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

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 < mg (as AlOH 3 ) 2.5 mg 2-PE

4 Basis for Licensure Indication: 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 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 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 Tdap/001: Study Design  Prospective, randomized, observer-blinded, comparative multi-center study  Adolescents years of age  Stratified by age before enrollment into two groups  years of age (N=3000)  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 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 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 mg (as AlPO 4 ) Thimerosal

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 Tdap/001: Overview of Study Procedures 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 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 Results

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 years of age  24.8% subjects years

15 Tdap/001 IMMUNOGENICITY

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 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 Tdap/001: Pre-vaccination anti-toxoid levels (ATP cohort for immunogenicity) Antigen Boostrix™N= Td MPHBL N= % (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 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 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 (-0.6, 0.3)** Boosterresponse (3.4, 7.0)**  1.0 IU/mL  1.0 IU/mL (1.0, 2.8) § Boostrix: N= , Td: N= ** Non-inferiority criterion met § Non-inferiority criteria were not pre-specified

21 EndpointBoostrix™ Td MPHBL Td - Boostrix™  (95% CI) (%)(%) %  0.1 IU/mL  0.1 IU/mL (-0.4, 0.2)** Boosterresponse (0.6, 4.9)**  1.0 IU/mL  1.0 IU/mL (-0.4, 0.7) § Boostrix: N= , Td: N= ** 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 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 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 Tdap/001: Booster response (BR) to pertussis antigens one month post-Boostrix™ in 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 Serologic bridge to pertussis efficacy study

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 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: %) 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 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 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 Ratios of GMCs between Boostrix™ and Infanrix® one month post-vaccination (TVC) Antigen Infanrix ® Boostrix ™ Infanrix®/ ** Boostrix ™ NGMC*NGMC* Ratio (95% CI) anti-PT (0.50,0.55) anti-FHA (0.13,0.15) anti-PRN (0.21,0.27) * ELISA units / mL ** pre-specified non-inferiority criteria met

31 Safety

32 Overall Safety Database  3289 subjects, age 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 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 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 Tdap/001: Incidence of Pain within 15 days post-vaccination in subjects years of age (TVC) Intensity Boostrix ™ % Td MPHBL % Boostrix – Td Boostrix – Td  % (95% CI) Any (0.55,6.89) Grade > (5.13,12.17) Grade (-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 Tdap/001: Incidence of local symptoms in subjects years within 72 hours of vaccination (TVC) EventIntensity Boostrix ™ (%) Td MPHBL (%) RednessAny > 20 mm > 50 mm SwellingAny > 20 mm > 50 mm Increased arm circumference >5 mm > 20 mm > 40 mm

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 > 38°C > 39°C Headache Any Grade  Grade Fatigue Any Grade  Grade GI Symptoms Any Grade  Grade

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 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 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 ER visit Non-routine medical visit

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 / F Diabetes20 10 / F Appendicitis23 12 / F LOCimmediate 49 / F Uveitis7 6 / F Polypectomy29

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