# Presentation: 667251

## FluMistInfluenza Virus Vaccine, Live, Intranasal(Cold Adapted, Trivalent)MedImmune Inc. 

**VRBPAC – Dec 17, 2002 **
**FDA Introduction**
**ChrisAnna M. Mink, MD**

## 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 10****7**** TCID****50**** of each of the 3 strains in normal allantoic fluid (NAF).**

## FluMist - Regulatory Time Course

## 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 **

## 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.**

## 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**

## 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)**

## 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 **

## 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**

## 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 (**_**>**_** 6****0 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.**

## 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.**

## 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****.**

## 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.**

## 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.**

## 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?**

## FluMistInfluenza Virus Vaccine, Live, Intranasal(Cold Adapted, Trivalent)MedImmune Inc. 

**VRBPAC – Dec 17, 2002 **
**FDA Clinical Summary**
**ChrisAnna M. Mink, MD**

## 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**

## Number of Vaccinees by Age Group in the Finalized Database

## Study AV019Large Safety Trial in Northern California Kaiser Permanente (NCKP)

## 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**

## 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**** **

## 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)**

## 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**

## 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**

## 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**

## 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)**

## AV019 – Results: Number of Subjects with MAEs, by Setting

## 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) **

## 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**

## AV019 - Number of 18-35 Month Old Subjects and Increased RR (90% CI) for Asthma Events in All Settings Combined

## 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**

## AV019 – RR for Asthma Events Post-Dose 1 by Age in 6-Month Increments (Selected Ages)

## AV019 – Number of Subjects and RR for Asthma Events, by Dose,All Settings Combined*

## 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 **

## 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**

## AV019 - Number of Subjects and Increased RR (90% CI) for URI Events by Age and Setting

## AV019 – Results: Pneumonia Events

**No increase in RR was observed for pneumonia, bronchitis or bronchiolitis in any age group, setting or dose**

## 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**

## 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**

## 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 for**
**children over 60 months observed**

## 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******

## Study AV012 - Texas HMO TrialYears 1 and 2

## 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**

## 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**

## 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**
**	**

## 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**

## 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**

## 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**

## 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)**** **

## 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)**

## 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 in**
**	****Year 1 and Year 2**

## AV012 - Texas HMO Trial Conclusions

**7448 subjects received 9549 doses of FluMist******** (37% of total 1****st**** 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**

## 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**

## 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**

## 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**

## Asthma/RAD/Wheezing/SOB Events –Relative Risk in Protocol-Defined Age Groups in Three Pivotal Trials

## 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**

## Wyeth-Lederle Vaccines (WLV)-Sponsored Trial D145-P500

**Assessment of Transmissibility of CAIV-T (FluMist********)  in Daycare Attendees **

## 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**

## 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)**

## 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) **

## Study D145-P500 – Duration of Shedding of Influenza Viruses for FluMist Recipients (N=98)

## 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**

## 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**

## 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%)]**

## 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**

## 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**

## 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)**

## 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**

## 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**

## Selected Data forPost-Vaccination Solicited Reactogenicity Eventsin Children (AV006) and Adults (AV009)

## 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**

## AV006 Year 1 – Percent of Subjects with Selected REs by Group and Dose

## 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**

## AV009 – Percent of Subjects with REs  by Study Group for 18 – 64 Years

## SummaryPost-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**

## Additional Concerns from VRBPAC July 2001

## 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.**

## Pneumonia Events – Relative Risk in Pediatric Pivotal Placebo-Controlled Trials

## 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.**

## 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******

## 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**

## 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**

## Clinical Testing For New Strain Release

## 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 **_**>**_** 101****o****F) in adult CAIV and placebo recipients from Days 0 – 7**
**Based upon fever rates in AV009**

## Annual Clinical Release Testing Methods

**2002 MVS vaccine ******** 0.5 ml 10****7**** TCID****50**** 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 **

## Annual Clinical Release TestingResults

**Enrolled n=330; **
**	****CAIV n=264, placebo n=66**
**Initial safety phase (Days 0-7), **
**	****rate of fever **_**>**_** 101****o****F:**
**	****	****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**

## Studies Submitted in Support of Efficacy

## 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: 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**

## AV006 – Efficacy Results

**No A/H1N1 circulating in Year 1 or Year 2 and thus, do not have field efficacy data for this strain.**

## AV006 - Year 1:  Efficacy

## AV006 - Year 1:  Efficacy by Age

## 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)**

## AV006 - Year 2 Efficacy

## AV006 - Year 2:  Efficacy Against Any Influenza by Age Group 

## 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**

## 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  **

## 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)**

## AV009 – Effectiveness against Illnesses during Influenza Outbreaks in Subjects 18-64 Years of Age 

## AV009 - Rates of AFI-Associated Events in Total Study Cohort, 18-64 Years 

## AV009 – Number of Subjects Enrolled, by Age Group

## AV009 – Percent Reduction in Occurrence of Illness Categories for Subjects < 40 Years and > 40 Years 

## AV009 – Percent Reduction (95% CI) in Occurrence of Illness Categories for Subjects < 50 Years and 50 – 64 Years 

## 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  **

## 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**

## 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 **

## AV003 - Efficacy Against Laboratory-Documented Influenza Illness, All Strains Combined

## 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  **

## 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 **

## 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 **

## 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.**
**	**

## 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****.**

## 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.**

## 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.**

## 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?**