1. 1 AVIRON COLD-ADAPTED LIVE ATTENUATED INFLUENZA VIRUS VACCINE, TRIVALENT FLUMIST  VRBPAC - July 26, 2001 FDA Clinical Summary ChrisAnna M. Mink, MD

2. 2 Clinical Review Team Antonia Geber, M.D. Wasima N. Rida, Ph.D.

3. 3 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.

4. 4 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.

5. 5 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.

6. 6 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.

7. 7 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

8. 8 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).

9. 9 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

10. 10 Results - Year 1 Enrollment

11. 11 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.

12. 12 AV006 - Year 1 Efficacy No H1N1 circulating in Year 1 and thus, do not have field efficacy data for this strain.

13. 13 AV006 - Year 1: Efficacy

14. 14 AV006 - Year 1: Efficacy by Age

15. 15 AV006 - Year 1: Efficacy by Gender and Ethnicity

16. 16 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.

17. 17 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.

18. 18 AV006 - Illness Profiles of Subjects with Cxs in 1st 14 Days

19. 19 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.

20. 20 AV006 - Year 1 Immunogenicity: Strain-specific HAI GMT Results

21. 21 AV006 - Year 1: GMFR from Pre to Post-Dose 1 or 2 in FluMist  Subjects

22. 22 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.

23. 23 AV006 - Year 2 Efficacy

24. 24 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.

25. 25 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

26. 26 AV011 - Efficacy Against Shedding Vaccine CAIV-M (H1N1)

27. 27 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.

28. 28 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.

29. 29 AV009 - Effectiveness Results

30. 30 AV009 - Rate of AFI-Assoc. Events

31. 31 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

32. 32 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

33. 33 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

34. 34 AV003 - Efficacy Against Laboratory- Documented Influenza Illness

35. 35 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.

36. 36 AV007-Results: Post-Dose 2 HAI GMT Ratios Among Consistency Lots

37. 37 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.

38. 38 AV014 - Post-Dose 2 to Baseline Percent Seroconversion

39. 39 AV014 - Post-Dose 2 GMT Ratios in All Participants

40. 40 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.

41. 41 Aviron FluMist  Safety Summary

42. 42 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.

43. 43 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

44. 44 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.

45. 45 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.

46. 46 First Dose Vaccinees by April 30, 2001

47. 47 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).

48. 48 AV009 - RE Results by Group

49. 49 AV009 - Results: Unsolicited “Other” AEs

50. 50 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).

51. 51 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.

52. 52 AV006 Year 1 - Selected REs by Group

53. 53 AV006 - Year 1 Selected “Other AEs” by Group and Dose

54. 54 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).

55. 55 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.

56. 56 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.

57. 57 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.

58. 58 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.

59. 59 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

60. 60 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).

61. 61 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

62. 62 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.

63. 63 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).

64. 64 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).

65. 65 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.

66. 66 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).

67. 67 AV010 - AE Profiles of Subjects

68. 68 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.

69. 69 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.

70. 70 Pediatric Pneumonia Cases

71. 71 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.

72. 72 SAEs - Deaths 65 deaths were reported –63 in VA study. –1 accidental drowning, associated with alcohol intoxication. –1 due to pneumonia, as described.

73. 73 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.

74. 74 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.