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Transcript of 1 FluMist Influenza Virus Vaccine, Live, Intranasal (Cold Adapted, Trivalent) MedImmune Inc. VRBPAC...
1
FluMistInfluenza Virus Vaccine,
Live, Intranasal(Cold Adapted, Trivalent)
MedImmune Inc.
VRBPAC – Dec 17, 2002 FDA Introduction
ChrisAnna M. Mink, MD
2
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).
3
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
4
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
5
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.
6
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
7
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)
8
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
9
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
10
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.
11
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.
12
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.
13
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.
14
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.
15
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?
16
FluMistInfluenza Virus Vaccine,
Live, Intranasal(Cold Adapted, Trivalent)
MedImmune Inc.
VRBPAC – Dec 17, 2002 FDA Clinical Summary
ChrisAnna M. Mink, MD
17
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
18
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)
20
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
21
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
22
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)
23
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
24
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
25
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
26
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)
27
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)
28
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)
29
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
30
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
31
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
32
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
33
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
34
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
35
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
36
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)
37
AV019 – Results: Pneumonia Events
• No increase in RR was observed for pneumonia, bronchitis or bronchiolitis in any age group, setting or dose
38
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
39
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
40
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
41
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
42
Study AV012 - Texas HMO Trial
Years 1 and 2
43
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
44
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
45
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
46
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
47
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
48
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
49
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)
50
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)
51
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
52
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
53
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
54
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
55
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
56
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
57
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
58
Wyeth-Lederle Vaccines (WLV)-Sponsored Trial
D145-P500
Assessment of Transmissibility of
CAIV-T (FluMist) in Daycare Attendees
59
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
60
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)
61
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)
62
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
63
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
64
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
65
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%)]
66
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
67
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
68
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)
69
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
70
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
71
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
73
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
74
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
75
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
76
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
77
Additional Concerns from VRBPAC July 2001
78
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.
79
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
80
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.
81
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
84
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
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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?