1 AVIRON COLD-ADAPTED LIVE ATTENUATED INFLUENZA VIRUS VACCINE, TRIVALENT FLUMIST VRBPAC - July 26, 2001 FDA Clinical Summary ChrisAnna M. Mink, MD.

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AVIRON COLD-ADAPTED LIVE

ATTENUATED INFLUENZA VIRUS VACCINE, TRIVALENT

FLUMIST

VRBPAC - July 26, 2001 FDA Clinical Summary

ChrisAnna M. Mink, MD

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Clinical Review Team

• Antonia Geber, M.D.

• Wasima N. Rida, Ph.D.

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Indication Sought

• Active immunization for the prevention of influenza in children, adolescents, and adults from 1-64 years of age.

– 2 dose regimen (at least 30 days apart) for 1st use in 1-9 years of age.

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

• Also, for immunization of travelers to areas where influenza viruses are circulating.

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Studies in Support of Efficacy

• AV006 (Years 1 and 2) – Efficacy against Cx-confirmed influenza

illness in children 15-71 months of age.• AV011

– Efficacy against shedding of vaccine strain (H1N1) following challenge in AV006 subset.

• AV009– Efficacy against illness during influenza

outbreak periods in adults, 18-64 years. • AV003

– Efficacy against challenge with wild-type influenza in adults, 18-40 years.

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Studies in Support of Consistency of Manufacturing

• AV007 – Lot consistency trial, including comparison with the

efficacy lot, performed in children 12-36 months of age.

• AV014– Manufacturing bridging study of FluMist

blended and filled at two facilities: Aviron-PA and Medeva, performed in children 12-42 months of age.

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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.

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AV006 Design:Vaccines

• CAIV- T, FluMist via Accuspray device, dose of 0.5 ml (0.25 ml/nostril) of 106.7 TCID50 :

• A/Texas/36/91 (H1N1) - Year 1• A/Shenzhen/227/95 (H1N1) - Year 2• A/Wuhan/359/95 (H3N2) - both years• B/Harbin/7/94-like - both years

• Placebo - Normal allantoic fluid (NAF) stabilized with SPG

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AV006 Design: Monitoring for Efficacy

• Active surveillance with phone calls every 2-3 weeks starting on Day 11 post-vaccination. Calls to every 7-10 days with influenza outbreak.

• Parents were to call if the child had illness c/w influenza.

• Pre-defined criteria for obtaining influenza cultures or at the investigators’ discretion (after Day 11).

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AV006 Design: Endpoints

• Primary – 1st episode of cx-confirmed influenza illness

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

• Secondary – 1st episode of cx-confirmed influenza illness

occurring at least 15 days after the 1st dose of study vaccine in a subject after: • receipt of 1 or 2 doses• enrolled to receive 2-doses • enrolled to receive 1 dose

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Results - Year 1 Enrollment

FluMistN=1070

PlaceboN=532

Mean age(S.D.)

43(16.6)

41.5(16.5)

Caucasian % 85 84

Female % 53 51

Primary caretakerworks outside of thehome

49 50

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AV006 - Results: Cx Obtained

• 139 Cx positive for influenza of 3127 Cxs obtained: – 18 obtained within 1st 14 days*– 7 not included – 6 placebo had Cx + for H3N2 and then B

• 114 influenza-positive Cxs from 108 subjects included in efficacy analysis.

