1

FluMistInfluenza Virus Vaccine,

Live, Intranasal(Cold Adapted, Trivalent)

MedImmune Inc.

VRBPAC – Dec 17, 2002 FDA Introduction

ChrisAnna M. Mink, MD

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FluMist - The Product• FluMist Influenza Virus Vaccine, Trivalent

A and B contains 3 strains of live attenuated, cold-adapted, temperature sensitive influenza viruses: two type A (H1N1 and H3N2) and one type B.

• 0.5ml dose contains 107 TCID50 of each of the 3 strains in normal allantoic fluid (NAF).

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FluMist - Regulatory Time Course

Original BLAa Submission October 30, 2000

VRBPAC Meeting July 26-27, 2001

CBER CRLb #1 August 31, 2001

Sponsor’s Response to #1 January 7, 2002

CBER CRLb #2 July 10, 2002

Sponsor’s Response to #2 August 26, 2002

Sponsor Revised Age Indication

November 1, 2002

VRBPAC Meeting December 17, 2002

aBiologic License Application bComplete Response Letter

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Regulatory History

• Sponsor’s changes in indications sought:– Proposed age indication for healthy

individuals: • 12 mos – 64 years 10/2000 (original)• 60 mos – 64 years 11/2002 (current)

– Request for an indication for travelers to areas where influenza viruses are circulating has been removed

• VRBPAC July 2001 - unresolved concerns

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VRBPAC 2001 – Efficacy Vote for Children and Adolescents

• Vote for efficacy data for supporting indication for 1 year -17 years of age:

– “Yes” n=8 and “no” n=7

– 5 of 7 voting “no” stated would vote yes if request was starting at older age,

e.g., 15 - 24 mo.

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VRBPAC 2001 – Expressed Concerns for Efficacy in Children and Adolescents

• Expressed concerns included:– Few subjects < 2 years– No concurrent immunization data– No A/H1N1 field efficacy data– Extrapolating data for children 7 – 17 years

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VRBPAC 2001 – Efficacy Vote and Expressed Concerns for Use in Adults

• Vote for adult indication, 18 - 64 years: “Yes” n=13 and “no” n=2

• Expressed concerns included:– Few subjects > 50 years of age– Defining “healthy” recipients– No re-vaccination data– No concomitant immunization data– Use of clinical endpoints (effectiveness) not

confirmed with influenza cultures (efficacy)

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VRBPAC 2001 – Safety Vote and Expressed Concerns for All Ages

• Vote for safety data for 1-64 years of age:“Yes” n=5 and “no” n=9

• Expressed concerns included:– Final data for some critical studies not yet

submitted to CBER– Possible association of FluMist with

adverse respiratory events including pneumonia and asthma/wheezing

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VRBPAC 2001 – Safety Vote and Expressed Concerns, continued

– Occurrence of other AEs post-vaccination – Few subjects in extreme age groups

(< 2 years and > 50 years)– No concomitant immunization data– Paucity of transmissibility data– Possibility of reassortment (including with

wild type influenza) and the risk of reversion of the attenuated strains

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Current Indication Being Sought• Active immunization for the prevention of

disease caused by influenza A and B viruses in healthy children, adolescents, and adults from 5 years (> 60 months) - 64 years of age.– 2 dose regimen (60 + 14 days apart) for

1st use for children 5 years - 8 years of age.

– 1 dose for > 9 years - 64 years of age.

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VRBPAC - 2002

• With consideration for the revised age indication and availability of final dataset, a review of efficacy and effectiveness data and additional safety analyses of FluMist will be presented for the Committee’s deliberations.

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Question #1 – Safety (Vote)

1a. Are the data adequate to support safety of FluMist for individuals:

• 5 – 17 years of age?• 18 – 49 years of age?• 50 – 64 years of age?

Please consider data related to:• Respiratory events, e.g. asthma and URI• Shedding and transmission of vaccine strains

following receipt of FluMist• Annual revaccination

1b. If the data are not adequate for specific age groups or there are other safety concerns, please discuss what

additional data should be requested.

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Question #2 – Efficacy (Vote)

2a. Are the data adequate to support efficacy of FluMist in individuals:

• 5 – 17 years of age?

• 18 – 49 years of age?

• 50 – 64 years of age?

2b. If the data are not adequate for specific age groups, please discuss what additional data should be requested.

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Discussion Point #3 Clinical Studies for

Release of New Strains

• Please comment on the design and endpoints for the clinical study performed in adults for the release of new strains.

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Discussion Point #4 Additional Studies

• If the data are adequate to support safety and efficacy, please discuss what additional information, if any, should be requested from post-marketing studies?

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FluMistInfluenza Virus Vaccine,

Live, Intranasal(Cold Adapted, Trivalent)

MedImmune Inc.

