1. Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (Boostrix TM ) Ann T. Schwartz, MD CBER, FDA Vaccines and Related Biological Products Advisory Committee Meeting March 15, 2005 GlaxoSmithKline Biologicals

2. 2 Outline  Boostrix vs Infanrix  Basis for Licensure  Indication: single dose, 10-18 years  Immunogenicity  Study Tdap/001  Bridge to Pertussis Efficacy  Safety  Study Tdap/001  Eleven non-IND studies  Questions for the Committee

3. 3 Boostrix™ formulation per 0.5mL/dose comparison with Infanrix® COMPONENTBOOSTRIX™INFANRIX® Tetanus Toxoid Diphtheria Toxoid Pertussis Toxoid (PT) Filamentous Hemagglutinin (FHA) Pertactin (PRN) AluminumPreservative 5.0 Lf 2.5 Lf 8.0 µg 2.5 µg 0.3 mg (as AlOH 3 ) None 10 Lf 25 Lf 25 µg 8.0 µg < 0.625 mg (as AlOH 3 ) 2.5 mg 2-PE

4. 4 Basis for Licensure Indication: 10-18 years, single dose booster  Demonstration of safety  Demonstration of non-inferiority of anti- tetanus and anti-diphtheria seroprotection and booster response vs. Td  Demonstration of booster response to pertussis antigens  Demonstration of serologic bridge to pertussis efficacy  Demonstration of lot-to-lot consistency of Boostrix

5. 5 Pivotal Safety and Immunogenicity Study Tdap/001  Safety, immunogenicity and lot consistency of Boostrix™  Comparator vaccine: a U.S.-licensed Td vaccine (Massachusetts Public Health Biologic Laboratories)

6. 6 Tdap/001: Primary Objectives  To demonstrate:  non-inferiority of Boostrix™ vs. Td wrt anti- D and anti-T seroprotection rates  non-inferiority of Boostrix™ vs. Td wrt anti- D and anti-T booster response rates  anti-PT, anti-FHA and anti-PRN booster responses in vaccinees administered Boostrix™  non-inferiority of Boostrix™ vs. Td wrt Grade 3 pain at the injection site

7. 7 Tdap/001: Study Design  Prospective, randomized, observer-blinded, comparative multi-center study  Adolescents 10-18 years of age  Stratified by age before enrollment into two groups  10-14 years of age (N=3000)  15-18 years of age (N=1000)  Randomized 1:1:1:1 to four groups:  Boostrix™ lot 1 (N=1000)  Boostrix™ lot 2 (N=1000)  Boostrix™ lot 3 (N= 1000)  Td MPHBL (N=1000)

8. 8 Tdap/001: Pertinent Inclusion / Exclusion Criteria  Completed routine childhood vaccinations against diphtheria, tetanus and pertussis diseases (4 or 5 doses)  DTwP doses 1-3  DTwP or DTaP 4 and/or 5  At least 5 years since the receipt of the pre- school dose of DTP  Subjects who had received a Td booster within the previous 10 years were excluded

9. 9 Tdap/001: Study Vaccine Composition per 0.5mL dose Component Boostrix™ Td MPHBL Tetanus toxoid Diphtheria toxoid Pertussis toxoid (PT) Filamentous hemagglutinin (FHA) Pertactin (PRN) AluminumPreservative 5.0 Lf 2.5 Lf 8.0 µg 2.5 µg 0.3 mg (as AlOH 3 ) None 2.0 Lf ------ 0.45 mg (as AlPO 4 ) Thimerosal

10. 10 Tdap/001: Safety surveillance and monitoring  Immediate reactions  30 minutes post-vaccination  Solicited local and systemic adverse events  0-14 days post-vaccination collected by diary card  Unsolicited adverse events  Recorded for 6 months post-vaccination  Serious adverse events  Reported and recorded for 6 months post- vaccination