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AV006 - Year 1 Efficacy

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

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AV006 - Year 1: EfficacyAnalysisGroup

Strain Cx-positiveFM P

Estimate Efficacy %(95% CI)

Any 10 73 93.4 (87.5, 96.5)

H3N2 4 48 96.0 (89.4, 98.5)

ReceivedTwoDoses

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 inOne 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)

AllRandomizedParticipants

B 7 37 79.5 (79.5, 95.7)

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AV006 - Year 1: Efficacy by AgeEfficacy % (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)

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AV006 - Year 1: Efficacy by Gender and Ethnicity

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

Category N Any Strain H3N2 B

Gender

Female 684 91.8(83.8, 95.8)

94(85.6, 97.6)

86.4(61.1, 95.3)

Male 630 93.8(85, 97.4)

95.5(82.8, 98.8)

93.2(79, 97.8)

Ethnicity

Caucasian 1159 92.3(96.5, 95.7)

94.8(88.8, 97.7)

89.5(76.9, 95.2)

Non-Caucasian

155 94.9(70, 99.2)

91.6(47.6, 98.7)

100(52, 100)

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AV006 - Year 1: Subjects with Illness and Cultures Obtained in 1st 14 Days

• 116 subjects, with illness, had 117 Cxs in 1st 14 days post-vaccination.

• Of 116, placebo N=38:– N= 16 with Cxs after Day 11 (per protocol).– N= 22 with Cxs from Days 2-10,

• 0 CAIV +

• Of 116, FluMist N=78:– N=66 with Cxs after Day 11 (per protocol). – N=17 with Cxs from Days 2-10,

• 18 Cxs CAIV positive.

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AV006 - Year 1: Subjects with Illness and Cultures Obtained in 1st 14 Days

• 17 FluMist recipients had 18 positive Cxs which grew 20 CAIV isolates: – 11 type B, 5 type A and 2 type A and B.– growth of other viruses not reported.

• Of note, 16 of 17 subjects from Houston.

• Culturing at Houston: – 31/144 (21%) of FluMist recipients and

13/72 (18%) placebo recipients had Cxs obtained within 1st 14 days.

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AV006 - Illness Profiles of Subjects with Cxs in 1st 14 Days

FluMistCAIV Cx Status

PlaceboCAIV Cx

PositiveN=17

NegativeN=60

NegativeN=36/38

Event - %Any Event 100 86.7 78.9> 3 events,same day

70.6 41.7 50

CDC-ILI 41.2 13.3 21.5

Runnynose/Congestion

100 73.3 71.1

Fever>100.6oF (R)

70.6 23.3 23.7

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Immunogenicity

• No correlate of immunity identified following FluMist.

• HAI titers > 1:32, assoc. with protection after natural influenza and inactivated vaccine.

• AV006 subset assessed serum HAI titers, ELISA serum IgG and nasal IgA anti-HA.

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AV006 - Year 1 Immunogenicity: Strain-specific HAI GMT Results

FluMist - GMT (95% CI) Placebo(95% CI)

Strain

Pre –VaccineN= 136

Post-Dose1N=131

Post-Dose2N=115

Post-Dose2N=58

H1N1 5.4(4.2, 6.9)

8.9(6.6, 12)

18.8(14.2, 25)

5.0(3.4, 7.1)

H3N2 9.5(7.2, 12.5)

39.5(33.5, 46.7)

43.8(37.4, 51.3)

10.5(6.8, 16.1)

B 4.1(3.4, 5.0)

18.3(15.6, 21.3)

25.8(22.6, 29.4)

4.5(3.3, 6)

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AV006 - Year 1: GMFR from Pre to Post-Dose 1 or 2 in FluMist

Subjects GMFR (95% CI)Post-Dose 1N = 131

GMFR (95% CI)Post-Dose 2N= 115

Strain

H1N1 1.7 (1.4, 1.9) 3.4 (2.7, 4.2)

H3N2 4.3 (3.3, 5.6) 4.7 (3.5, 6.2)

B 4.5 (3.7, 5.6) 6.3 (5.0, 7.8)

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AV006 - Year 2 • 1358 subjects (87%) returned for Year 2.

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

• Primary endpoint - efficacy against 1st episode of cx-confirmed influenza illness caused by subtype antigenically similar to vaccine strains.

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

• No H1N1 circulating in Year 2.