VRBPAC – Dec 17, 2002 FDA Clinical Summary

ChrisAnna M. Mink, MD

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Studies in Final Database

• 20 studies submitted to the BLA– 14 randomized double-blind, placebo-

controlled• 3 pivotal safety trials, randomized 2:1

(AV006, AV009 and AV019)– 6 non-placebo controlled– Final reports for 3 of 20 trials were

submitted on January 7, 2002:• AV019 – Large safety trial• AV012 – Texas HMO trial• D145-P500 – Transmissibility in Daycare

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Number of Vaccinees by Age Group in the Finalized Database

Age (years)

FluMist 1st dose

FluMist 2nd dose

Placebo

1 - 4 5963 3145 3323

5 - 8 4418 2643 1970

9 - 17 5903 1028 1371

18 - 49 3322 38 1495

50 - 64 511 0 209

> 65 111 0 101

Total 20,228 7354 8469

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Study AV019Large Safety Trial in

Northern California Kaiser Permanente (NCKP)

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AV019 – NCKP FluMist Safety Trial

• Healthy children 1 - 17 yrs at NCKP

• Randomized FluMist vs. placebo (2:1): – 2 doses (28 - 42 days later) for 1- 8 yr olds– 1 dose for 9 - 17 yr olds

• Started 10/00, used 1999-2000 vaccine (both A strains differed, B was the same)

• Exclusion criterion – reported history of asthma or possible asthma

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AV019 – Methods• No active monitoring for solicited reactogenicity

events post-vaccination (e.g., cough, fever, coryza)• NCKP database searched after each dose

(28 – 42 days) for primary safety outcomes:– Serious adverse events (SAEs)

• Defined c/w 21 CFR 312– Medically attended events (MAEs)

• Encounter with healthcare provider• 170 individual events• 4 pre-specified group categories

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AV019 – Endpoints and Analyses • 4 pre-specified event categories:

– acute respiratory events– systemic bacterial infections– acute gastrointestinal events– rare events, historically-associated

(“potentially-related”) with wild type influenza • Utilization settings:

– hospital, outpatient clinic, emergency department (ED), combined

• Stratification by age (pre-specified):– 12-17mo, 18-35 mo, 1-8yr, 9-17 yr, All (1-17 yr)

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AV019 – Statistical Methods

• Estimate incidence of MAEs and SAEs in FluMist recipients relative to placebo, post-vaccination – Expressed as relative risk, RR (90% CI),

constructed using binomial method– 90% CIs – safety assessments

• Interim analysis with un-blinding was performed to provide safety data for VRBPAC 2001

• Over 1500 analyses were performed – No adjustments for multiple comparisons

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AV019 - Results: Enrollment

• 9689 evaluable subjects– FluMist n=6473, placebo n=3216– 8.5% of participants had Hx of asthma,

75% of these subjects were 1-8 years of age

• Age Distribution– 5637 (58%) 1-8 years– 4052 (42%) 9-17 years

• Demographic characteristics – similar age, gender and ethnicity in the 2

treatment groups

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AV019 – Results: Compliance

• 87% (4904/5637) 1-8 year olds received Dose 2 of vaccine

• Reasons for NOT receiving Dose 2:– Unable to contact – Non-compliance– Adverse event after Dose 1:

• FluMist n=39, placebo n=27• Most were related to respiratory tract

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AV019 - Results: SAEs

• No deaths reported

• 20 SAEs reported; rate of 0.02% for both FluMist (n=13) and placebo (n=7)

• Of 13 SAEs in FluMist, 12 after Dose 1

• Events:– 11 hospitalizations, – 6 psychiatric hospitalizations, – 3 others (1 ED visit, 1 clinic, 1 outpt surgery)

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AV019 – Results: Number of Subjects with MAEs, by Setting

FluMist N=6473

Placebo N=3216

Utilization Setting

n (%) n (%)

Hospital 31 (0.5) 19 (0.6)

ED 188 (2.9) 104 (3.2)

Clinic 2305 (35.6) 1191 (37)

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AV019 – Results: Pre-Specified Group Diagnoses

• None of the 4 pre-specified group diagnoses occurred at significantly increased rates in FluMist recipients

• No systemic bacterial infections were reported

RR for acute respiratory events in FluMist recipients for all ages, settings and doses combined, RR= 0.9 (90% CI: 0.82, 0.98)

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AV019 – Results: Asthma Events

• Interim analysis – increased RR for asthma events after FluMist in children, 18-35 months of age

• Final analyses - increased RR for asthma events in 18-35 months still observed

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

Setting Dose

FluMist n/N

Placebo n/N

RR (90%CI)

All 1 10/728 0/369 -- (1.95, NA*)

All Combined 16/728 2/369 4.06 (1.29, 17.86)

*NA = not able to calculate, due to zero events in placebo group

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AV019 – Asthma Events in Children 18 – 35 Months of Age

• 18 subjects (FluMist =16 and placebo = 2) had 20 asthma events

• 17 subjects in clinic, 1 FluMist subject in ED • All subjects received treatment:

– 94% -agonist– 56% antibiotics– 33% systemic corticosteroids– 17% inhaled steroids

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AV019 – RR for Asthma Events Post-Dose 1 by Age in 6-Month Increments (Selected Ages)

28/42 Day Summary Period

Age (mo) Relative Risk 90% CI

12-35 2.83 0.85, 12.80

12–41 2.89 0.87, 13.09

12-47 2.9 0.87, 13.12

12-53 3.06 0.94, 13.77

12-59 3.53 1.10, 15.66

12-65 1.76 0.71, 4.92

12-71 2.03 0.83, 5.60

12-77 2.03 0.92, 4.97

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AV019 – Number of Subjects and RR for Asthma Events, by Dose,

