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FluMist Influenza Virus Vaccine, Live, Intranasal Cold Adapted, Trivalent MedImmune Inc.

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 (N

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FluMist Influenza Virus Vaccine, Live, Intranasal Cold Adapted, Trivalent MedImmune Inc.

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    1. 1 FluMist? Influenza Virus Vaccine, Live, Intranasal (Cold Adapted, Trivalent) MedImmune Inc. VRBPAC Dec 17, 2002 FDA Introduction ChrisAnna M. Mink, MD

    2. 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. 3 FluMist? - Regulatory Time Course

    4. 4 Regulatory History Sponsors 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. 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. 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. 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. 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. 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. 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. 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 Committees deliberations.

    12. 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. 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. 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. 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. 16 FluMist? Influenza Virus Vaccine, Live, Intranasal (Cold Adapted, Trivalent) MedImmune Inc. VRBPAC Dec 17, 2002 FDA Clinical Summary ChrisAnna M. Mink, MD

    17. 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. 18 Number of Vaccinees by Age Group in the Finalized Database

    19. 19 Study AV019 Large Safety Trial in Northern California Kaiser Permanente (NCKP)

    20. 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. 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. 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. 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. 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. 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. 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. 27 AV019 Results: Number of Subjects with MAEs, by Setting

    28. 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. 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. 30 AV019 - Number of 18-35 Month Old Subjects and Increased RR (90% CI) for Asthma Events in All Settings Combined

    31. 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. 32 AV019 RR for Asthma Events Post-Dose 1 by Age in 6-Month Increments (Selected Ages)

    33. 33 AV019 Number of Subjects and RR for Asthma Events, by Dose, All Settings Combined*

    34. 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. 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. 36 AV019 - Number of Subjects and Increased RR (90% CI) for URI Events by Age and Setting

    37. 37 AV019 Results: Pneumonia Events No increase in RR was observed for pneumonia, bronchitis or bronchiolitis in any age group, setting or dose

    38. 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. 39 AV019 Results: Rare Events, Potentially Related to Influenza No cases of encephalitis, encephalopathy, Guillain-Barre Syndrome, Reyes 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. 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 for children over 60 months observed

    41. 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. 42 Study AV012 - Texas HMO Trial Years 1 and 2

    43. 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. 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. 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. 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. 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. 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. 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. 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. 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 in Year 1 and Year 2

    52. 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. 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. 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. 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. 56 Asthma/RAD/Wheezing/SOB Events Relative Risk in Protocol-Defined Age Groups in Three Pivotal Trials

    57. 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. 58 Wyeth-Lederle Vaccines (WLV)-Sponsored Trial D145-P500 Assessment of Transmissibility of CAIV-T (FluMist?) in Daycare Attendees

    59. 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. 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 Sponsors post hoc analysis ? probability that a vaccinee will infect a placebo subject (Reed-Frost Model)

    61. 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. 62 Study D145-P500 Duration of Shedding of Influenza Viruses for FluMist? Recipients (N=98)

    63. 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. 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. 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. 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. 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. 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. 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. 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. 71 Selected Data for Post-Vaccination Solicited Reactogenicity Events in Children (AV006) and Adults (AV009)

    72. 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. 73 AV006 Year 1 Percent of Subjects with Selected REs by Group and Dose

    74. 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. 75 AV009 Percent of Subjects with REs by Study Group for 18 64 Years

    76. 76 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

    77. 77 Additional Concerns from VRBPAC July 2001

    78. 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. 79 Pneumonia Events Relative Risk in Pediatric Pivotal Placebo-Controlled Trials

    80. 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. 81 Adverse Events Rare Events Potentially Associated with Influenza Review across 20 studies, no reported cases of: encephalitis encephalopathy Guillain-Barre Syndrome Reyes Syndrome No ? RR for central nervous system events, including seizures, following receipt of FluMist?

    82. 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. 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. 84 Clinical Testing For New Strain Release

    85. 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. 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

    87. 87 Annual Clinical Release Testing Results 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. 88 Studies Submitted in Support of Efficacy

    89. 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. 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. 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. 92 AV006 - Year 1: Efficacy

    93. 93 AV006 - Year 1: Efficacy by Age

    94. 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. 95 AV006 - Year 2 Efficacy

    96. 96 AV006 - Year 2: Efficacy Against Any Influenza by Age Group

    97. 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. 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. 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. 100 AV009 Effectiveness against Illnesses during Influenza Outbreaks in Subjects 18-64 Years of Age

    101. 101 AV009 - Rates of AFI-Associated Events in Total Study Cohort, 18-64 Years

    102. 102 AV009 Number of Subjects Enrolled, by Age Group

    103. 103 AV009 Percent Reduction in Occurrence of Illness Categories for Subjects < 40 Years and > 40 Years

    104. 104 AV009 Percent Reduction (95% CI) in Occurrence of Illness Categories for Subjects < 50 Years and 50 64 Years

    105. 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. 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. 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. 108 AV003 - Efficacy Against Laboratory-Documented Influenza Illness, All Strains Combined

    109. 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. 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. 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. 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. 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. 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. 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. 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?

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