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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)

FM Strains* 0 5 100 (63.1, 100)

All Year 2 Part-icipants

A/Sydney (H3N2)

15 51 85.9 (78, 91.9)

*A/Wuhan (H3N2) and B

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AV011 - H1N1 Challenge Study• In AV006, no efficacy data for H1N1.

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

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

• Subset of AV006 subjects (N=222, ~20 per site; mean age ~60 mos) were challenged with vaccine strain CAIV-M (H1N1);then viral shedding was assessed, as surrogate for vaccine efficacy.

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AV011 - Design

• Day 0 - challenge with 0.5 ml of 107 TCID50 of CAIV - M, A/Shenzhen/227/95 (H1N1) - same lot of H1N1 as in CAIV-T for 1997-98 (Year 2) vaccine (5-8 months after Year 2 dose).

• Days 1-4, had NP Cxs obtained

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AV011 - Efficacy Against Shedding Vaccine CAIV-M (H1N1)

PriorFluMist(N=144)

PriorPlacebo(N=78)

Shedding onany day, k (%)

6 (4%) 19 (25%)

Efficacy(95% CI)

82.9%(60.2, 92.7)

Day 1 – % 1 3Day 2 - % 3 13*Day 3 - % 0.7 12*Day 4 - % 0 8*

* p < 0.05

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AV009 - Adult Effectiveness Trial

• Healthy working adults, 18-64 years of age, randomized 2:1, FluMist to placebo, to receive 1 dose of vaccine with 1997-98 vaccine strains: – A/Shenzhen/227/95 (H1N1)– A/Wuhan/359/95 (H3N2)– B/Harbin/7/94-like

• Vaccines could be self-administered or given by study personnel.

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AV009 - Primary Objectives

• To show similar safety and tolerability of FluMist and placebo

• To show a smaller proportion of FluMist recipients has any febrile illness (AFI) during influenza outbreaks.

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AV009 - Effectiveness ResultsFluMistN=2883

PlaceboN=1420

% 95% CI1

p-valueunadjusted

Endpoint % with % with

AnyFebrileIllness2

13.2 14.6 9.7(-5.8, 22.7)

0.19

SFI 10.1 12.1 17.4(1.4, 30.8)

0.031

FURI 8.5 10.8 21.9(5.5, 35.6)

0.011

CDC-ILI3 10.7 13.9 23.2(9.2, 34.9)

0.0018

DoD-ILI3 10.4 13.7 23.5(9.5, 35.5)

0.0017

1CBER generated, 2primary endpoint, 3post hoc analysis, influenza-like illness

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AV009 - Rate of AFI-Assoc. EventsFluMistN=2883

PlaceboN=1420

% p-valueunadjusted

Endpoint # of days or events/1000subjects per 7-week outbreakperiod)

Days ofOTCMeds

576.9 752.3 23.3 0.0002

Days ofAbx use

195.6 342.9 42.9 <0.0001

Dayswith HCPvisit

44 51.5 14.7 0.055

MissedWork

173.3 199.5 13.1 0.065

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AV003 - Wild-type Influenza Challenge in Adults

• 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

• To assess safety and tolerability of FluMist in adults serosusceptible to at least 1 of the strains in the vaccine

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AV003 - Design: Definitions• Laboratory-documented illness:

– Symptoms (syxs) of influenza with:

– shedding of wild-type influenza on one or more days and/or

– > 4-fold rise in HAI antibody titers to the challenge virus from Days 28 to 56

• Illness was defined as 2 consecutive days:

– > 1 respiratory syx of moderate or greater severity OR

– 2 syxs of any severity

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AV003 - Vaccines and Challenge Strains

• FluMist - 1994-95 strains

– A/Texas/36/91-like (H1N1)

– A/Shangdong/9/93 (H3N2)

– B/Panama/45/90

• Trivalent inactivated vaccine (TIV) - Evans Medeva licensed, same strains

• Challenge - same strains, wild-type

• Placebos– intranasal NAF in SPG– injection Saline with 0.01% thimerosal

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AV003 - Efficacy Against Laboratory-Documented Influenza Illness

N

Laboratory-documentedIllness(Any Strain)

Efficacy,compared toplacebo(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

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AV007 - Lot Consistency Trial

• Performed to compare the safety, tolerability, and immunogenicity of 2 doses (given 28-60 days apart) of 3 consistency lots of FluMist in healthy children 12-36 months of age.

