# Presentation: 051153

## Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (BoostrixTM)

**Ann T. Schwartz, MD**
**CBER, FDA**

**Vaccines and Related Biological Products**
**Advisory Committee Meeting**
**March 15, 2005**

**GlaxoSmithKline Biologicals**** **

## 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**

## BoostrixTM formulation per 0.5mL/dose comparison with Infanrix®

| COMPONENT | BOOSTRIXTM | INFANRIX® |
| --- | --- | --- |
| Tetanus Toxoid
Diphtheria Toxoid

Pertussis Toxoid (PT)
Filamentous Hemagglutinin (FHA)
Pertactin (PRN)

Aluminum

Preservative | 5.0 Lf
2.5 Lf

8.0 μg

8.0 μg
2.5 μg

0.3 mg 
(as AlOH3)

None | 10 Lf
25 Lf

25 μg

25 μg
8.0 μg

< 0.625 mg (as AlOH3)

2.5 mg 2-PE |

## 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***

## Pivotal Safety and Immunogenicity Study Tdap/001

**Safety, immunogenicity and lot consistency of Boostrix****TM**
**Comparator vaccine: a U.S.-licensed Td vaccine (Massachusetts Public Health Biologic Laboratories) **

## Tdap/001:  Primary Objectives 

**To demonstrate: **
**non-inferiority of BoostrixTM vs.  Td wrt anti-D and anti-T seroprotection rates**** **
**non-inferiority of BoostrixTM vs.  Td wrt anti-D and anti-T booster response rates**** **
**anti-PT, anti-FHA and anti-PRN booster responses in vaccinees administered BoostrixTM**
**non-inferiority of BoostrixTM vs. Td wrt Grade 3 pain at the injection site**

## 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****TM**** lot 1 (N=1000)**
**Boostrix****TM**** lot 2 (N=1000)**
**Boostrix****TM**** lot 3 (N= 1000)**
**Td****MPHBL**** (N=1000)**

## 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**

## Tdap/001: Study Vaccine Composition per 0.5mL dose

| Component | BoostrixTM | Td MPHBL |
| --- | --- | --- |
| Tetanus toxoid
Diphtheria toxoid

Pertussis toxoid (PT)
Filamentous hemagglutinin (FHA)
Pertactin (PRN)

Aluminum

Preservative | 5.0 Lf
2.5 Lf

8.0 μg

8.0 μg
2.5 μg

0.3 mg 
(as AlOH3)

None | 2.0 Lf
2.0 Lf

--

--
--

0.45 mg 
(as AlPO4)

Thimerosal  |

## 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**

## Tdap/001:Overview of Study Procedures

**10-18 years**

**Visit 1****	****	****Diary card****	****Visit 2****	****	****             Phone call**
**Bleed #1/ **
**Vaccination****	****	****	****Bleed #2****	****	****End study**
**Day 0****	****	****Day 14****	****	****Day 30****	****	****	****Month 6**

**Boostrix****TM**** N = 3000**
**Td****MPHBL**** N = 1000**

**Safety follow-up**

## 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**

## 
Results

**Results**

## 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**

## Tdap/001

**IMMUNOGENICITY **

## Tdap/001:Immunogenicity

**Definitions, endpoints and results **
**Diphtheria and Tetanus toxoids**
**Seroprotection **
**Pre-vaccination**
**Booster response**
**Results**
**Pertussis antigens**
**Booster response**
**Results**
**Serologic Bridge to Infanrix pertussis antigens**

## Tdap/001:  Seroprotection and Booster response to diphtheria and tetanus toxoids one month post-vaccination

_**Seroprotection**_**	****	****	**** **_**>**_** 0.1 IU/mL **
_**Booster response**_
**Pre:  < 0.1 IU/mL****	****	****Post:  **_**>**_** 0.4 IU/mL **
**Pre:  **_**>**_** 0.1 IU/mL****	****	****Post:  Four-fold rise**

## Tdap/001:  Pre-vaccination anti-toxoid levels(ATP cohort for immunogenicity) 

| Antigen | BoostrixTM
N=2466-2471 | TdMPHBL
N=814-817 |
| --- | --- | --- |
|  | %  (95% CI)  | %  (95% CI)  |
| Diphtheria
  0.1 IU/mL  | 85.8  (84.3, 87.1)  | 84.8  (82.1, 87.2) |
|   1.0 IU/mL  | 17.1  (15.6, 18.6)  | 19.5  (16.9, 22.4) |
| Tetanus
  0.1 IU/mL  | 97.7  (97.1, 98.3)  | 96.8  (95.4, 97.9) |
|   1.0 IU/mL  | 36.8  (34.9, 38.7) | 39.9  (36.5, 43.4) |

