# Presentation: 664753

## Vaccines and Related Biologic Products Advisory Committee (VRBPAC)May 16, 2007 FluMist® Influenza Virus Vaccine Live, IntranasalSafety and Effectiveness of FluMist in a Pediatric Population Less than 59 Months of Age

- R. Douglas Pratt, MD, MPH
- Chief, Clinical Trials Branch
- DVRPA/OVRRCBER/FDA

## Background Overview

- Current Label Indication and Warnings
- Review VRBPAC #1:  July 26, 2001
- Review VRBPAC #2:   Dec 17, 2002
- FluMist® Licensure June 17, 2003
- FluMist® Liquid: Licensed Jan 5, 2007
- Review of Post-Marketing Vaccine Adverse Event Reports (VAERS)
- Proposed Label Indication
- Preview Questions to the Committee

## FluMist: Current Label

**INDICATION**
- FluMist® is indicated for active immunization of
- healthy children and adolescents, 5-17 years of
- age, and healthy adults, 18-49 years of age,
- against disease caused by influenza types A
- and B contained in the vaccine.

## FluMist: Current Label

**WARNINGS**
- The safety of FluMist in individuals with asthma or reactive airways disease has not been established. FluMist should not be administered to individuals with a history of asthma or reactive airways disease.
- The safety of FluMist in individuals with underlying medical conditions that may predispose them to severe disease following wild-type influenza infection has not been established.

## FluMist VRBPAC # 1July 26, 2001

- Proposed Use: For ages 1-64 yrs
- _Committee Vote_:
- Effectiveness was demonstrated across the age range
- Safety, was not demonstrated
- Concerns included cases of pneumonia, wheezing in children
- No information about vaccine co-administration in second year of life (e.g., MMR+V)
- Main safety study (AV019) ongoing at time

## Safety Study AV019

- 9,689 children 1-17 years of age enrolled
- Randomized 2:1 (FluMist:Placebo)
- Conducted at N California Kaiser Permanente
- Medically Attended Events (MAE) evaluated
- Electronic database queried for:
-        Clinic visits, ER visits, Hospitalizations
- Data Collection Period:   42 days after dose
**Main finding:  Asthma/Wheezing in children ****	****	****	****       younger than 5 yrs of age**

## AV019 - Number of 18-35 Month Old Subjects and Increased Relative Risk (90% CI) for Asthma Events in All Settings Combined

## AV019 – Relative Risk for Asthma Events Post-Dose 1 by Age in 6-Month Increments* (Selected Ages)

## FluMist VRBPAC # 2December 17, 2002

- Proposed Use: Healthy persons age 5-64 yrs
- Completed Study 019 safety data presented
- Committee was asked to discuss and vote on the adequacy of safety and effectiveness data by age groups:
- 				5-17 years
- 			18-49 years
- 			50-64 years

## VRBPAC # 2December 17, 2002  (cont.)

- _Committee Vote_
- Effectiveness:
- Demonstrated for ages 5-49 years
- Not effective in age group > 50 years
- Safety:
- Demonstrated for healthy persons age 		5-64 yrs

## FluMist: Post Marketing StudiesLicensed June 17, 2003

- MedImmune agreed to:
- Conduct an open-label multi-year clinical safety trial in 60,000
- FluMist recipients, 20,000 in each of the following age groups:
- 	 	5-8 years
- 		9-17 years
- 		18-49 years.
- Safety outcomes to include asthma/wheezing; all medically attended
- adverse events (MAEs), serious adverse events (SAEs), including
- deaths; and rare events potentially related to wild-type influenza virus
- infection.
- Final Study Report anticipated in 2011.

## FluMist Liquid Formulation

- Approved Jan 2007--replaced frozen formulation
- Storage at 2-8 °C for 18 weeks, but not beyond June 30 of given influenza season
- Smaller volume (0.2 mL)
- Change supported by:
- Potency through dating period
- Clinical data in children and adults, age 5-49 years, demonstrating an immunologic bridge (non-inferiority) to frozen formulation

## FluMist Adverse Events Reported to the Vaccine Adverse Event Reporting System (VAERS)

**As of February 28, 2007**

## After FluMist By Age Group* 

**After FluMist By Age Group***

| Age group | All reports |  |
| --- | --- | --- |
|  | N | % |
| 6-23 months | 1 | 0.1 |
| 2-4 years | 14 | 1.9 |
| 5-17 years | 266 | 35.8 |
| 18-49 years | 370 | 49.7 |
| ≥ 50 years | 26 | 3.5 |
| Unknown | 67 | 9.0 |
| Total | 744 | 100 |