• Lot consistency: rule-out a > 4-fold range in post-dose 2 strain-specific HAI GMTs across lots with 95% confidence.

• 100 subjects per each study group.

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AV007-Results: Post-Dose 2 HAI GMT Ratios Among Consistency Lots

Ratio ofHAI GMTs

95% CI for Ratios ofHAI GMTs

H1N1Lot 1/Lot 2Lot 1/Lot 3Lot 2/Lot 3

0.701.492.12

0.48, 1.031.01, 2.191.44, 3.11

H3N2Lot 1/Lot 2Lot 1/Lot 3Lot 2/Lot 3

0.791.241.56

0.49, 1.290.76, 2.010.96, 2.53

BLot 1/Lot 2Lot 1/Lot 3Lot 2Lot 3

1.030.900.88

0.72, 1.490.63, 1.30.61, 1.25

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AV014 - Manufacturing Bridging

• Prospective, randomized (3:2), double-blind trial to compare the safety, tolerability and immunogenicity of FluMist blended and filled at 2 facilities: Medeva and Aviron-PA.

• 2 co-primary objectives:

– Seroconversion rate in seronegatives differ by no more than 20%.

– 90% CI for GMT ratio within 1/4 & 4.

• 2 doses (28-42d apart) in healthy children 12-42 mos, performed in Australia.

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AV014 - Post-Dose 2 to Baseline Percent Seroconversion

Strain N Aviron-PA Medeva Differencein %

95 % CI ofDifference

H1N1 %N

85%88

69%130

16% 5.3, 27.1

H3N2 %N

100%40

100%51

0 -12.7, 9.5

B %N

100%71

100%104

0 -7.3, 4.9

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AV014 - Post-Dose 2 GMT Ratios in All Participants

Strain Aviron-PA

N=88

Medeva

N=131

GMTRatio

95 % CIfor GMT

H1N1 18.3 10.9 1.67 1.27, 2.17

H3N2 81.7 74.2 1.1 0.93, 1.3

B 42.2 41.7 1.01 0.87, 1.17

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Efficacy Conclusions• Efficacy against culture-confirmed

influenza illness was demonstrated after 1 or 2 doses in healthy children 15-71 mo in Yr 1 and after revaccination in Yr 2.

• Influenza-like illnesses occurred in children who shed CAIV strains post-vaccination.

• In adults, no significant in AFI during influenza outbreak periods.

• No field efficacy data for H1N1 .

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Aviron FluMistSafety Summary

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Safety Monitoring Categories

• Reactogenicity events (REs)- solicited post-vaccination events, 10 days in pediatric and 7 days in adult trials.

• “Other Adverse Events” (other AEs) - unsolicited AEs in post-vaccination monitoring period.

• Serious Adverse Events (SAEs) - definitions c/w with 21 CFR 312.32.

• Not all studies had active monitoring for all categories of adverse events.

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Studies in Support of Safety - Selected Pediatric Trials

• AV006 (Years 1 and 2) and AV015

– Safety data from Pediatric Efficacy Trial, including Year 3 follow-up

• AV012

– SAE reports in Herd Immunity Trial, in an HMO in Texas

• AV019

– MAEs and SAEs in children 1-17 years of age in NCKP

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Studies in Support of Safety - Selected Adult Trials

• AV009

– Safety profiles of FluMist compared to placebo recipients in the adult effectiveness trial.