All Settings Combined* Age

Dose

FluMist n/N

Placebo n/N

RR 90% CI

12 – 59 Months

1 14/2020 2/1011 3.53 1.1, 12.15

2 21/1728 8/861 1.31 0.66, 2.59

60 – 107 Months

1 8/1748 5/858 0.78 0.31, 2.01

2 4/1514 6/739 0.33 0.11, 0.94

9 – 17 Years

1 11/2705 9/1347 0.61 0.29, 1.28

*CBER-generated table

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AV019 – RR for Asthma Events by Age in 6-Month Increments

RR = 3.53 (90% CI: 1.1, 15.66) after Dose 1 for children 12-59 months, and declined thereafter

• No in RR after Dose 2

• No RR in children 60-107 months after Dose 1 or 2

• No RR in children 9-17 years of age after a single dose

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AV019 – Results: URI Events

• No RR for URI in combined analysis for all ages, settings and doses

• One SAE in a placebo recipient (hospitalization for URI and croup on Day 4 post-vaccination)

RR for URI in 3 of 41 separate analyses

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AV019 - Number of Subjects and Increased RR (90% CI) for URI Events

by Age and Setting

Age

Setting Dose

FluMist n/N

Placebo n/N

RR (90%CI)

1-17 y ED Dose 1

11/6473 0/3216 -- (2.14, NA)

1-8 y ED Dose 1

9/3769 0/1869 -- (1.7, NA)

18-35 mo

All Combined

153/728 60/369 1.3 (1.01, 1.67)

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AV019 – Results: Pneumonia Events

• No increase in RR was observed for pneumonia, bronchitis or bronchiolitis in any age group, setting or dose

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AV019 – Results: Abdominal Pain• Abdominal pain reported in 0.7% of FluMist

and 0.8% of placebo subjects RR in 2 analyses

– 9-17 yr in ED post-dose 1– 1-17 yr in ED after both doses

RR in 2 analyses– 1-8 yr in clinic post-Dose 1– 1-8 yr in all setting post-Dose 1

• No specific abdominal disorders identified• No intussusception, mesenteric adenitis or

intestinal obstruction reported

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AV019 – Results: Rare Events, Potentially Related to Influenza

• No cases of encephalitis, encephalopathy, Guillain-Barre Syndrome, Reye’s Syndrome or other influenza-associated disorders were reported.

• 10 subjects (FluMist n=7 and placebo n=3) reported 11 seizure events, RR = 1.16 (90% CI: 0.38, 4.09)– 5 of 7 FluMist subjects and 1 of 3 placebo

subjects were < 5 years

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AV019 – Conclusions• Major contributor to safety database.• SAEs occurred at rate of 0.2%• Many children with asthma enrolled despite

exclusion criterion• Increase RR for asthma events in

– 18 - 35 mo after Dose 1 – 12 - 59 mo after Dose 1 – Children with asthma events received treatment

• No significant increase in RR for asthma forchildren over 60 months observed

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AV019 – Conclusions• No RR for pneumonia events• No rare events events possibly related to

influenza were reported RR for URI events and musculoskeletal

pain in children 18 – 35 months• 1500 analyses performed, RR for some

MAEs may be due to chance alone.• Additional studies are needed to assess

the association of asthma events following receipt of FluMist

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Study AV012 - Texas HMO Trial

Years 1 and 2

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AV012 –Texas HMO Trial: Design

• Design Open-label, non-randomized • Subjects children 18 mo – 18 years

– History of mild asthma permitted• Vaccine single dose given in each year • Planned to assess herd immunity of FluMist,

safety monitoring as secondary objective • Several limitations for the design• Presenting only safety data from Years 1 and 2• Contributes safety experience following

9549 doses in 7448 children

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AV012 –Texas HMO Trial: Design

Revised plan for safety assessments (implemented after trial initiated):

• SAEs for 42 days post-vaccination primary measure of safety – Captured by postcard reporting or database

searches

• Medically attended acute respiratory illness (MAARI) secondary measure of safety– Captured by database searches

• Overall MAARI • Selected respiratory events, including asthma

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AV012 – Revised Analysis Plan • Data analysis of MAARI events used a post-

marketing method (Griffin et al, 1990, 1991)• Each participant served as own control:

event rates within a specified vaccination period compared to event rates within a reference period

• Two Vaccination Periods:– Days 0 - 14– Days 0 - 42

• Single Reference Period was constructed by combining pre-vaccination period and the post-vaccination period

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AV012 - Texas HMO Trial Years 1 and 2 - Results

• Enrolled – Year 1 (8/17/98 – 1/30/99)– N = 4298– Asthma history ~13%

• Enrolled – Year 2 (9/13/99 – 2/10/00)– N = 5251– Asthma history ~17%– 40% (n=2101) re-vaccinees

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AV012 - Texas HMO Trial Years 1 and 2 – SAE Results

• No deaths reported

• Year 1

– 8 SAEs in 4131 evaluable subjects, 0.2%

– 6 of 8 SAEs occurred beyond Day 21 • Day 3 – hospitalization for depression in

16 year old• Day 21 – “aseptic meningitis” in 7 year old

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AV012 - Texas HMO Trial Years 1 and 2 – SAE Results

