# Presentation: 567798

## PENTACEL®

**Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus Vaccine and Haemophilus***** *****b Conjugate (Tetanus Toxoid Conjugate) Vaccine Combined ****(DTaP-IPV/Hib Combined)**

**Vaccine and Related Biological Products Advisory Committee**
**January 25, 2007**

**Notes:**
Mister chairman, members of the advisory committee, ladies and gentlemen, good morning.
I am Luc Kuykens, vice president of regulatory affairs for sanofi pasteur.
Sanofi Pasteur is pleased today to have the opportunity to present Pentacel, our infant and toddler tetanus, diphtheria, acellular pertussis, polio and haemophilus influenza combination vaccine. 

## PENTACEL - Agenda

| Introduction | Luc Kuykens, MD, MPHVP Regulatory Affairs |
| --- | --- |
| Safety | Luc Kuykens, MD, MPHVP Regulatory Affairs |
| Immunogenicity  | Michael Decker, MD, MPH VP Scientific and Medical Affairs |
| Canadian Post-Marketing Effectiveness | Scott Halperin, MDProfessor of PediatricsDalhousie University, Halifax, Canada |
| US Perspective | David Greenberg, MDDirector Scientific and Medical Affairs |
| Conclusion | Luc Kuykens, MD, MPHVP Regulatory Affairs |

**Notes:**
Following this introduction, I will present the safety profile of Pentacel; Dr. Decker will review the immunogenicity data of our application, Dr. Halperin will give you an overview of  9 years of post marketing experience with Pentacel in Canada and Dr. Greenberg will address the current epidemiology of pertussis and Hib disease in the US.
Given the time constraints, our presentation will focus on the key data.  A complete overview of the clinical data submitted in our application is available in the  briefing document.
Pause
Why did we develop this combination vaccine? 

## PENTACEL: First Candidate DTaP-IPV-Hib Combination Vaccine in the US

**Unique Benefits for Entire Immunization Community**
**Patient Benefits**
**Maximum shot reduction**
**Well established safety profile; 9 years exclusive use****in Canada**
**Health Care Provider Benefits**
**Optimizes implementation of immunization recommendations**
**Simplifies administration**
**Public Health Benefits**
**May improve vaccination coverage rates and timeliness**
**Improves combination vaccine supply**

**Notes:**
As the first candidate DTaP-IPV-Hib combination vaccine in the US, Pentacel offers unique benefits for the entire immunization community.
Patient benefits by  providing the greatest shot reduction compared to any other single combination vaccine and a well established safety profile after 9 years of experience in Canada with over 12 million doses distributed.
Healthcare provider benefits by  optimizing the implementation of immunization guidelines and simplifiying administration. 
And public health benefits, by potentially improving vaccination coverage rates and timeliness as well as  vaccine supply. 
Dr. Greenberg will elaborate on these important  points later in his presentation.

## PENTACEL Formulation

|  | Quadracel | PENTACEL |
| --- | --- | --- |
| Tetanus Toxoid | 5 Lf | 5 Lf |
| Diphtheria Toxoid | 15 Lf | 15 Lf |
| Pertussis Toxoid | 20 μg | 20 μg |
| Filamentous Hemagglutinin | 20 μg | 20 μg |
| Pertactin  | 3 μg | 3 μg |
| Fimbriae Types 2 and 3 | 5 μg | 5 μg |
| IPV Types 1, 2, 3 | 40, 8, 32 DAU | 40, 8, 32 DAU |
| PRP-T (ActHIB) | - | 10 μg |

**Adjuvant: 0.33 mg aluminum; ****0.6% v/v ****2-phenoxyethanol**

**Notes:**
Pentacel is based on a liquid combination vaccine of tetanus, diphtheria, pertussis and IPV antigens, also called Quadracel which itself is a licensed vaccine in Canada.  Quadracel is used to reconstitute ActHIB prior to injection. 

## Vaccine Formulation

|  | PENTACEL |  | Daptacel | Adacel |
| --- | --- | --- | --- | --- |
| Tetanus Toxoid | 5 Lf |  | 5 Lf | 5 Lf |
| Diphtheria Toxoid | 15 Lf |  | 15 Lf | 2 Lf |
|               5 Component Pertussis Antigens |  |  |  |  |
| Pertussis Toxoid |  | 20 μg | 10 μg | 2.5 μg |
| Filamentous Hemagglutinin |  | 20 μg | 5 μg | 5 μg |
| Pertactin  |  | 3 μg | 3 μg | 3 μg |
| Fimbriae Types 2 and 3 |  | 5 μg | 5 μg | 5 μg |
| IPV Types 1, 2, 3 |  | 40, 8, 32 DAU | - | - |
| PRP-T |  | 10 μg | - | - |

**Adjuvant: 0.33 mg aluminum; ****0.6% v/v ****2-phenoxyethanol**

**Notes:**
The composition of Pentacel for diphtheria and tetanus  reflects the current US standard of care, our licensed pediatric DTaP vaccine, Daptacel.