• Additional trials

– Phase 1 and 2 studies (AV001, AV004 and AV005), AR001 and AV003.

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Studies in Support of Safety - Selected Trials in “At-risk” Subjects

• AV010– Safety profiles of FluMist compared to

placebo in 9-17 year old asthmatics.• AV012

– Evaluation of FluMist in a subset subjects identified with asthma.

• NIH DMID - #98-005– Safety profiles of FluMist compared to

placebo in HIV-infected adults compared to HIV-negative adults.

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First Dose Vaccinees by April 30, 2001

FluMist Placebo TIV

< 2 years 1254 378 0

2-5.9 5864 1651 0

6-12.9 6626 1500 0

13-18.9 2499 572 3

19-49.9 3181 1464 30

50-64.9 511 209 0

> 65 years 111 101 0

Total 20,046 5875 33

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AV009 - Effectiveness in Healthy Adults: Safety Results

• Enrolled:

– FluMist = 3041; Placebo = 1520.

• REs and other unsolicited AEs - 7 days post-vaccination; 98% returned the diary card.

• SAEs - phone call at 28 days post- vaccination, passive reporting after 28 days (5 mo illness surveillance).

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AV009 - RE Results by GroupStud Group

RandomizedDiary Card

FluMistN=3041N=2985

PlaceboN=1520N=1490

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 > 100oF (O) 1.3 1.3*Can not rule out > 10% difference

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AV009 - Results: Unsolicited “Other” AEs

Study Group

RandomizedDiary Card

FluMistN=3041N=2985

PlaceboN=1520N=1490

Event - %

Any AE 30.2 21.5*

Respiratory 18.1 7.5

Allergic rxn 0.8 0.5

Digestive 5.6 6.1*p<0.001

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AV009 - Safety Results

• Asthma Subjects

– 46 subjects with asthma enrolled (FluMist = 23). in REs in FluMist and placebo recipients.

• Pregnancy

– 7 pregnancies (FluMist = 5). Five exposures in 1st trimester - all FT live births. 2 spontaneous abortions ( 1 each for FluMist and placebo).

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AV006 Safety Monitoring for Years 1, 2 and 3

• REs - captured on diary card for 10 days after each vaccination.

– Per protocol, culturing for illness was discouraged during the 10 day period post-vaccination RE monitoring.

• Other AEs - unsolicited AEs, also recorded on diary card for 10 days.

• SAEs - no active monitoring post-vaccination.

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AV006 Year 1 - Selected REs by GroupDose 1 Dose 2

FluMist Placebo FluMist Placebo

N 1070 532 881 433

Card, N 1056 530 850 415

% with

Any RE 74 66* 69 62*

Runnynose

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 1 Selected “Other AEs” by Group and Dose

Dose 1 Dose 2

FluMist Placebo FluMist Placebo

N 1070 532 881 433

% % % %

Any AE 18 15 14 15

Abd pain 2 0.2* 0.8 0.5

Rash 0.4 2.1* 0.2 0

Allerg. rxn 1 0.6 0 0

Respiratory 2.3 1.5 2.8 3.1

* p < 0.05, Fishers exact

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AV006 - Year 2 REs

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

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

• 58% of both groups experienced > 1 RE.

• Runny nose/congestion (~42%) and cough (~24%) were most common.

• 6yo had allergic rxn (hives and angioedema) 30 min post-placebo (NAF).

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AV006 - Year 3 [AV015]

• Subjects who completed Years 1 and 2 were eligible for Year 3 - open-label FluMist. Subjects could have participated in AV011 (total of 1-4 doses).

• Prior FluMist recipients - received 1 dose of FluMist .

• Prior placebo recipients - received 1 or 2 doses (28-60 d later) of FluMist.

• Day 42 phone call - collect SAEs.

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AV006 - Year 3 Results

• REs between Groups – Runny nose/congestion had largest difference

between groups: prior FluMist (37% of 649) and prior placebo (49% of 192) post-dose 1.