• Year 2– 16 SAEs (all hospitalizations) reported in

15 of the 5033 evaluable subjects, 0.3%

– 9 of 16 occurred on or Day 21

– 2 SAEs were related to respiratory tract:• Day 11 – RSV pneumonitis and febrile

seizure in 23 month old• Day 44 – pneumonia in ~ 4 year old

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AV012 - Texas HMO Trial MAARI Results

• Year 1– No RR for overall MAARI for either

Vaccination Period (Days 0-14 or Days 0-42)• Year 2

RR for MAARI events for Day 0-14 Period (RR=1.12, 90% CI: 1.00, 1.25)

RR for MAARI events for Day 0-42 Period (RR=1.13, 90% CI: 1.03, 1.24)

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AV012 - Texas HMO Trial: Asthma Events

• Rate of asthma events was ~ 1% for all participants in each Year 1 and Year 2

• Year 1– No RR for asthma events for either

Vaccination Period (Days 0-14 or Days 0-42)• Year 2

– No RR for asthma events for Day 0-14 Vaccination Period

RR for asthma events for Day 0-42 Vaccination Period:RR = 1.83 (90% CI: 1.26, 2.67)

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AV012 - Texas HMO Trial Limitations

• Not randomized or blinded

• No control group for statistical comparisons

• Method used for data analysis may be problematic for pre-licensure safety evaluations

• MAARI for safety not prospectively defined

• Differences in MAARI rates observed inYear 1 and Year 2

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AV012 - Texas HMO Trial Conclusions

• 7448 subjects received 9549 doses of FluMist (37% of total 1st doses)

• Rates of SAEs captured was 0.2-0.3%, similar to rate in AV019

• No reported rare events, potentially-related to wild type influenza infection

RR for MAARI observed in some analyses

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Comparison of AV012 and AV019

• Rates of asthma events 0.5% - 1.5% among FluMist recipients in both trials

• Marked differences between designs of 2 trials:– Open – label vs. randomized, blinded and

controlled – Monitoring methods – Study populations (asthma history)– FluMist formulations– Geographic locations, calendar years

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Asthma/Wheezing: Review of 20 Trials in BLA

• Overlap in diagnoses of asthma, reactive airway disease (RAD), wheezing and shortness of breath (SOB)

• Across 20 studies, 82 - 88% of asthma/RAD/wheezing/SOB events and 74 - 83% of asthma/RAD occurred in children 1 - 9 years of age (50% of total study population)

• Asthma events occurred throughout 42 day post-vaccination period

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Serious Adverse Events – Asthma/Wheezing Review of 20 Trials in BLA

• 4 hospitalizations for asthma/RAD/wheezing/SOB events:– AV006 – Year 2 23 mo for status

asthmaticus on Day 8 after Dose 3 of FluMist– AV008 69 yo with heart disease, wheezing,

and CHF on Day 16 post-FluMist– AV002 2 hospitalizations for RAD on Day

4 and Day 33 in placebo subject with history of asthma

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Asthma/RAD/Wheezing/SOB Events –Relative Risk in Protocol-Defined Age

Groups in Three Pivotal Trials

28/42 Day Summary Period

Study Relative Risk 90% CI

AV006 – Year 1 15-71 m, Dose 1

0.68 0.14, 3.82

AV019 1-8 y, Dose 1

1.15 0.6, 2.29

AV019 9-17 y

0.46 0.18, 1.18

AV009 18-64 y

1.04 0.12, 15.08

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Asthma/Wheezing - Summary• Analyses by age sub groups in AV019:

– 12-59 months (post hoc, 6-month increments)– 18-35 months (pre-defined)

• AV019 major contributor of children < 9 years in database (78%), thus review over 20 studies c/w results in AV019

• Study AV010 (enrolled 9 – 17 year old subjects with moderate to severe wheezing)– 3/24 FluMist and 0/24 placebo recipients had

exacerbations in 32 days post-vaccination

• Concern on-going for risk of asthma/wheezing events in young children and subjects with history of asthma

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Wyeth-Lederle Vaccines (WLV)-Sponsored Trial

D145-P500

Assessment of Transmissibility of

CAIV-T (FluMist) in Daycare Attendees

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D145-P500 – Transmission Study

• Randomized (1:1), double-blind trial to assess shedding and transmission of FluMist (CAIV-T) influenza strains in daycare attendees, 8 – 36 months of age

• Subjects eligible if:– Attended daycare > 3 times/week for > 4

hours/day – > 4 contacts in play group with at least one

CAIV-T vaccinee

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D145-P500 – Transmission Study: Design

• 1 dose of CAIV-T or placebo• Nasal swabs Day 0, 1 and 3 alternating days

per week through Day 21• Isolated vaccine viruses were typed (A or B),

subtyped (H1N1 or H3N2), phenotyped (ca and ts) and genotyped (subset)

• Original primary objective % placebo subjects shedding virus, identified as vaccine strain

• Sponsor’s post hoc analysis probability that a vaccinee will infect a placebo subject (Reed-Frost Model)

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D145-P500 – Results: Shedding

• 197 subjects (FluMist = 98, placebo = 99) enrolled from 51 daycare centers– typical playgroup 2 CAIV-T and 2 placebo