## Vaccine Formulation

|  | PENTACEL |  | Daptacel | Adacel |
| --- | --- | --- | --- | --- |
| Tetanus Toxoid | 5 Lf |  | 5 Lf | 5 Lf |
| Diphtheria Toxoid | 15 Lf |  | 15 Lf | 2 Lf |
|               5 Component Pertussis Antigens |  |  |  |  |
| Pertussis Toxoid |  | 20 μg | 10 μg | 2.5 μg |
| Filamentous Hemagglutinin |  | 20 μg | 5 μg | 5 μg |
| Pertactin  |  | 3 μg | 3 μg | 3 μg |
| Fimbriae Types 2 and 3 |  | 5 μg | 5 μg | 5 μg |
| IPV Types 1, 2, 3 |  | 40, 8, 32 DAU | - | - |
| PRP-T |  | 10 μg | - | - |

**Adjuvant: 0.33 mg aluminum; ****0.6% v/v ****2-phenoxyethanol**

**Notes:**
The antigen concentrations for IPV and haemophilus influenza match the licensed Poliovax and Act-HIB vaccines and the pertussis antigens...

## Vaccine Formulation

|  | PENTACEL |  | Daptacel | Adacel |
| --- | --- | --- | --- | --- |
| Tetanus Toxoid | 5 Lf |  | 5 Lf | 5 Lf |
| Diphtheria Toxoid | 15 Lf |  | 15 Lf | 2 Lf |
|               5 Component Pertussis Antigens |  |  |  |  |
| Pertussis Toxoid |  | 20 μg | 10 μg | 2.5 μg |
| Filamentous Hemagglutinin |  | 20 μg | 5 μg | 5 μg |
| Pertactin  |  | 3 μg | 3 μg | 3 μg |
| Fimbriae Types 2 and 3 |  | 5 μg | 5 μg | 5 μg |
| IPV Types 1, 2, 3 |  | 40, 8, 32 DAU | - | - |
| PRP-T |  | 10 μg | - | - |

**Adjuvant: 0.33 mg aluminum; ****0.6% v/v ****2-phenoxyethanol**

**Notes:**
... are the same as in Daptacel and Adacel.
Sanofi pasteur’s 5 component pertussis vaccine is unique in that it contains fimbriae types 2 and 3, as well as PT, FHA and pertactin. 

## Pertussis Antibody Levels vs Protection

| Pattern of Antibodies* |  |  | Protective Efficacy† |
| --- | --- | --- | --- |
| FIM | PRN | PT | % |
| Low | Low | High | 46 |
| High | Low | High or Low | 72 |
| Low | High | High or Low | 75 |
| High | High | High or Low | 85 |

***High (**_**>**_**5 units) or Low (0 to <5 units) levels of antibody before pertussis exposure.**
**†****Efficacy against WHO-defined pertussis.  Storsaeter et al. *****Vaccine.***** 1998;16:1907-16.**

**Notes:**
The importance of the fimbriae components was confirmed in the household contact study nested in the Sweden 1 pertussis efficacy trial. In addition these results showed that the multiplicity of responses to the pertussis antigens and their interactions contribute to the overall efficacy of the vaccine. When only PT antibody titers were high, efficacy was 46%. If either pertactin or fimbriae were high efficacy was 72 to 75%. When both were high, efficacy was 85%.
[PAUSE]
 The goal of our clinical development program was to demonstrate....

## PENTACEL Clinical Development Program

**Demonstration of safety and immunogenicity**
**Comparison to the standard of care**
**Comparison of 3 consistency lots**
**Concomitant administration of other ****recommended vaccines**
**Comparison ****of a 4****th**** dose ****when administered at ****15 to 16 vs 17 to 18 months of age**
**Immunogenicity of PENTACEL compared to ****Daptacel ****in the ****Sweden I Efficacy Study**

**Notes:**
........the safety and immunogenicity of the combination vaccine, Pentacel, compared to the standard of care and also to the Sweden 1 infant efficacy trial for pertussis, which has shown 85% efficacy against WHO defined pertussis.
In addition, we compared the consistency of 3 Pentacel lots.
Finally, we studied the concomitant administration of Pentacel with hepatitis B, pneumococcal conjugate, MMR and varicella vaccines.
The indication requested is for active immunization against diphtheria, tetanus, pertussis, polio and haemophilus influenza with a four dose series beginning in infants at age 2 months with the 4th dose given between 15 and 18 months of age.