– No other difference in RE rates exceeded 10%.

• REs across 3 Years of FluMist– In Year 1, ~73% of subjects had “any RE”,

to 56% in Year 2 and in Year 3.– No in REs with subsequent doses.

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AV006 - Pneumonia Cases

• Year 1 - pneumonia within 21days of vaccination: 6 FluMist and 1 placebo recipients RR of 2.98 (0.36, 24.72)

• All cases: 8 FluMist and 2 placebo recipients RR= 1.99 (0.42, 9.33)

• One subject at Houston - Cx + CAIV• Year 2 - 2 FluMist subjects with

pneumonia; cases occurred 15 and 68 days post-vaccination.

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AV019 - SAEs and Medically Attended Events (MAEs)

• 9689 healthy children 1 - 17 yrs at NCKP starting 10/00. FluMist vs. placebo (2:1 ratio). 2 doses (28-42 days) for 1-9 yr olds and 1 dose for 9 - 17 yr olds.

• Database searched for MAEs and SAEs for 42 days after each dose of vaccine.

• Database locked on 12/31/00 for interim analysis for safety (~ 89% in 9-17y; 68% in 1-8 yr completed 42 day post-dose).

• Submitted to CBER on 4/30/01.

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AV019 - Interim Analysis• 4 clinical events, pre-specified:

– acute respiratory events

– systemic bacterial infections

– acute gastrointestinal events

– rare, potentially related to influenza

• Utilization settings:

– hospital, outpatient clinic, ED, combined

• Stratification by age:

– all, 9-17 yr, 1-8 yr, 18 - <36 mo, 12 - <18 mo

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AV019 - Interim Results: SAEs

• SAEs: N=20 through 4/15/01.

• FluMist N=13 SAEs, 4 within 14 days:

– H.U.S. in a 12 mo F; A.G.E. in a 14 mo F, abd/gyn pain in 16 yo F, and appendicitis in 15 yo M (all on day 11).

• Placebo N= 7 SAEs, 3 within 14 days:

– Croup in 17 mo F; trauma in 17 mo F; and psychiatric disorder in 12 yo (all on day 4).

61

AV019 - Interim Results: MAEs

• MAEs: n=5850 through 12/31/01 (not reported by study group):– 20% Well child/Reassurance

– 11% URI

– 7% Otitis media

– 7% Trauma

– 6% Psychiatric disorders

62

AV019 - Interim Results: Pneumonia

• In 1- 17 year olds, pneumonia < 21 days post-vaccination: 10 FluMist and 6 placebo recipients RR = 0.83 (0.3, 2.28).

• All cases identified: 14 FluMist and 10 placebo recipients RR = 0.7 (0.31, 1.57).

• Analysis by age group, pending.

63

AV019 - MAEs, Sponsor Assessed as Plausibly Related for FluMist vs. Placebo

(per 1000 person months) • Conjunctivitis in 1-17 yo, 1-8yo, and 18-36

months (6.6-14.5 vs. 0-5.2).• URI in 1-17 yo (1.24 vs. 0).• Abd pain in 1-17 yo (1.2 vs. 0.22)• Musculoskeletal pain in 1-8 yo, 18-36 mo

(4.4-9.0 vs. 0-1.7).• Asthma in 18-36 mo (7.75 vs. 0).• Otitis media with effusion in 1-8 yo in clinic

post-dose 2 (10.8 vs. 4.1).

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AV012 - Texas Community Study

• 1 dose of FluMist in children 18 mo - 18 years in Scott&White HMO in Texas to assess effectiveness against MAARI.

• For the BLA, SAEs within 42 days were reported (postcard reporting with reminder calls; database searches for 79% in HMO). Also, passive collection of parental reports of concerning AEs.

• 531 of 4298 subjects identified to have asthma, RAD or wheezing (not exclusion).