• All available shedding population (n=197)• 78 (80%) CAIV-T recipients shed at least 1 strain

of vaccine virus:– 43 shed type A– 72 shed type B– 6 shed types A and B– 6 shed all 3 types– 13 shed viruses, not able to be subtyped or

genotyped (6 type A and 7 type B)

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Study D145-P500 – Duration of Shedding of Influenza Viruses for

FluMist Recipients (N=98)

Strain

N*

Vaccine Strain

Median (Days)

Range (Days)

A/H1N1 31 31 3 1-21

A/H3N2 12 12 8 3-17

B 72 65 8 1-15

*No wild type influenza isolates

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D145-P500 – Results: Transmission

• Placebo subjects:– All available, n=93– All evaluable, n=57 (no protocol violations)

• Viruses recovered from 7 placebo subjects:– 1 subject shed type B/Ann Arbor, vaccine

strain on Day 15 – 6 subjects shed a total of 9 type A isolates

• 2 subjects shed wild type isolates on 2 different days (n=4 isolates)

• 4 subjects shed a total of 5 isolates that could not be identified

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D145-P500 – Subject with Transmitted Type B Vaccine Virus

• Placebo subject shed type B/Ann Arbor, vaccine strain on Day 15 (negative cultures on other days)

• Had contact with 2 CAIV-T recipients who were shedding type B

• B/Ann Arbor detected 5 days after last day of identified shedding by vaccinees

• Subject had coryza Days 8-18, cough on Days 8 and 9 and irritability Days 0, 14, 17

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D145-P500 – Results: Probability of Transmission (Original Analysis)

• Including isolates identified as vaccine virus (n=1, type B) among 57 eligible placebo subjects, rate of transmission:

1/57 [Rate = 1.75% (95% CI: 0.1%, 8.75%)]• All available transmission (n=93), assuming all

subjects with unidentified isolates had vaccine strain (n=5, 1 type B + 4 type A), rate of transmission:

5/93 [Rate = 5.38% (95% CI: 2.6%, 10.4%)]

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D145-P500: Genotype of Selected Shed Isolates

• Consensus genomic sequences of isolates from all placebo and subset of FluMist recipients and the relevant viral harvest strains for the vaccine formulation used in the trial were compared

• B/Ann Arbor transmitted isolate had 3 nucleotide changes

• 55 of 237 isolates from FluMist subjects were tested, nucleotide changes were found in:– 16/21 (76%) A/H1N1– 11/12 (92%) A/H3N2– 17/22 (77%) B

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D145-P500 – Results: Genotype and Phenotype

• Nucleotide changes were not random– Type A (H1N1 combined with H3N2):

occurred in PB1, PB2, NP and M genes– Type B:

occurred in the M gene• All tested isolates (n=55) maintained attenuated

cold-adapted (ca) and temperature-sensitive (ts) phenotype

• Evaluation of retention of attenuation of the shed viruses in animal model is on-going

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D145-P500 - Conclusions

• Several limitations for this trial, e.g., small sample, many protocol violations

• Shedding of vaccine strains was frequent (~80%) and lasted through Day 21

• Transmission occurred, estimate crude rate• Recovered vaccine viruses had a high frequency

of nucleotide changes:– ca and ts phenotype markers retained – not random but clinical significance not

known (evaluation of attentuation on-going)

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Additional Assessments of Shedding

• Routine Cultures (performed in 4 trials)– 196 of 569 (~ 34.5%) subjects shed vaccine

virus identified from routine cultures post-vaccination Days 0 – 10

• Illness Cultures– 40 of 290 (13.8%) FluMist subjects with

illnesses post-vaccination shed an influenza virus on culture obtained Days 0-10• 20 of these 40 isolates were tested

(genotype/phenotype) and proved to be vaccine strain

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Genotype and Phenotype Stability of Strains Recovered from Ill Subjects

• Of the 20 vaccine strains isolated from ill FluMist subjects, none were reported to have altered ca or ts phenotype

• Reassortment of vaccine strains and wild type influenza strains not identified in circumstances when wild type strains (A/H3N2 and B) were known to circulate

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Selected Data forPost-Vaccination Solicited

Reactogenicity Eventsin Children (AV006) and Adults (AV009)

72

Solicited Reactogenicity Events (REs)

• Included runny nose/nasal congestion, sore throat, cough, irritability, headache, chills, myalgia, decreased activity and fever

• Solicited for 10 days in AV006 and

7 days in AV009

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AV006 Year 1 – Percent of Subjects with Selected REs by Group and Dose

Dose 1 Dose 2

FluMist Placebo FluMist Placebo

Card, N 1056 %

530 %

850 %

415 %

Any RE 74 66* 69 62*

Runny nose

59 48* 51 46

Vomiting 6 4* 7 5

Myalgias 5 3* 3 2

Fever > 100.6oF (R)

16 12* 11 11

*p < 0.05, Fishers exact

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AV006 - Year 2: Solicited REs following Re-Vaccination with FluMist

• In Year 2 no statistically significant differences for REs between the FluMist and placebo groups

• Rates of REs similar in subjects who received 1 or 2 doses in Year 1

• Runny nose/congestion (~ 42%) and cough (~ 24%) were most common REs in both treatment groups

