**
- _Relative Risk of FluMist to TIV_
- Based on Medically Significant Wheezing* (MSW)

- *Occurring through 42 days after vaccination

## MI-CP111 Safety Results (Safety population)

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

Age (months) | 

N | # of Subjects with Medically Significant Wheezing-related Hospitalization  | 

N | # of Subjects with Medically 
Significant Wheezing-related Hospitalization  | 
Relative Risk 
of FluMist compared to TIV
(95% CI) |
| 6-23 | 1992 | 10 (0.50%) | 1975 | 4 (0.20%) | 2.48   (0.82, 7.46) |
| 6-11 | 684 | 4 (0.58%) | 683 | 2 (0.29%) | 2.00    (0.43, 9.31) |
| 12-23 | 1308 | 6 (0.46%) | 1292 | 2 (0.15%) | 2.96    (0.69, 12.8) |

**MI-CP111 Safety Results (Safety population)**
- _Relative Risk of FluMist to TIV_
- Based on Medically Significant Wheezing-related Hospitalization*

- * Medically significant wheezing (MSW) –related hospitalizations comprise hospitalizations within 7
-   days after MSW, provided that the MSW event occurred within 42 days after vaccination

- 	Per the preceding two tables, in the FluMist group compared to TIV, rates of medically significant wheezing and MSW-related hospitalizations were not only higher in children 6-11 months of age, but also higher in those 12-23 months of age.

## SUMMARY

- In general, since the 6-11 month age group (12-23 month group likewise) is a post-hoc, non-randomized subgroup, statistical results could be misleading and therefore should be interpreted with caution.
- Specifically, in terms of MSW and MSW-related hospitalization, 6-11 months, and 12-23 months subgroups show similar safety profiles.
- Thus, statistical rationale for excluding 6-11 months group and not entire 6-23 months group appears unclear.

## MI-CP111 Safety Results (Safety population)

|  | CAIV-T |  | TIV |  |   |
| --- | --- | --- | --- | --- | --- |
| Age (months) | N | # of Subjects with Medically Significant Wheezing  | N | # of Subjects with Medically Significant Wheezing   | Relative Risk 
of FluMist compared to TIV
(95% CI) |
| 6 ~59 | 4179 | 163 (3.9%) | 4173 | 131 (3.1%) | 1.24     (0.99, 1.56) |
| 6-23 | 1992 | 117 (5.9%) | 1975 | 75 (3.8%) | 1.55     (1.17, 2.05) |
|        6-11 | 684 | 47 (6.9%) | 683 | 29 (4.2%) | 1.62        (1.04, 2.53) |
|      12-23 | 1308 | 70 (5.4%) | 1292 | 46 (3.6%) | 1.50        (1.05, 2.16) |
| 24-35 | 1372 | 33 (2.4%) | 1379 | 32 (2.3%) | 1.04     (0.64, 1.67) |
| 36-59 | 815 | 13 (1.6%) | 819 | 24 (2.9%) | 0.54     (0.28, 1.05) |

|  | CAIV-T |  | TIV |  |   |
| --- | --- | --- | --- | --- | --- |
| Age (months) | N | # of Subjects with Medically Significant Wheezing  | N | # of Subjects with Medically Significant Wheezing   | Relative Risk 
of FluMist compared to TIV
(95% CI) |
| 6 ~59 | 3275 | 88 (2.7%) | 3305 | 68 (2.1%) | 1.31     (0.96, 1.78) |
| 6-23 | 1660 | 66 (4.0%) | 1680 | 47 (2.8%) | 1.42   (0.99, 2.05) |
|        6-11 | 607 | 31 (5.1%) | 620 | 24 (3.9%) | 1.32    (0.79, 2.21) |
|      12-23 | 1053 | 35 (3.3%) | 1060 | 23 (2.2%) | 1.53    (0.92, 2.56) |
| 24-35 | 1049 | 17 (1.6%) | 1042 | 13 (1.2%) | 1.30     (0.64, 2.62) |
| 36-59 | 566 | 5 (0.9%) | 583 | 8 (1.4%) | 0.64     (0.22, 1.86) |

**MI-CP111 Safety Results (Safety population)**
- _Relative Risk of FluMist to TIV_
- Based on Medically Significant Wheezing* (MSW)

**(excluding subjects w/ hx of wheezing/asthma)**

## (excluding subjects w/ hx of wheezing/asthma)

|  | CAIV-T |  | TIV |  |   |
| --- | --- | --- | --- | --- | --- |
| Age (months) | N | # of Subjects with Medically Significant Wheezing Hospitalization  | N | # of Subjects with Medically Significant Wheezing Hospitalization  | Relative Risk 
of FluMist Compared to TIV
(95% CI) |
| 6 ~59 | 4179 | 12 (0.29%) | 4173 | 8 (0.19%) | 1.50     (0.63, 3.56) |
| 6-23 | 1992 | 10 (0.50%) | 1975 | 4 (0.20%) | 2.48   (0.82, 7.46) |
|        6-11 | 684 | 4 (0.58%) | 683 | 2 (0.29%) | 2.00        (0.43, 9.31) |
|      12-23 | 1308 | 6 (0.46%) | 1292 | 2 (0.15%) | 2.96        (0.69, 12.8) |
| 24-35 | 1372 | 1 (0.07%) | 1379 | 2 (0.15%) | 0.50     (0.07, 3.83) |
| 36-59 | 815 | 1 (0.12%) | 819 | 2 (0.24%) | 0.50     (0.07, 3.83) |

|  | CAIV-T |  | TIV |  |   |
| --- | --- | --- | --- | --- | --- |
| Age (months) | N | # of Subjects with Medically Significant Wheezing Hospitalization  | N | # of Subjects with Medically Significant Wheezing Hospitalization  | Relative Risk 
of FluMist Compared to TIV
(95% CI) |
| 6 ~59 | 3275 | 7 (0.21%) | 3305 | 5 (0.15%) | 1.41     (0.47, 4.21) |
| 6-23 | 1660 | 5 (0.30%) | 1680 | 2 (0.12%) | 2.53   (0.57, 11.3) |
|        6-11 | 607 | 3 (0.49%) | 620 | 1 (0.16%) | 3.06        (0.44, 21.4) |
|      12-23 | 1053 | 2 (0.19%) | 1060 | 1 (0.09%) | 2.01        (0.26, 15.4) |
| 24-35 | 1049 | 1 (0.09%) | 1042 | 2 (0.19%) | 0.50     (0.07, 3.79) |
| 36-59 | 566 | 1 (0.18%) | 583 | 1 (0.17%) | 1.03     (0.11, 9.86) |

**(excluding subjects w/ hx of wheezing/asthma)**

**MI-CP111 Safety Results on Safety population**
- _Relative Risk of FluMist to TIV_
- Based on Medically Significant Wheezing-related Hospitalization*