## Tdap/001:  Primary Immunogenicity Endpoints and Non-inferiority Criteria (BoostrixTM vs TdMPHBL)

| Antigen                  | Endpoint | Td -Boostrix TM |
| --- | --- | --- |
| 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**

**Tdap/001:  Differences in anti-diphtheria response rates between BoostrixTM  and Td****MPHBL****  one month post vaccination ****(ATP cohort for immunogenicity)**

| Endpoint
 | BoostrixTM | TdMPHBL
 | Td - BoostrixTM 
 (95% CI) |
| --- | --- | --- | --- |
|  |  (%)  | (%)  |  % |
|   0.1 IU/mL 
 | 99.9 | 99.9 | 0.0 (-0.6, 0.3)** |
| Booster
response | 90.6 | 95.9 | 5.3 (3.4, 7.0)** |
|   1.0 IU/mL  | 97.3 | 99.3 | 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**

## Tdap/001:  Differences in anti-tetanus response rates between BoostrixTM  and TdMPHBL one month post vaccination (ATP cohort for immunogenicity)

| Endpoint
 | BoostrixTM | TdMPHBL
 | Td - BoostrixTM
 (95% CI)  |
| --- | --- | --- | --- |
|  | (%)  | (%)  |  %  |
|   0.1 IU/mL 
 | 100 | 100 | 0.0 (-0.4, 0.2)** |
| Booster
response | 89.7 | 92.5 | 2.9 (0.6, 4.9)** |
|   1.0 IU/mL  | 99.5 | 99.8 | 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 BoostrixTM  and Td****MPHBL**** one month post vaccination ****(ATP cohort for immunogenicity)**

## Tdap/001:  Booster response to pertussis components one month post- vaccination

**Booster response to PT, FHA, PRN**
**Pre:  < 5 EU/mL****	****	****	****Post: **_**>**_** 20 EU/mL**
**Pre:  **_**>**_** 5 EU/mL< 20 EU/mL ****	****Post:  4-fold rise**
**Pre: **_**>**_** 20 EU/mL****	****	****	****Post: **_**>**_** 2-fold rise**

## Tdap/001:  Primary Immunogenicity Endpoints  (BoostrixTMpertussis antigens)

| Antigens  | Endpoint  | Evaluation criteria 
LL of 2-sided 95% CI |
| --- | --- | --- |
|   anti-PT | % booster | 80%  |
|   anti-FHA | % booster | 80%  |
|   anti-PRN | % booster | 80%  |

## Tdap/001: Booster response (BR) to pertussis antigens one month post-BoostrixTM in 10-18 years old (ATP cohort for immunogenicity)

| Antigen  | BR Rate (%) | 95% CI |
| --- | --- | --- |
|  PT  | 84.5 | (83.0, 85.8)** |
|  FHA 
 | 95.1 | (94.2, 95.9)** |
|  PRN 
 | 95.4 | (94.5, 96.1)** |

**BoostrixTM  N = 2677 – 2752**
****Primary endpoint met**

## Serologic bridge to pertussis efficacy study 

## 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****®**

## 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**

## 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**

## Endpoints for serologic bridge

| Pertussis antigens | Endpoint 
(EU/mL) | Ratio
 Infanrix®/BoostrixTM |
| --- | --- | --- |
| anti-PT | GMC | UL  95% CI < 1.5  |
| anti-FHA | GMC | UL  95% CI < 1.5  |
| anti-PRN | GMC | UL  95% CI < 1.5  |

## Ratios of GMCs between BoostrixTM  and Infanrix® one month post-vaccination (TVC)

| Antigen | Infanrix® |  | BoostrixTM |  | Infanrix®/    ** BoostrixTM |
| --- | --- | --- | --- | --- | --- |
|  | N | GMC* | N | GMC* | Ratio (95% CI) |
| anti-PT | 2884  | 45.7 | 2941  | 86.9 | 0.53 (0.50,0.55) |
| anti-FHA | 685  | 83.6  | 2979  | 614.8 | 0.14 (0.13,0.15) |
| anti-PRN | 631  | 112.3  | 2978  | 470.7  | 0.24 (0.21,0.27) |

*** ELISA units / mL**
**** pre-specified non-inferiority criteria met**

## 
Safety 

**Safety**** **

## Overall Safety Database

**3289 subjects, age 10-18 years, received a single dose of Boostrix****TM (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**