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AV009 – Percent of Subjects with REs by Study Group for 18 – 64 Years

Study Group

Diary Card

FluMist N=2985

Placebo N=1490

Reactogenicity Event % %

Any RE 70.9 61.9

Runny nose/ congestion

44.3 26.6*

Sore throat 26.6 16.3*

Cough 13.6 10.2

Myalgia 16.1 14.5

Fever > 101oF (O) 0.57 0.60

*Can not rule out > 10% difference

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SummaryPost-Vaccination Reactogenicity

• Between FluMist and placebo (NAF) groups, significant differences were observed for:– Runny nose and low-grade fever for children – Runny nose and sore throat for adults

• REs occurred commonly (> 60%) in both treatment groups in children and adults

• No solicited RE data for 7 – 17 year olds• No apparent differences in RE rates by age

group, < 50 years and 50 – 64 years of age• Most safety data generated in healthy subjects

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Additional Concerns from VRBPAC July 2001

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Adverse Events - Pneumonia

• Concern at VRBPAC 2001 for possible increase in pneumonia after receipt of FluMist in AV006 – Year 1, not all studies finalized

• Updated assessment across all 20 studies,

NO increase in pneumonia, bronchitis, or bronchiolitis events post-vaccination identified.

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Pneumonia Events – Relative Risk in Pediatric Pivotal Placebo-Controlled Trials

Study and Age

Dose

FluMist n/N

Placebo n/N

RR

90% CI

AV006 – Yr 1 15 – 71 mos

1 7/1070 1/532 3.48 0.69, 39.25

AV019 12 – 59 mos

1 6/2020 4/1011 0.75 0.26, 2.17

2 14/1728 9/861 0.78 0.39, 1.58

AV019 60 –107 mos

1 3/1748 3/858 0.49 0.13, 1.88

2 4/1514 2/739 0.98 0.24, 4.07

AV019 9 – 17 yrs

1 2/2705 0/1347 NA 0.43, NA

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Adverse Events – Abdominal Pain

• VRBPAC 2001, RR for abdominal pain was reported in children in AV006 – Year 1, Dose 1 (solicited event post-vaccination)

RR = 2.69 (90% CI: 1.24, 6.44)• Updated assessment across 20 trials,

RR in subjects < 9 years in AV019 (MAEs) RR in subjects 18-64 years in AV009

• No intussusception, intestinal obstruction or mesenteric adentitis reported.

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Adverse Events – Rare Events Potentially Associated with Influenza

• Review across 20 studies, no reported cases of: – encephalitis – encephalopathy – Guillain-Barre Syndrome – Reye’s Syndrome

• No RR for central nervous system events, including seizures, following receipt of FluMist

82

Additional Concerns – Concurrent Immunization

• No data for efficacy or safety with concomitant immunizations in any age group

• For use of FluMist for 5-64 years of age, possible concurrent vaccinations:

• 4 - 6 years DTaP, MMR, IPV

• Adults pneumococcal vaccine

83

Additional Concerns -Annual Re-Vaccination

• Adults– No data for revaccination of adults

• Older Children and Adolescents– AV012 safety data for 1054 subjects

immunized in both Years 1 and 2 with data available (459 were 10 - 18 yrs)

• Young Children (< 9 years)– AV006 – Year 2 and Year 3 (AV015) safety

and efficacy data: • No reactogenicity in repeat vaccinees• Demonstrable efficacy in Year 2

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Clinical Testing For New Strain Release

85

Annual Clinical Release Testing

• Master Seed Virus (MSV) is 6:2 reassortant containing 6 genes of attenuated Master Donor Virus (MDV) and 2 genes (HA and NA) of wild type strain, formulated annually

• Test attenuation of new reassortant strain in humans before incorporation into CAIV-T

• Primary objective – assess the safety of new strain, as demonstrated by similar rates of fever (oral temp > 101oF) in adult CAIV and placebo recipients from Days 0 – 7– Based upon fever rates in AV009

86

Annual Clinical Release Testing Methods

• 2002 MVS vaccine 0.5 ml 107 TCID50 of

B/Hong Kong/330/2001 in NAF• 300 healthy adults, randomized 4:1• Safety monitoring: Days 0 - 7, Days 0 - 14,

SAEs from Days 0-28, 6-month f/u• Reactogenicity events pre-defined• ~98% power to rule-out 5% absolute increase

in fever, assuming rate of fever of < 1% in control group, true difference of zero

87

Annual Clinical Release TestingResults

• Enrolled n=330; CAIV n=264, placebo n=66

• Initial safety phase (Days 0-7), rate of fever > 101oF:

CAIV n=1 (0.4%), placebo n=0, 95% CI: -4.9, 2.3

• Met primary endpoint, < 5% difference• < 5% difference for runny nose and sore throat• Demonstrated feasibility of annual testing

88

Studies Submitted in Support of Efficacy

89

AV006 - Pediatric Efficacy Trial

• U.S. multi-center, 2-year trial, prospective, double-blind, randomized FluMist to placebo (2:1 ratio) in healthy, 15-71 mo old children

• Initiated for 1996-97 influenza season

• 1 dose and 2 dose (60 + 14 days) regimens were evaluated

90

AV006 Design: Endpoints

• Primary – 1st episode of culture-confirmed influenza

illness anytime on the day of or after receipt of 2nd dose of study vaccine

• Secondary – Several additional secondary endpoints, will

not be discussed

91

AV006 – Efficacy Results

• No A/H1N1 circulating in Year 1 or Year 2 and thus, do not have field efficacy data for this strain.