11. 11 Tdap/001: Overview of Study Procedures 10-18 years Visit 1Diary cardVisit 2 Phone call Bleed #1/ VaccinationBleed #2End study Day 0Day 14Day 30Month 6 Boostrix™ N = 3000 Td MPHBL N = 1000 Safety follow-up

12. 12 Tdap/001: Populations for analysis  TVC for safety  Vaccinated subjects with safety data  TVC for immunogenicity  Vaccinated subjects with serologic data  ATP for immunogenicity  Vaccinated subjects complying with protocol with serologic data

13. 13 Results

14. 14 Tdap/001: Demographics Total Vaccinated Cohort (N= 4114)  52.1% males and 47.9% females  Ethnicity  85.7% Caucasian  5.6% African-Americans  5.7% Hispanics  0.8% Asians  ~ 2% Other  Mean age: 12.9 years  75.2% subjects 10-14 years of age  24.8% subjects 15-18 years

15. 15 Tdap/001 IMMUNOGENICITY

16. 16 Tdap/001: Immunogenicity  Definitions, endpoints and results  Diphtheria and Tetanus toxoids Seroprotection Seroprotection Pre-vaccination Pre-vaccination Booster response Booster response Results Results  Pertussis antigens Booster response Booster response Results Results  Serologic Bridge to Infanrix pertussis antigens

17. 17 Tdap/001: Seroprotection and Booster response to diphtheria and tetanus toxoids one month post-vaccination  Seroprotection > 0.1 IU/mL  Booster response Pre: 0.4 IU/mL Pre: > 0.1 IU/mLPost: Four-fold rise

18. 18 Tdap/001: Pre-vaccination anti-toxoid levels (ATP cohort for immunogenicity) Antigen Boostrix™N=2466-2471 Td MPHBL N=814-817 % (95% CI) Diphtheria  0.1 IU/mL  0.1 IU/mL 85.8 (84.3, 87.1) 84.8 (82.1, 87.2)  1.0 IU/mL  1.0 IU/mL 17.1 (15.6, 18.6) 19.5 (16.9, 22.4) Tetanus  0.1 IU/mL  0.1 IU/mL 97.7 (97.1, 98.3) 96.8 (95.4, 97.9)  1.0 IU/mL  1.0 IU/mL 36.8 (34.9, 38.7) 39.9 (36.5, 43.4)

19. 19 Tdap/001: Primary Immunogenicity Endpoints and Non-inferiority Criteria (Boostrix™ vs Td MPHBL ) AntigenEndpoint Td -Boostrix ™ anti-diphtheria %  0.1 IU/mL UL 95% CI   10% % booster UL 95% CI   10% anti-tetanus %  0.1 IU/mL UL 95% CI   10% % booster UL 95% CI   10% 2-sided 95% CI

20. 20 Tdap/001: Differences in anti-diphtheria response rates between Boostrix™ and Td MPHBL one month post vaccination (ATP cohort for immunogenicity) Endpoint Boostrix™ Td MPHBL Td - Boostrix™  (95% CI) (%) (%)(%) %  0.1 IU/mL  0.1 IU/mL 99.999.9 0.0 (-0.6, 0.3)** Boosterresponse 90.695.9 5.3 (3.4, 7.0)**  1.0 IU/mL  1.0 IU/mL 97.399.3 2.0 (1.0, 2.8) § Boostrix: N= 2463-2516, Td: N=814-834 ** Non-inferiority criterion met § Non-inferiority criteria were not pre-specified

21. 21 EndpointBoostrix™ Td MPHBL Td - Boostrix™  (95% CI) (%)(%) %  0.1 IU/mL  0.1 IU/mL100100 0.0 (-0.4, 0.2)** Boosterresponse89.792.5 2.9 (0.6, 4.9)**  1.0 IU/mL  1.0 IU/mL99.599.8 0.3 (-0.4, 0.7) § Boostrix: N= 2463-2516, Td: N=814-834 ** Non-inferiority criterion met § Non-inferiority criteria were not pre-specified Tdap/001: Differences in anti-tetanus response rates between Boostrix™ and Td MPHBL one month post vaccination (ATP cohort for immunogenicity)