## PENTACEL Clinical Studies for US Licensure†

**Total number of PENTACEL recipients:     ****	****7146**

| Study | Purpose | N | PENTACEL |
| --- | --- | --- | --- |
| P3T06 | PENTACEL vs Standard of Care (SC) (Daptacel, IPOL, ActHIB)  | 1939  | 485  |
| 494-01 | Lot consistency, PENTACEL vs Formulation Equivalent (FE) (HCPDT, Poliovax, ActHIB) | 3538 | 2506 |
| M5A07 | Interaction with Prevnar(Infant Series) | 1166 | 1166 |
| 494-03 | Interaction with Prevnar, MMR and Varivax vaccines (4th Dose)  | 1207 | 1207 |
| 5A9908 | Administration at 15-16 vs 17-18months of age | 1782 | 1782 |

**†****All subjects who received at least one dose**

**Notes:**
ISS: 9.2, ISI: 9.71
We will present data from 5 different clinical studies considered pivotal for US licensure.
The first 2 studies, P3T06 and 494-01, were controlled studies. Study P3T06 compared Pentacel to the standard of care. You will note the abbreviation SC on subsequent slides for this control group. 
 494-01 was the PENTACEL lot consistency study;  it also compared Pentacel to its formulation equivalent components. This control group is abbreviated FE. 
The next 2 studies, M5A07 and 494-03, investigated the lack of interaction after the concomitant administration of Pentacel with Prevnar, MMR and Varivax vaccines.
Study 5A9908 compared the administration of a 4th dose of Pentacel at 15 to 16 versus 17 to 18 months of age.

## Composition of Studied Vaccines

|  |  | Standard of Care (SC) |  |  | Formulation Equivalent (FE) |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Antigen | PENTACEL | Daptacel | IPOL | ActHIB | HCPDT† | Poliovax | ActHIB |
| Diphtheria Toxoid | 15 Lf | 15 Lf |  |  | 15 Lf |  |  |
| Tetanus Toxoid | 5 Lf | 5 Lf |  |  | 5 Lf |  |  |
| PT | 20 μg | 10 μg |  |  | 20 μg |  |  |
| FHA | 20 μg | 5 μg |  |  | 20 μg |  |  |
| PRN | 3 μg | 3 μg |  |  | 3 μg |  |  |
| FIM  | 5 μg | 5 μg |  |  | 5 μg |  |  |
| Poliovirus Type 1 | 40 DAU |  | 40 DAU |  |  | 40 DAU |  |
| Poliovirus Type 2 | 8 DAU |  | 8 DAU |  |  | 8 DAU |  |
| Poliovirus Type 3 | 32 DAU |  | 32 DAU |  |  | 32 DAU |  |
| PRP-T | 10 μg |  |  | 10 μg |  |  | 10 μg |

**†****PENTACEL formulation component**

**Notes:**
The composition of Pentacel compared to the vaccines used in the controlled studies was as follows:
Study P3T06 compared Pentacel to Daptacel, IPOL and Act-HIB, the licensed standard of care vaccines. 
Study 494-01 compared Pentacel to its formulation equivalent components HCPDT, Poliovax, and ActHIB. HCPDT is an unlicensed product, manufactured for this study to match the Pentacel composition and not used in any other setting.

## Overall Summary (Infant Series): Safety and Immunogenicity Populations

|  | Safety |  | Immunogenicity† |  |
| --- | --- | --- | --- | --- |
| Study | PENTACEL | Control | PENTACEL | Control |
| P3T06 | 485 | 1454 | 374 | 1167 |
| 494-01 | 2506 | 1032 | 1136 | 403 |
| 494-03 | 1207 | NA | 274 | NA |
| M5A07 | NA | NA | 886 | NA |
| Total | 4198 | 2486 | 2670 | 1570 |

- Overall Summary (Infant Series): Safety and Immunogenicity Populations

**†****Per-protocol population**

**Notes:**
ISS: 9.2, ISI: 9.2, 9.71
Of the pivotal trials, 3 included both infants and toddlers, P3T06, 494-01 and 494-03.
M5A07 is a recent Prevnar interaction study for which only immunogenicity data in infants were included in the application.
The infant data obtained from these 4 studies provide us with Pentacel safety data in close to 4200 infants and immunogenicity data in almost 2700 infants.
Immunogenicity data were generated in subsets of the studies.
4th dose data ...