92

AV006 - Year 1: EfficacyAnalysis Group

Strain Cx-positive FM P

Estimate Efficacy % (95% CI)

Any 10 73 93.4 (87.5, 96.5)

H3N2 4 48 96.0 (89.4, 98.5)

Received Two Doses

B 6 37 90.5 (78.0, 95.9)

Any 3 14 88.8 (64.5, 96.5)

H3N2 2 8 86.5 (46.6, 96.8)

Enrolled in One Dose

B 1 6 91.3 (45.6, 98.6)

Any 14 94 92.6 (87.3, 95.7)

H3N2 7 63 94.5 (88.3, 97.4)

All Randomized Participants

B 7 37 79.5 (79.5, 95.7)

93

AV006 - Year 1: Efficacy by Age

Efficacy % (95% CI) Subjects enrolled in 2 doses

Category N Any Strain H3N2 B

Age (mo)

< 24 223 84.7 (57.5, 94.6)

89.6 (59.1, 97.4)

71.4 (-31.6, 93.8)

24-35 300 96.2 (85.8, 99)

94.3 (78.7, 98.5)

100 (81.2, 100)

36-47 269 87 (66.8, 94.9)

88.7 (63.1, 96.5)

83.4 (27.8, 96.2)

48-59 277 100 (89.9, 100)

100 (84.8, 100)

100 (77.1, 100)

> 60 245 90.6 (70.3, 97.1)

100 (79.2, 100)

83.6 (44.1, 95.2)

94

AV006 - Year 2 Efficacy

• 1358 subjects (87%) returned for Year 2

• Received 1 dose of same study vaccine received in Year 1 (not re-randomized)

• Circulating H3N2 strain (A/Sydney) was a variant from the vaccine strain (A/Wuhan)

95

AV006 - Year 2 Efficacy

Strain FluMist Isolates

N

Placebo Isolates

N

Estimated Efficacy -

% (95% CI) All

community acquired

15 56 87.1 (77.7, 92.6)

FluMist Strains*

0 5 100 (63.1, 100)

All Year 2 Subjects

A/Sydney (H3N2)

15 51 85.9 (78, 91.9)

*A/Wuhan (H3N2) and B

96

AV006 - Year 2: Efficacy Against Any Influenza by Age Group

Any Influenza %Efficacy (95% CI)

Age Category (months)

Any Strain

< 24 NA

24-35 84.4 (35.2, 96.3)

36-47 84.5 (56.8, 94.5)

48-59 92.2 (69.0, 98.0)

> 60 86.9 (70.8, 94.1)

97

AV011 – A/H1N1 Challenge Study

• Primary Objective:– To compare viral shedding of vaccine strain

CAIV-M (A/H1N1) in previous FluMist recipients vs. previous placebo recipients

• Subset of AV006 subjects (N=222, ~20 per site) challenged with A/Shenzhen/227/95 (H1N1)

5 - 8 mo after Year 2 vaccination; same lot of H1N1 as Year 2 vaccine; then assessed viral shedding on Days 1 - 4

• Results 82.9% (60.2, 92.7) protection against shedding of vaccine strain CAIV-M

98

AV009 - Adult Effectiveness Trial

• Healthy working adults, 18-64 years of age, randomized 2:1, to receive one dose of FluMist or placebo

• Primary effectiveness objective to show a smaller proportion of FluMist compared to placebo recipients had any febrile illness (AFI) during influenza outbreaks

99

AV009 – Selected Secondary Endpoints and Analyses

• Several additional secondary endpoints, including:– Severe Febrile Illness (SFI), – Febrile URI (FURI), – CDC-Influenza-like Illness (CDC-ILI)

• Comparison of effectiveness for subjects

< 40 years compared to > 40 years (prospective)• Comparison of effectiveness for subjects

< 50 years compared to > 50 years (post-hoc)

100

AV009 – Effectiveness against Illnesses during Influenza Outbreaks in

Subjects 18-64 Years of Age FluMist

N=2883 Placebo N=1420

% Reduction 95% CI

Endpoint % %

Any Febrile Illness1

13.2 14.6 9.7 (-5.8, 22.7)

SFI 10.1 12.1 17.4 (1.4, 30.8)

FURI 8.5 10.8 21.9 (5.5, 35.6)

CDC-ILI2 10.7 13.9 23.2 (9.2, 34.9)

1primary endpoint 2post hoc analysis, influenza-like illness

101

AV009 - Rates of AFI-Associated Events in Total Study Cohort, 18-64 Years

FluMist N=2883

Placebo N=1420

% Reduction

95% CI

Endpoint # of days or events/1000 subjects per 7-week outbreak period

Days of OTC Meds

576.9 752.3 23.3 (12.0, 33.2)

Days of Abx use

195.6 342.9 42.9 (33.1, 51.3)

Days with HCP visit

44 51.5 14.7 (-0.3, 27.5)

