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Vaccines and Related Biological Products Advisory Committee Meeting Clinical Review of Data Supporting the Immunogenicity, Safety and Effectiveness of Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted Andrea James, M.D. FDA/CBER/OVRR/DVRPA November 14, 2012. Outline. Product Information

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  1. Vaccines and Related Biological Products Advisory Committee MeetingClinical Review of Data Supporting the Immunogenicity, Safety and Effectiveness of Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted Andrea James, M.D.FDA/CBER/OVRR/DVRPANovember 14, 2012

  2. Outline • Product Information • Q-Pan-H5N1-001 and Q-Pan-002 Immunogenicity • Arepanrix™ (Q-Pan-H1N1+AS03A) Effectiveness Study • Q-Pan-H5N1-001 and -002 Safety • Solicited reactions • Unsolicited, medically attended and serious adverse events • Additional Safety Evaluations • Adverse Events of Special Interest (AESI)/potential Immune Mediated Diseases (pIMDs) • Integrated Summaries of Safety (ISS) • Post-marketing safety of Arepanrix™ and Pandemrix™ • Post-marketing Pharmacovigilance Plan • Discussion topics for the committee

  3. Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted • GSK’s candidate monovalent, pandemic influenza vaccine • Manufactured in Quebec, Canada using the licensed Flulaval™ process

  4. Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted • Proper Name: Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted • Trade Name: None • Naming Convention:Q(Quebec-manufactured) + Pan (pandemic vaccine) + subtype = “Q-Pan H5N1” • This discussion: Assume that the full dose of the adjuvant (AS03A) is added unless otherwise noted.

  5. Q-Pan-H5N1 • An inactivated, split virion A/H5N1 influenza virus antigen mixed with AS03 • AS03: an oil-in-water emulsion adjuvant containing: • Squalene - an unsaturated, metabolizable oil extracted from shark liver • D,L-Alpha-tocopherol (Vitamin E) • Polysorbate 80 • Thought to enhance both innate and adaptive immune responses by enhancing delivery of antigen to antigen presenting cells.

  6. Q-Pan H5N1 GSK’s Proposed Indication: • Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted is a vaccine indicated for active immunization for the prevention of disease in persons 18 years of age and older at increased risk of exposure to influenza A virus H5N1 subtype contained in the vaccine.

  7. Q-Pan H5N1 • Proposed Dosage:3.75μg H5N1 HA + AS03 • Antigen dose assessed in Study D-Pan-H5N1-007 • Dresden manufactured pandemic vaccine (D-Pan) • A/Vietnam H5N1 strain • Hemagglutinin-inhibiting (HI) antibody responses were • Assessed across doses: 3.75 μg, 7.5 μg,15 μg and 30μg H5N1 HA with and without AS03A • HI antibody responses were low across all doses without AS03A adjuvant • antigen dose-dependent fashion • HI antibody responses were high independent of the antigen dose with AS03A adjuvant

  8. Q-Pan-H5N1 • Vaccine Presentation: • Separate vials of H5N1 antigen and AS03 adjuvant • Mixed 1:1 volume prior to administration. • Proposed Administration: Two 0.5 mL intramuscular injections administered 21 days apart.

  9. Studies Q-Pan-H5N1-001 and -002

  10. Study Q-Pan H5N1-001 and -002Common Trial Elements • Conducted at multiple centers in the U.S. and Canada • Randomized, controlled, single-observer-blind • Evaluated immunogenicity and safety • Vaccine/Control administered on Days 0, 21 • Q-Pan active test arms: A/Indonesia/5/2005 strain • Enrolled healthy adult males and females • Subjects with prior H5N1 vaccination excluded

  11. Study Q-Pan-H5N1-001 Design • Phase I/II • 10 U.S. and Canada sites • Adults 18-64 years old • Active control (unadjuvanted H5N1, 3.75 µg HA)

  12. Study Q-Pan-H5N1-001 Objectives • Demonstrate adjuvant activity by comparing Q-Pan H5N1 adjuvanted with AS03A(full dose)and AS03B(half dose) vs. unadjuvanted H5N1 vaccine • Demonstrate safety of Q-Pan H5N1 vs. unadjuvanted H5N1 vaccine • Demonstrate immunologic equivalence of Q-Pan H5N1 vs. D-Pan H5N1

