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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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).
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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
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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.
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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).
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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.
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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).
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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.
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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
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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.
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SAEs - Deaths
• 65 deaths were reported– 63 in VA study.
– 1 accidental drowning, associated with alcohol intoxication.
– 1 due to pneumonia, as described.
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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.
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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.