# Presentation: 946733

## AVIRON COLD-ADAPTED LIVE ATTENUATED INFLUENZA VIRUS VACCINE, TRIVALENT FLUMIST

**VRBPAC - July 26, 2001 **
**FDA Clinical Summary**
**ChrisAnna M. Mink, MD**

## Clinical Review Team

**Antonia Geber, M.D.**
**Wasima N. Rida, Ph.D.**

## 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.**

## 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. **

## 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.**

## 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.**

## AV006 Design:Vaccines 

**CAIV- T, FluMist******** via Accuspray******** device, dose of 0.5 ml (0.25 ml/nostril) of 10****6.7**** TCID****50**** :**
**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**

## 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).  **

## 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**

## Results - Year 1 Enrollment

## 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.**

## AV006 - Year 1 Efficacy

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

## AV006 - Year 1:  Efficacy

## AV006 - Year 1:  Efficacy by Age

## AV006 - Year 1:  Efficacy by Gender and Ethnicity

## 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.**

## 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.**

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

## 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.**

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

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

## 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.**

## AV006 - Year 2 Efficacy

## 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.**

## AV011 - Design

**Day 0 - challenge with 0.5 ml of 10****7**** TCID****50**** 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**

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

## 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.**

## 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.  **

## AV009 - Effectiveness Results

## AV009 - Rate of AFI-Assoc. Events

## 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**

## 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**

## 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**

## AV003 - Efficacy Against Laboratory-Documented Influenza Illness

## 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.**

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

## 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.**

## AV014 - Post-Dose 2 to Baseline Percent Seroconversion 

## AV014 - Post-Dose 2 GMT Ratios in All Participants

## 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 .**

## Aviron FluMistSafety Summary

## 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.**

## 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 **

## 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.**

## 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.**

## First Dose Vaccinees by April 30, 2001

## 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).**

## AV009 - RE Results by Group

## AV009 - Results: Unsolicited “Other” AEs

## 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).**

## 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. **

## AV006 Year 1 - Selected REs by Group

## AV006 - Year 1 Selected “Other AEs” by Group and Dose

## 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).**

## 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.**

## 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.**

## 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.**

## 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.**

## 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**

## 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).**

## 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 **

## 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.**

## 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).**

## 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).**

## 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.**

## 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).**

## AV010 - AE Profiles of Subjects

## 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.**

## 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.**

## Pediatric Pneumonia Cases

## 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.**

## SAEs - Deaths

**65 deaths were reported**
**63 in VA study.**
**1 accidental drowning, associated with alcohol intoxication.**
**1 due to pneumonia, as described.**

## 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.**

## 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.**