  13. Study Q-Pan-H5N1-001Enrollment • 680 subjects enrolled 1:2:2:2:2 to: • unadjuvanted H5N1 vaccine(n=78) • Q-Pan (AS03A)(n=152) • Q-Pan (AS03B)(n=151) • D-Pan (AS03A)(n=151) • D-Pan (AS03B) (n=148)

  14. Study Q-Pan-H5N1-001 Demographics and Disposition • Mean age: 38.6 years • 54.6% of subjects were 18 – 40 years • Women: 57.8% • Caucasian: 86.8% • Disposition: • 97.8% received 2 doses of vaccine • 99% completed the study through Day 42. • 97.4% completed the study through Day 182. • No subjects withdrew due to an AE

  15. Study Q-Pan-H5N1-001 Immunogenicity Evaluations and Endpoints • Immunogenicity evaluations: Days 0, 21, 42 and 182 • Primary Endpoint • Vaccine-homologous virus antibody response in subjects receiving 2 doses of study vaccine, as demonstrated by the HI antibody titer at Day 42. • Secondary Endpoints • HI antibody response after a single dose of vaccine. • Persistence of HI antibody response 6 months post dose 1.

  16. Study Q-Pan-H5N1-001Immunogenicity Success Criteria • Demonstration of AS03 adjuvant activity • Supported if on Day 42 after two doses of study vaccine: • Lower bound of 95% CI of the difference in (Q-pan H5N1 – unadjuvanted H5N1) seroconversion rates (SCR)1 > 15% AND • Lower bound of 95% CI around the geometric mean titer (GMT) ratio (Q-Pan H5N1/unadjuvanted H5N1) > 2 • SCR = % of subjects with a pre-vaccination HI titer <10 and a post-vaccination titer ≥40 or with a pre-vaccination HI titer (Day 0) ≥10 and a fold-increase (post/pre) ≥4.

  17. Study Q-Pan-H5N1-001Immunogenicity Analysis Population • According-To-Protocol Cohort for Analysis of Immunogenicity (ATP-I) population: • Met all eligibility criteria • Complied with protocol procedures • No elimination criteria met • Provided a complete set of immunogenicity endpoint measures at Day 0 and Day 42 • Received the correct vaccine

  18. Study Q-Pan-H5N1-001Primary Immunogenicity Results: Day 42 • Activity of AS03 demonstrated • Difference in SCRs • 79.9% (95% CI = 69.4-87.3%) • Exceeded pre-specified difference of Q-Pan H5N1 (AS03A) – unadjuvanted H5N1 LBs > 15 • Adjusted GMT ratio • 43.4 (95% CI = 29.9-62.9) • Exceeded pre-specified difference of Q-Pan H5N1 (AS03A)/unadjuvanted H5N1 LB of > 2

  19. Study Q-Pan-H5N1-001Secondary HI Immunogenicity Results N = number of subjects with available data n = number of responders

  20. Q-Pan-H5N1-001 GSK’s post hoc Immunogenicity Analysis • Adjuvant effect of AS03A vs. AS03B • By age strata 18-40 yrs vs. 41-64 yrs. • AS03B performed less well in the older cohort • Lower GMTs as compared to AS03A • AS03A: 364.1 (299.2, 443.1) vs. AS03B: 209.7 (160.4, 274.2) • Results supported moving forward with AS03A in the adult population.

  21. Q-Pan-H5N1-001 Immunogenicity Conclusion • -001 Immunogenicity data supported: • Selected antigen dose: 3.75 μg • Selected adjuvant dose: AS03A • Need for two doses of vaccine to produce an adequate HI antibody response

  22. Study Q-Pan-H5N1-002 Design • Phase III • 40 U.S. and Canada sites • Adults > 18 years old • Control: saline placebo • Immunogenicity evaluations: Days 0, 21, 42 and 182

  23. Study Q-Pan-H5N1-002 Enrollment • Total N = 4,561 • Stratified by age: 18 – 64 and > 64 years • Randomization 3:1 • Q-Pan H5N1 (N = 3422) • Saline placebo (N = 1139) • Immunogenicity subset: N=2,083 • Lot consistency subset: N=1,260

  24. Study Q-Pan-H5N1-002 Objectives • Demonstrate an immune response that met CBER’s suggested immunogenicity criteria to support accelerated approval of a pandemic influenza vaccine • Demonstrate lot consistency for 3 antigen and 3 adjuvant lots* • Demonstrate the safety of Q-Pan vs. saline placebo *Lot consistency was met

  25. Study Q-Pan-H5N1-002 Demographics and Disposition • Mean age: • 39 years (18 – 64 years) • 72 years (> 64 years) • Women: 56% • Caucasian: • 86% (18-64 years) • 94% (> 64 years) • Disposition: • 97% received 2 doses of vaccine • 98% completed the study through Day 42 • 95.2% completed the study through Day 182 • 76.2% completed the study through Day 364* *Study Q-Pan-H5N1-002 was amended to add a safety evaluation on Day 364 and subjects needed to be reconsented.