22. 22 Tdap/001: Booster response to pertussis components one month post- vaccination  Booster response to PT, FHA, PRN  Pre: 20 EU/mL  Pre: > 5 EU/mL 5 EU/mL< 20 EU/mL Post: 4-fold rise  Pre: > 20 EU/mLPost: > 2-fold rise

23. 23 Tdap/001: Primary Immunogenicity Endpoints (Boostrix™pertussis antigens) AntigensEndpoint Evaluation criteria LL of 2-sided 95% CI anti-PT anti-PT % booster  80% anti-FHA anti-FHA % booster  80% anti-PRN anti-PRN % booster  80%

24. 24 Tdap/001: Booster response (BR) to pertussis antigens one month post-Boostrix™ in 10-18 years old (ATP cohort for immunogenicity) Antigen BR Rate (%) 95% CI PT PT84.5 (83.0, 85.8)** FHA FHA95.1 (94.2, 95.9)** PRN PRN95.4 (94.5, 96.1)** Boostrix™ N = 2677 – 2752 **Primary endpoint met

25. 25 Serologic bridge to pertussis efficacy study

26. 26 Serologic bridge to clinical efficacy Study: Tdap/001 and APV/039, APV/050  Non-inferiority to Infanrix®, administered as a 3-dose primary series  GMCs one month post Boostrix compared to GMCs one month after completing infant series with Infanrix®

27. 27 Serologic bridge: APV-039 and APV-050  Study APV-039  Safety, immunogenicity and lot consistency study of Infanrix®  3-dose series at 3, 4, and 5 months of age  Pop. for household contact study APV-050  Study APV-050  Efficacy 89% (95% CI: 77- 95%) against WHO- defined pertussis > 21 days of paroxysmal cough with positive culture and/or serologic testing > 21 days of paroxysmal cough with positive culture and/or serologic testing

28. 28 Serologic bridge: Testing of study samples  TVC of APV-039  Subjects who had serologic data for at least one pertussis antigen  Majority had anti-PT toxoid serological data only  APV-039 Serologic assays performed in 1994  Tdap/001 Serologic assays performed in 2003  Used same assays and same laboratory

29. 29 Endpoints for serologic bridge Pertussis antigens Endpoint(EU/mL)Ratio Infanrix®/Boostrix™ Infanrix®/Boostrix™ anti-PTGMC UL 95% CI < 1.5 anti-FHAGMC anti-PRNGMC

30. 30 Ratios of GMCs between Boostrix™ and Infanrix® one month post-vaccination (TVC) Antigen Infanrix ® Boostrix ™ Infanrix®/ ** Boostrix ™ NGMC*NGMC* Ratio (95% CI) anti-PT288445.7294186.9 0.53 (0.50,0.55) anti-FHA68583.62979614.8 0.14 (0.13,0.15) anti-PRN631112.32978470.7 0.24 (0.21,0.27) * ELISA units / mL ** pre-specified non-inferiority criteria met

31. 31 Safety

32. 32 Overall Safety Database  3289 subjects, age 10-18 years, received a single dose of Boostrix™ (Studies Tdap/001 and Tdap/029)  2163 additional subjects, 4-78 years of age, analyzed for safety after receipt of a single dose of Tdap (0.5 mg Al) in eleven non-IND studies

33. 33 Tdap/001: Safety  Primary Safety Endpoint  Non-inferiority of Boostrix™ vs. Td wrt Grade 3 pain at the injection site  Solicited local adverse events  72 hours and 15 days  Solicited systemic adverse events  72 hours and 15 days  Unsolicited adverse events  Serious adverse events

34. 34 Tdap/001: Primary Safety Endpoint and Non-inferiority criterion EventEndpoint Boostrix ™ - Td Grade 3 pain* % UL 95% CI   4% *Grade 3 pain = spontaneously painful and/or prevented normal activity