65

AV012 - Year 1: SAE and AEs

• 8 SAEs - 6 occurred > 21 days post-dose

• 149 of 4063 subjects with 42 day data had reported onset of > 1 new illnesses, and 87 events in 78 subjects were judged to be “clinically significant” and recorded on CRF and entered into the database.

• On FDA review of line listings, 65 were respiratory events with 10 diagnoses of pneumonia and/or bronchitis.

• Asthma subjects - analysis not complete.

66

AV010 - Asthma Study

• 48 subjects (FluMist =24) 9-17 years with moderate to severe asthma were given 1 dose of study vaccine (FluMist or placebo) and monitored for safety, tolerability and asthma stability for 35 days (7 pre and 28 post-vaccination).

67

AV010 - AE Profiles of Subjects

FluMistN = 24

PlaceboN = 23/24

Event % %

Any RE 91.3 91.3

Runny nose 75 56.5

Cough 45.8 43.5

Fever > 100o F(O) 0 17.4

Other AE - any 12.5 20.8

SAE 0 0

>15% inpredicted FEV1

8.3 4.2

AsthmaExacerbation

8.3 0

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HIV-Infected Adults: Results

• 57 HIV-infected vs. 54 HIV-negative adults received FluMist vs. placebo (1:1).

• One HIV+ subject shed CAIV- type B.

• AEs - 15.8% in HIV+ vs. 11.8% in HIV neg. HIV+ subjects - 3 respiratory events.

• CD4 8% in HIV+ FluMist recipients at Day 28, by Day 90.

• In HIV+, no in viral load post-vaccination, followed for 6 months.

69

VA Study - SAE Reports

• Study synopsis in BLA. Evaluated 2215 adults > 50 years with COPD; received 1 dose of FluMist or placebo (1:1 ratio) given concurrently with TIV.

• SAE reports were submitted in 3/01, included 63 deaths (FluMist = 34 and placebo = 29). 8 deaths (4 in each group) within 28 days of vaccination.

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Pediatric Pneumonia Cases

FluMist Placebo RR (95% CI)

Study N All <21d N All <21d < 21 d

006-Y1 1070 8 6 532 2 1 2.98(0.36, 24.78)

006-Y2 917 2 1 441 0 0

007 400 1 1 100 0 0

012-Y1 4298 2 1 - - -

012-Y2 5251 6 4 - - -

015 949 1 1 - - -

017 1175 3 3 70 0 0

019 6495 14 10 3238 10 6 0.83(0.30, 2.28)

Total 37 12

71

Other AEs - Pneumonia

• CBER review for pneumonia of all available data is ongoing. Of note:

• 1 death occurred due to pneumonia, 23 days post-dose 2 of FluMist in an 18 month old boy in Wyeth-sponsored trial in South Africa.

• 1 pneumonia case was identified by CBER inspectors. Occurred 15 days post-dose 3 in 4.7 yo boy in AV006-Year 2 (parents reported to site 1 year later).

• 1 case assoc. with positive Cx for CAIV virus.

72

SAEs - Deaths

• 65 deaths were reported– 63 in VA study.

– 1 accidental drowning, associated with alcohol intoxication.

– 1 due to pneumonia, as described.

73

Safety Conclusions

• Review is on-going.• Review of respiratory events, including

pneumonia and bronchitis, not complete.• FluMist and placebo (NAF) are

reactogenic. • Most safety data generated in healthy

subjects. Few high-risk subjects; suggestion of REs in asthmatics.

• No in REs with annual dosing in children.

• Few subjects at ends of age spectrum.

74

Additional Concerns

• Concurrent Immunization

– No data for efficacy or safety with concomitant immunizations, including traveler’s vaccines, in any age group.

• Transmissibility

– Finnish trial in a daycare shedding of CAIV strain in 1 of 99 placebo recipients.

• Annual Vaccination

– No data for revaccination of adults.