## Overall Summary (4th Dose): Safety and Immunogenicity Populations

|  | Safety |  | Immunogenicity† |  |
| --- | --- | --- | --- | --- |
| Study | PENTACEL | Control | PENTACEL | Control |
| P3T06 | 431 | 418 | 371 | 349 |
| 494-01 | 1862 | 739 | 883 | 291 |
| 494-03 | 958 | NA | 819 | NA |
| 5A9908 | 1782 | NA | 735 | NA |
| Total | 5033 | 1157 | 2808 | 640 |

- Overall Summary (4th Dose): Safety and Immunogenicity Populations

**†****Per-protocol population**

**Notes:**
ISS: 9.2, ISI: 9.2
...were collected in more than 5000 toddlers for safety and 2800 for immunogenicity across 4 studies, the 3 previously mentioned that included both infants and toddlers and study 5A9908 a specific toddler study. In total more than 19,000 doses of Pentacel were administered to infants and 6,900 to toddlers in the US licensure trials.
The results of the clinical trials demonstrate...

## PENTACEL Key Findings

**Comparable immunogenicity to standard of care **
**Safety profile similar to separate vaccines **
**Can be given concomitantly with other recommended vaccines**
**In Canada, where PENTACEL was introduced in 1997 and is used universally**
**Invasive Hib disease remains rare**
**Rates of pertussis have decreased among children aged 1-9 years**

**Notes:**
......that Pentacel was safe and well tolerated and achieved a safety and immunogenicity profile similar to that of the current standard of care 
Pentacel can be given simultaneously with hepatitis B, pneumococcal conjugate, MMR and varicella vaccines.
And Pentacel has controlled Hib and pertussis disease in the target population through 9 years of exclusive use in Canada.
(PAUSE)
At this point I would like to...

## PENTACEL - Agenda

| Introduction | Luc Kuykens, MD, MPHVP Regulatory Affairs |
| --- | --- |
| Safety | Luc Kuykens, MD, MPHVP Regulatory Affairs |
| Immunogenicity  | Michael Decker, MD, MPH VP Scientific and Medical Affairs |
| Canadian Post-Marketing Effectiveness | Scott Halperin, MDProfessor of PediatricsDalhousie University, Halifax, Canada |
| US Perspective | David Greenberg, MDDirector Scientific and Medical Affairs |
| Conclusion | Luc Kuykens, MD, MPHVP Regulatory Affairs |

**Notes:**
.....review the clinical safety data of our application

## Safety Objectives

**Compare safety of PENTACEL against safety of control vaccines**
**Assess safety of PENTACEL with or without other recommended vaccines**

**Safety Population: defined as those who had at least 1 scheduled dose of study vaccines**

**Notes:**
The key objectives of the safety assessment were to compare the safety profile of Pentacel to that of the control vaccines
And secondly, to characterize the overall safety profile of Pentacel, given separately or simultaneously with other recommended vaccines.
By every measure, the safety profile of Pentacel was at least comparable to that of its components.
The safety population analyzed consisted of all participants that received at least one dose of vaccine.

## Infant Series and 4th Dose: Safety Profile

**Immediate Reactions **
**30 minutes post-vaccination**
**Solicited Local and Systemic Reactions**
**Non-Serious Unsolicited Adverse Events**
**Events of Special Interest**
**Serious Adverse Events**

**Notes:**
For the remainder of the clinical safety presentation, I will always present infant data first, followed by toddler data for each of the safety parameters.
Immediate reactions were collected for 30 minutes post vaccination.

For all data slides . . . .

## Infant Series: Immediate Reactions 

|  | Controlled Studies |  |  |  |  |  | Non-controlled Studies |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | PENTACEL494-01, P3T06
N=2293 |  | SCN=418 |  | FEN=739 |  | PENTACEL
494-03, 5A9908
N=2740 |  |
|  | n | % | n | % | n | % | n | % |
| Total participants with at least one reaction | 1 | <0.1 | 3 | 0.2 | 1 | 0.1 | 0 | 0.0 |
| 	Urticaria | 1 | <0.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
| 	Allergic reaction | 0 | 0.0 | 1 | 0.1 | 0 | 0.0 | 0 | 0.0 |
| 	Crying | 0 | 0.0 | 1 | 0.1 | 0 | 0.0 | 0 | 0.0 |
| 	Erythema | 0 | 0.0 | 1 | 0.1 | 0 | 0.0 | 0 | 0.0 |
| 	Diarrhea | 0 | 0.0 | 0 | 0.0 | 1 | 0.1 | 0 | 0.0 |
| 	Irritability | 0 | 0.0 | 1 | 0.1 | 0 | 0.0 | 0 | 0.0 |

**Notes:**
...we are presenting Pentacel data from the controlled studies P3T06 and 494-01 to the left,  data from the control groups in the middle, and the PENTACEL data from the non-controlled studies to the right. 
Less than 0.1% of Pentacel recipients and 0.2 % of control vaccines recipients experienced at least one immediate reaction during the Infant Series. 
There were no anaphylactic reactions reported and no reaction was classified as a Serious Adverse Event. All resolved without sequelae.