35. 35 Tdap/001: Incidence of Pain within 15 days post-vaccination in subjects 10-18 years of age (TVC) Intensity Boostrix ™ % Td MPHBL % Boostrix – Td Boostrix – Td  % (95% CI) Any75.371.7 3.66 (0.55,6.89) Grade >2 51.242.5 8.67 (5.13,12.17) Grade 3 4.64.0 0.54 (-1.01, 1.87)§ Any pain = painful on touch Grade 2 pain = painful when limb moved Grade 3 pain = spontaneously painful and/or prevented normal activity § non-inferiority criterion met (upper limit 95% CI on the difference  4%)

36. 36 Tdap/001: Incidence of local symptoms in subjects 10-18 years within 72 hours of vaccination (TVC) EventIntensity Boostrix ™ (%) Td MPHBL (%) RednessAny 21.919.5 > 20 mm 4.03.8 > 50 mm 1.61.5 SwellingAny 20.219.8 > 20 mm 5.04.8 > 50 mm 2.43.2 Increased arm circumference >5 mm 21.423.2 > 20 mm 1.61.5 > 40 mm 0.30.3

37. 37 Tdap/001: Incidence of solicited systemic symptoms within 15 days following administration of Boostrix™ or Td MPHBL (TVC) EventIntensity Boostrix™ (%) N = 3030 Td MPHBL (%) N = 1013 Fever(oral/axillary) > 37.5°C 13.413.1 > 38°C 5.04.7 > 39°C 1.41.0 Headache Any 43.141.5 Grade  2 15.712.7 Grade 3 3.72.7 Fatigue Any 37.036.7 Grade  2 14.412.9 Grade 3 3.73.2 GI Symptoms Any 26.025.8 Grade  2 9.89.7 Grade 3 3.03.2

38. 38 Tdap/001: Occurrence of Serious Adverse events  Serious adverse events occurring during the 6 month post vaccination:  0.5% (15) events in the Boostrix™ group  0.2% (2) events in the Td MPHBL group  No SAEs reported during days 0-30 post- vaccination

39. 39 Study Tdap/001: SAEs within 6 months post- vaccination with Boostrix™ or Td MPHBL  Wounds/fractures (4)  Overdose/drug abuse(3)  Depression/ADHD (2)  Cholecystitis (1)  Headache (1)  Spontaneous AB (1)  Menorrhagia (1)  Sinusitis w/ migraine(1)  Pleural effusion with pneumothorax status-post surgery for repair of pectus excavatum(1)  Appendicitis (1/Td)  Tooth abscess (1/Td)

40. 40 Tdap/001: Percentage of subjects (10-18 years old) reporting AEs during the 5 month follow-up period by type (TVC) AE Type Boostrix™ (%) N = 3005 Td MPHBL (%) N = 1003 n(%)n(%) Chronic illness 220.790.9 ER visit 1013.4252.5 Non-routine medical visit 521.7161.6

41. 41 Occurrence of Serious adverse events in eleven additional studies post-vaccination Vaccine N= 2372 Age/GenderEvent Onset (days) Boostrix™ 14 / F Alcohol intoxication 21 Non-USformulationBoostrix 13 / M Syncope28 11 / F Diabetic hypoglycemia / seizure 37 11 / F Diabetes20 10 / F Appendicitis23 12 / F LOCimmediate 49 / F Uveitis7 6 / F Polypectomy29

42. 42 Summary  Primary immunogenicity endpoints: all met  Primary safety endpoint: met  No unexpected adverse events or serious safety concerns  Serologic Bridge: Non-inferiority criteria met

43. 43 Questions and discussion items for the committee 1. Are the available data adequate to support the efficacy of Boostrix™ in individuals 10-18 years of age? VOTE VOTE 2. Are the available data adequate to support the safety of when administered to individuals 10-18 years of age? 2. Are the available data adequate to support the safety of Boostrix™ when administered to individuals 10-18 years of age? VOTE VOTE 3. Please identify any issues which should be addressed, including post-licensure studies. Discussion Discussion