## Tdap/001:Safety

**Primary Safety Endpoint**
**Non-inferiority of BoostrixTM 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**

## Tdap/001: Primary Safety Endpoint and Non-inferiority criterion

| Event                | Endpoint | BoostrixTM - Td |
| --- | --- | --- |
| Grade 3 pain* | % | UL 95% CI   4% |

***Grade 3 pain = spontaneously painful and/or prevented normal activity**

## Tdap/001:  Incidence of Pain within 15 days post-vaccination in subjects 10-18 years of age (TVC)

| Intensity | BoostrixTM
% | TdMPHBL
% |  Boostrix – Td
 % (95% CI) |
| --- | --- | --- | --- |
| Any | 75.3 | 71.7 | 3.66 (0.55,6.89)  |
| Grade >2  | 51.2 | 42.5 | 8.67 (5.13,12.17)  |
| Grade 3  | 4.6 | 4.0 | 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%)**
** **

## Tdap/001:  Incidence of local symptoms in subjects 10-18 years within 72 hours of vaccination (TVC)

| Event | Intensity | BoostrixTM (%) | Td MPHBL (%) |
| --- | --- | --- | --- |
| Redness | Any  | 21.9 | 19.5 |
|  | > 20 mm  | 4.0 | 3.8 |
|  | > 50 mm  | 1.6 | 1.5 |
| Swelling | Any  | 20.2 | 19.8 |
|  | > 20 mm | 5.0 | 4.8 |
|  | > 50 mm | 2.4 | 3.2 |
| Increased arm circumference | >5 mm  | 21.4 | 23.2 |
|  | > 20 mm | 1.6 | 1.5 |
|  | > 40 mm | 0.3 | 0.3 |

## Tdap/001:  Incidence of solicited systemic symptoms within 15 days following administration of BoostrixTM or TdMPHBL (TVC)

| Event | Intensity | BoostrixTM (%)
N = 3030 | Td MPHBL (%)
N = 1013 |
| --- | --- | --- | --- |
| Fever
(oral/axillary) | > 37.5°C | 13.4 | 13.1 |
|  | > 38°C | 5.0 | 4.7 |
|  | > 39°C | 1.4 | 1.0 |
| Headache | Any  | 43.1 | 41.5 |
|  | Grade 2  | 15.7 | 12.7 |
|  | Grade 3  | 3.7 | 2.7 |
| Fatigue | Any  | 37.0 | 36.7 |
|  | Grade 2  | 14.4 | 12.9 |
|  | Grade 3  | 3.7 | 3.2 |
| GI Symptoms | Any  | 26.0 | 25.8 |
|  | Grade 2  | 9.8 | 9.7 |
|  | Grade 3  | 3.0 | 3.2 |

## Tdap/001:  Occurrence of Serious Adverse events

**Serious adverse events occurring during the 6 month post vaccination:**
**0.5% (15) events in the BoostrixTM group **
**0.2% (2) events in the Td****MPHBL**** group**
**No SAEs reported during days 0-30 post-vaccination**
**	**

## Study Tdap/001:  SAEs within 6 months post-vaccination with BoostrixTM or TdMPHBL

**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)**

## Tdap/001:  Percentage of subjects (10-18 years old) reporting AEs during the 5 month follow-up period by type (TVC)

| AE Type | BoostrixTM (%)
N = 3005 |  | TdMPHBL (%)
N = 1003 |  |
| --- | --- | --- | --- | --- |
|  | n | (%) | n | (%) |
| Chronic illness | 22 | 0.7 | 9 | 0.9 |
| ER visit | 101 | 3.4 | 25 | 2.5 |
| Non-routine medical visit | 52 | 1.7 | 16 | 1.6 |

## Occurrence of Serious adverse events in eleven additional studies post-vaccination

| Vaccine 
N= 2372 | Age/Gender | Event | Onset (days) |
| --- | --- | --- | --- |
| BoostrixTM | 14 / F | Alcohol intoxication | 21 |
| Non-US
formulation
Boostrix | 13 / M | Syncope | 28 |
|  | 11 / F | Diabetic hypoglycemia / seizure | 37 |
|  | 11 / F | Diabetes | 20 |
|  | 10 / F | Appendicitis | 23 |
|  | 12 / F | LOC | immediate |
|  | 49 / F | Uveitis | 7 |
|  | 6 / F | Polypectomy | 29 |

## Summary

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

## Questions and discussion items for the committee

**1.  Are the available data adequate to support                the efficacy of BoostrixTM in individuals 10-18 years of age? **
**VOTE**
**2.  Are the available data adequate to support the safety of ****BoostrixTM**** when administered to individuals 10-18 years of age?**
**VOTE**
**3.  Please identify any issues which should be addressed, including post-licensure studies.**
**Discussion**