- * Reports received as of February 28, 2007

## VAERS Reports:

**Main Outcomes of Interest by Age Group**

| Age group | All 
reports | Asthma/
Wheezing |  | Pneumonia |  | Bronchitis |  | Possible Anaphyl-axis |  | GBS |  | Bell’s palsy |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  |  | N | (%)* | N | (%)* | N | (%)* | N | (%)* | N | (%)* | N | (%)* |
| 6-23 mos | 1 † | 0 | (0) | 0 | (0) | 0 | (0) | 0 | (0) | 0 | (0) | 0 | (0) |
| 2-4 yrs | 14 ‡ | 0 | (0) | 0 | (0) | 0 | (0) | 0 | (0) | 0 | (0) | 0 | (0) |
| 5-17 yrs | 266 | 16 | (6.0) | 7 | (2.6) | 2 | (0.8) | 5 | (1.9) | 0 | (0) | 4 | (1.5) |
| 18-49 yrs | 370 | 5 | (1.4) | 5 | (1.4) | 3 | (0.8) | 8 | (2.2) | 5 | (1.4) | 4 | (1.1) |
| ≥ 50 yrs | 26 | 0 | (0) | 1 | (3.8) | 1 | (3.8) | 0 | (0) | 1 | (3.8) | 1 | (3.8) |
| Unknown | 67 | 1 | (1.5) | 2 | (3.0) | 2 | (3.0) | 0 | (0) | 1 | (1.5) | 0 | (0) |
| Total | 744 | 22 | (3.0) | 15 | (2.0) | 8 | (1.1) | 13 | (1.7) | 7 | (0.9) | 9 | (1.2) |

- * Percentage of total reports in the corresponding age group
- † Includes vaccine administration error (n=1)
- ‡ Includes vaccine failure (n=1), rhinitis (n=2), secondary transmission (n=2),
- rash/other allergic (n=2), abdominal/GI (n=1), seizures (n=1), and vaccine administration error (n=5)

## VAERS Reports of Asthma/Wheezing by 

**Age Group and Chronic Condition**

| Age group | All Reports | Asthma/Wheezing |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  |  | Total | Pre-existing chronic condition |  |  |
|  |  |  | Asthma | Other chronic | None |
| 6-23 mos | 1 | 0 | 0 | 0 | 0 |
| 2-4 years | 14 | 0 | 0 | 0 | 0 |
| 5-17 years | 266 | 16 | 7 | 0 | 9 |
| 18-49 years | 370 | 5 | 3 | 0 | 2 |
| ≥ 50 years | 26 | 0 | 0 | 0 | 0 |
| Unknown | 67 | 1 | 0 | 0 | 1 |
| Total | 744 | 22 | 10 | 0 | 12 |

## VAERS Limitations

- VAERS is a voluntary, passive surveillance system
- Risk of underreporting or reporting bias
- Possibly incomplete, unreliable data
- Outcomes requiring timely laboratory confirmation should be investigated in settings other than VAERS

## FluMist : Proposed Label

**	****Proposed INDICATION**
- 	FluMist® is indicated for the active immunization of individuals 1-49 years of age against influenza disease caused by influenza virus types A and B contained in the vaccine.

## FluMist VRBPAC #3May 16, 2007

- 	Data from additional clinical studies were submitted in the license supplement that are intended to support use of FluMist in children < 5 years of age.
- 	The main study of efficacy and safety in children          < 5 years of age was:
- 	MI-CP111:  Comparative Efficacy and Safety of
- 			  Liquid FluMist vs TIV in Children
- 			  6-59 months of age

## Clinical Study MI-CP111: Design

- Randomized (1:1), controlled and comparative, FluMist vs. TIV
- Double-blind:  placebos for intramuscular and intranasal routes
- Enrollment stratified by age, country, previous influenza vaccination and history of ≥ 3 wheezing illnesses
- Exclusions for history of severe asthma or recent wheezing
- Efficacy:
- Relative efficacy (vs. TIV) for culture-confirmed modified CDC-ILI influenza as primary efficacy outcome
- Safety:
- Study defined “Medically Significant Wheezing (MSW)” as primary safety outcome
**8,475 **children enrolled (**4,117 US**)

## Questions for the Committee

- 1.	Do the data demonstrate the efficacy of FluMist for prevention of influenza illness* *in the following:
- In the applicant's proposed population, i.e., children age 12-59 months without history of wheeze?
- Children in the age strata 6 – 23 months?
- Children in the age strata 24 – 59 months?

## Questions for the Committee(continued)

- 2.	Do the safety data demonstrate that the benefits will exceed the risks of FluMist for use in:
- a.  	The applicant’s proposed population, i.e., children age 12-59 months without history of wheeze?
- Children in the age strata 6 – 23 months, regardless   of wheezing history?
- c.  	Children in age strata 24- 59 months, regardless of wheezing history?

## Questions for the Committee(continued)

- 3.	If approved for children less than 5 years of age, what additional post-marketing studies or surveillance activities would you recommend?