  26. Q-Pan-H5N1-002Immunogenicity Endpoints • Primary endpoints (D42 - 21 days post Dose 2) • Vaccine-homologous virus HI seroconversion rates • Proportion of subjects with vaccine-homologous virus HI reciprocal titers ≥ 40 • The GMT ratio of vaccine-homologous virus reciprocal HI titers with 2-sided 95% CIs within 0.67 to 1.5 for lot consistency • Secondary endpoints included • Persistence of HI antibody response through 6 months post Dose 1

  27. Immunogenicity Success Criteria1 • These criteria and the 1:40 HI antibody titer are borrowed from seasonal influenza. • Historical data suggest that at a titer of 1:40 ~50% of subjects may be protected from illness due to seasonal influenza virus. 1Clinical Data Needed to Support the Licensure of Pandemic Influenza Vaccines (2007) 2SCR = % of subjects with a pre-vaccination HI titer <10 and a post-vaccination titer ≥40 or with a pre-vaccination HI titer (Day 0) ≥10 and a fold-increase (post/pre) ≥4.

  28. Study Q-Pan-H5N1-002 Primary Immunogenicity Results N – Number of subjects with both pre- and post- vaccination results available n – number of responders

  29. Q-Pan-H5N1-002 Day 182 Immunogenicity Results N – Number of subjects with both pre- and post- vaccination results available n – number of responders number of seroconverters ** number of subjects w/ HI titer > 1:40

  30. Summary of Q-Pan-H5N1 Immunogenicity • Q-Pan H5N1 • Antigen dose sparing (3.75 μg/dose) • Two doses of vaccine are needed • Achieve an adequate HI antibody response • Exceed CBER’s suggested immunogenicity criteria.

  31. Vaccine Effectiveness

  32. ArepanrixTM (H1N1+AS03A)Effectiveness Study • “A Test-negative Case-Control Study to Evaluate the Effectiveness of GSK Biologicals’ Adjuvanted Monovalent Inactivated H1N1 Influenza Vaccine (ArepanrixTM) in Young Children (6 months to < 10 years of age)” • Sponsored by: New Brunswick Department of Health Canada • Conducted by: Dr. Van Buynder, et al

  33. Arepanrix (H1N1+AS03A)Effectiveness Study • GSK did not participate in the study conduct • CBER did not provide input into the study design • Safety data were not collected • Arepanrix evaluated at a single, 0.25 mL dose (1.9μg H1N1 HA+ AS03B)

  34. Arepanrix (1.9 H1N1+AS03B)Effectiveness Study Population • Of the ~73,000 children aged 6 months to 9 years in New Brunswick • 116 (0.16% of total population) were tested for H1N1 • Eligible for the study (n=116) • 91 children met study criteria and agreed to participate • 28 cases -- PCR confirmed H1N1+ nasal swabs • 63 controls -- PCR negative for H1N1

  35. Arepanrix (1.9 H1N1+AS03B)Effectiveness Results • When subjects were vaccinated > 14 days prior to symptom onset: • Estimated vaccine effectiveness (VE) = 100% (95% CI: 79.5,100) • When subjects were vaccinated > 10 days prior to symptom onset: • Estimated VE = 96% (95% CI: 66, 99.4)

  36. Arepanrix (1.9 μg H1N1+AS03B)Effectiveness Study • Limitations of the study • Small sample size • Large percentage of subjects excluded from the effectiveness analysis • Potential for bias e.g. selection, reporting • Retrospective study design • Conclusions: • Study suggests a single, 0.25mL dose of Arepanrix H1N1 was effective against H1N1 influenza virus in this small, study in children • Given limitations, CBER is unable to use the results of this study to confirm effectiveness of Q-Pan H5N1

  37. Safety Results of Studies Q-Pan-H5N1-001 and -002

  38. Studies Q-Pan-H5N1-001 and -002Primary Safety Population • Total Vaccinated Cohort (TVC) • Received at least 1 dose of vaccine • Any post-vaccination data • Based on treatment actually received.