Missed Work

173.3 199.5 13.1 (-0.9, 25.2)

102

AV009 – Number of Subjects Enrolled, by Age Group

Age Category

FluMist N=3041 n (%)

Placebo N=1520 n (%)

All N=4561 n (%)

18-29 y 747 (16.4) 375 (8.2) 1122 (24.6)

30-39 y

998 (21.9) 486 (10.7) 1484 (32.5)

40-49 y 857 (18.8) 457 (10.0) 1314 (28.8)

50-59 y 390 (8.6) 181 (4.0) 571 (12.5)

60-65 y 49 (1.1) 21 (0.5) 70 (1.5)

103

AV009 – Percent Reduction in Occurrence of Illness Categories for Subjects < 40 Years and > 40 Years

<40 years N=2378

> 40 years N=1875

AFI 9.3 11.2

SFI 19.9* 13.4

FURI 16.9 31.2*

CDC-ILI 20.2* 28.8*

*p < 0.05 – FluMist compared to placebo

104

AV009 – Percent Reduction (95% CI) in Occurrence of Illness Categories for

Subjects < 50 Years and 50 – 64 Years

<50 years N=3920

50 – 64 years N=641

AFI 10.9 (-5.1, 24.4)

-7.3 (-81.2, 35.8)

SFI 19.5* (3.0, 33.2)

-7.3 (-91.1, 39.2)

FURI 23.7* (6.7, 37.5)

-3.4 (-98.4, 45.5)

CDC-ILI 24.4* (9.8, 36.6)

8.1 (-57.4, 45.8)

*p < 0.05, FluMist vs. placebo

105

AV009 – Percent Reduction (FluMist vs. Placebo) in Illness-Associated Outcomes for Subjects 50 Years and 50 – 64 Years of Age

• For AFI, SFI, FURI and CDC-ILI subjects 50 – 64 years of age compared to subjects < 50 years, had significantly greater reductions illness-associated events for:– Missed worked days – Antibiotic use – HCP visits

106

AV003 - Wild-type Influenza Challenge in Adults

• Efficacy objective:

– To assess the efficacy post-challenge with wild-type influenza against laboratory-documented influenza illness in 18-42 yo:

• FluMist compared to placebo

• FluMist compared to TIV

107

AV003 - Design: Definitions

• Laboratory-documented illness:

– Symptoms of influenza with:• Shedding of wild-type influenza and/or• > 4-fold rise in HAI antibody titers to the

challenge virus

108

AV003 - Efficacy Against Laboratory-Documented Influenza Illness,

All Strains Combined

N

Laboratory-documented

Illness (All Strains Combined)

Efficacy,

compared to placebo (95% CI)

FluMist 29 2 (7%) 85* (28, 100)

TIV 32 4 (13%) 71** (2, 97)

Placebo 31 14 (45%)

* p=0.001 **p=0.006

109

Efficacy Conclusions• Efficacy against culture-confirmed

influenza illness demonstrated after 1 or 2 doses in healthy children 15 to 72 mo in Year 1 and after revaccination in Year 2

• Efficacy demonstrated for children in subgroup of 60 months to 72 months in AV006. These are the only efficacy data for children 60 months to 17 years

• No field efficacy data for A/H1N1

110

Effectiveness Conclusions

• Effectiveness not demonstrated in healthy working adults, 18 years - 64 years against the primary endpoint of AFI

• Effectiveness observed against SFI, FURI and CDC-ILI (post-hoc)

• Post-hoc analyses for > 50 – 64 years, no decrease in AFI, SFI, FURI or CDC-ILI

• Efficacy against culture-confirmed influenza not assessed in adults

111

Safety Conclusions

• 14,154 individuals ages 60 months – 64 years vaccinated with FluMist

• Few subjects > 50 years• Increased risk of asthma events in

children 12 - 59 months (AV019) post-vaccination; not observed in subjects > 60 months

• No increased risk for pneumonia events• SAEs reported < 1% of subjects

112

Clinical Review Team

• Douglas Pratt, M.D., M.P.H.

• Antonia Geber, M.D.

• Wasima Rida, Ph.D. (Statistical)

BLA Committee Chairman -

Roland Levandowski, M.D.

113

Question #1 – Safety (Vote)

1a. Are the data adequate to support safety of FluMist for individuals:

• 5 – 17 years of age?• 18 – 49 years of age?• 50 – 64 years of age?

Please consider data related to:• Respiratory events, e.g. asthma and URI• Shedding and transmission of vaccine strains

following receipt of FluMist• Annual revaccination

1b. If the data are not adequate for specific age groups or there are other safety concerns, please discuss what

additional data should be requested.

114

Question #2 – Efficacy (Vote)

2a. Are the data adequate to support efficacy of FluMist in individuals:

• 5 – 17 years of age?

• 18 – 49 years of age?

• 50 – 64 years of age?

2b. If the data are not adequate for specific age groups, please discuss what additional data should be requested.

115

Discussion Point #3 Clinical Studies for

Release of New Strains

• Please comment on the design and endpoints for the clinical study performed in adults for the release of new strains.

116

Discussion Point #4 Additional Studies

• If the data are adequate to support safety and efficacy, please discuss what additional information, if any, should be requested from post-marketing studies?