AVIRON COLDADAPTED LIVE ATTENUATED INFLUENZA VIRUS VACCINE, TRIVALENT FLUMIST

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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 gt9 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 (21
  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 DesignVaccines

• 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
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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 Efficacy
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AV006 - Year 1 Efficacy by Age
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AV006 - Year 1 Efficacy by Gender and Ethnicity
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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 N38
• N 16 with Cxs after Day 11 (per protocol).
• N 22 with Cxs from Days 2-10,
• 0 CAIV
• Of 116, FluMist? N78
• N66 with Cxs after Day 11 (per protocol).
• N17 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
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Immunogenicity

• No correlate of immunity identified following
  FluMist?.
• HAI titers gt 132, 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
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AV006 - Year 1 GMFR from Pre to Post-Dose 1 or 2
in FluMist? Subjects
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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
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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 (N222, 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)
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AV009 - Adult Effectiveness Trial

• Healthy working adults, 18-64 years of age,
  randomized 21, 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 Results
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AV009 - Rate of AFI-Assoc. Events
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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
• gt 4-fold rise in HAI antibody titers to the
  challenge virus from Days 28 to 56
• Illness was defined as 2 consecutive days
• gt 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
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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 gt 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
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AV014 - Manufacturing Bridging

• Prospective, randomized (32), 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
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AV014 - Post-Dose 2 GMT Ratios in All Participants
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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 FluMist?Safety 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
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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 Group
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AV009 - Results Unsolicited Other AEs
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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 Group
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AV006 - Year 1 Selected Other AEs by Group and
Dose
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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 gt 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 (21
  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 - lt36 mo, 12 - lt18 mo

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AV019 - Interim Results SAEs

• SAEs N20 through 4/15/01.
• FluMist? N13 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 n5850 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 lt 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 ScottWhite 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 gt 21 days post-dose
• 149 of 4063 subjects with 42 day data had
  reported onset of gt 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
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HIV-Infected Adults Results

• 57 HIV-infected vs. 54 HIV-negative adults
  received FluMist vs. placebo (11).
• 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 gt
  50 years with COPD received 1 dose of FluMist?
  or placebo (11 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
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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 travelers 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.