  39. Studies Q-Pan-H5N1-001 and -002Safety Evaluations • Safety evaluations: • Days 0-6 diary card solicited reactogenicity events • Days 0-84 unsolicited adverse events (AEs) • Days 0 – 182 medically attended and serious AEs (-001) • Days 0 - 364 medically attended and serious AEs (-002)

  40. Studies Q-Pan-H5N1-001 and -002Solicited AE Grading • Severity grading • Mild (Grade 1) – no interference with normal activities • Moderate (Grade 2) – some interference with normal activities • Severe (Grade 3) – prevented normal activity • Redness and swelling • Grade 3 -- > 100 mm

  41. Study Q-Pan-H5N1-001: Local Reactions By Subject for Dose 1 or Dose 2 N = number of subjects with at least one documented dose n = number of subjects reporting AE at least once Any = any grade Gr 3 - Grade 3, severe

  42. Study Q-Pan-H5N1-001: Systemic Reactions By Subject for Dose 1 or Dose 2 N = number of subjects with at least one documented dose n = number of subjects reporting AE at least once Any = any grade Gr 3 - Grade 3, severe

  43. Study Q-Pan-H5N1-001: Systemic Reactions By Subject for Dose 1 or Dose 2 N = number of subjects with at least one documented dose n = number of subjects reporting AE at least once Gr 3 - Grade 3, severe

  44. Study Q-Pan-H5N1-001:Reactogenicity Event Outcomes • Antipyretics required : • 32% of Q-Pan H5N1 (AS03A) subjects vs. 21% unadjuvanted H5N1subjects • Q-Pan H5N1 (AS03A) subjects • Resolved in a median of: 3 days • No medical attention needed

  45. Study Q-Pan-H5N1-001: AEs and MAEs • Unsolicited AEs reported (by subject) • Day 42: Q-Pan H5N1 (AS03A) – 44% and unadjuvanted H5N1 -- 39% • Day 84: Q-Pan H5N1 (AS03A) – 51% and unadjuvanted H5N1 -- 45% • Events occurring exclusively in Q-Pan (AS03A) subjects (2 – 3%) • Diarrhea, anemia, lymphadenopathy, dizziness, muscle spasms and sinusitis • MAEs reported (by subject) • Day 42: Q-Pan H5N1 (AS03A) – 7% and unadjuvanted H5N1 -- 12% • Day 182: Q-Pan H5N1 (AS03A) – 19% and unadjuvanted H5N1 -- 21%

  46. Study Q-Pan-H5N1-001:SAEs • SAEs (through Day 182) • 3 SAEs in 2 Q-Pan H5N1 (AS03A)subjects • Cholelithiasis and pancreatitis(1) and Chest pain (1) • Deemed vaccine unrelated by investigators • No deaths were reported.

  47. Study Q-Pan-002: Local Reactions By Subject, Dose 1 or Dose 2 N = number of subjects with at least one documented dose n = number of subjects reporting reaction at least once Any = any grade Gr > 2 – at least moderate, Grade 2 Gr 3 - Grade 3, severe

  48. Study Q-Pan-002: Systemic Reactions By Subject, Dose 1 or Dose 2 N = number of subjects with at least one documented dose n = number of subjects reporting reaction at least once Any = any grade Gr > 2 – at least moderate, Grade 2 Gr 3 - Grade 3, severe

  49. Study Q-Pan-002 Safety: Systemic Reactions By Subject, Dose 1 or Dose 2 (cont) N = number of subjects with at least one documented dose n = number of subjects reporting reaction at least once Gr > 2 – at least moderate, Grade 2 Gr 3 - Grade 3, severe

  50. Study Q-Pan-H5N1-002: Unsolicited AEs • Day 42: Q-Pan H5N1 (38%) and saline placebo (35%) • Day 84: Q-Pan H5N1(43.4%) and saline placebo (39.6%) • Imbalances in unsolicited adverse events • Most common imbalances (by subject) occurred in the preferred terms • Injection site pruritus: Q-Pan 1.64% (n=64) vs. placebo 0.35% (n=4) • Injection site warmth: Q-Pan 1.34% (n=46) vs. placebo 0.18% (n=2) • Insomnia: Q-Pan 0.4% (n=14) vs. placebo 0.09% (n=1)

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