## 4th Dose: Immediate Reactions

|  | Controlled Studies |  |  |  |  |  | Non-controlled Studies |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | PENTACEL494-01, P3T06
N=2293 |  | SCN=418 |  | FEN=739 |  | PENTACEL
494-03, 5A9908
N=2740 |  |
|  | n | % | n | % | n | % | n | % |
| Total participants with at least one reaction | 2 | 0.1 | 1 | 0.2 | 0 | 0.0 | 31 | 1.1 |
| 	Injection site erythema | 2 | 0.1 | 0 | 0.0 | 0 | 0.0 | 24 | 0.9 |
| 	Injection site bruising | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 2 | 0.1 |
| 	Injection site burning | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1 | <0.1 |
| 	Injection site induration | 0 | 0.0 | 1 | 0.2 | 0 | 0.0 | 1 | <0.1 |
| 	Injection site irritation | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1 | <0.1 |
| 	Local edema upper limb | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1 | <0.1 |
| 	Dermatitis | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1 | <0.1 |
| 	Mottled skin | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1 | <0.1 |
| 	Urticaria | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1 | <0.1 |
| 	Nasopharyngitis | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1 | <0.1 |
| 	Tremor | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1 | <0.1 |

**Notes:**
Ater the 4th dose for the controlled studies, the rates of immediate reactions in Pentacel recipients versus control were similar.
We noticed a higher rate of reactions in one non-controlled study (494-03), however upon further investigation the majority of these were local injection site reactions, of short duration and mild in severity reported as immediate reactions by some investigators.
There were no anaphylactic reactions reported and no reaction was classified as a Serious Adverse Event. All resolved without sequelae.

## Infant Series and 4th Dose: Safety Profile

**Immediate Reactions **
**Solicited Local ****and Systemic**** Reactions**
**Redness, swelling, tenderness, and change in limb circumference (4****th**** dose, only) collected on diary cards,****days 0-7, severity documented**
**Non-Serious Unsolicited Adverse Events**
**Events of Special Interest**
**Serious Adverse Events**

**Notes:**
Solicited local reactions were collected daily on a diary card from days 0 to 7 after vaccination. 
The pre-established list of reactions contained redness, injection site swelling and tenderness, and for the 4th dose, change in limb circumference. 
Information on the severity of these reactions was collected daily.
This allowed us to determine the overall duration of an event and the duration of the most intense portion of the reported event.
On this graph...

## Infant Series: Solicited Local Reactions After PENTACEL, Days 0-7, Any Dose

**0**

**20**

**40**

**60**

**80**

**100**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**Days**

**Percent**

**Notes:**
ISS: 9.39
...... we analyzed the percentage of participants reporting solicited local reactions over time after vaccination. Rates for Pentacel during the Infant Series were only elevated within the first 3 days after vaccination. A similar observation...

## 4th Dose: Solicited Local Reactions After PENTACEL, Days 0-7

- 4th Dose: Solicited Local Reactions After PENTACEL, Days 0-7

**0**

**20**

**40**

**60**

**80**

**100**

**Percent**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**Days**

**Notes:**
ISS: 9.40
....can be made after the 4th dose

## Infant Series: Solicited Local Reactions After PENTACEL, Days 0-3, by Dose

**Tenderness**

**Swelling**

**Redness**

| Any | 5.7  | 4.8  | 4.8  | 5.6  | 3.8  | 2.8  | 44.2  | 36.4  | 37.4  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Mild | 3.9  | 4.0  | 3.9  | 3.2  | 2.8  | 2.1  | 25.6  | 26.2  | 27.3  |
| Moderate | 1.4  | 0.6  | 0.9  | 1.8  | 0.8  | 0.7  | 14.0  | 7.9  | 8.3  |
| Severe | 0.4  | 0.1  | 0.1  | 0.5  | 0.2  | 0.0  | 4.6  | 2.2  | 1.9  |

**5.7**

**4.8**

**4.8**

**5.6**

**3.8**

**2.8**

**44.2**

**36.4**

**37.4**

**0**

**20**

**40**

**60**

**80**

**100**

**Dose 1**

**Percent**

**Dose 2**

**Dose 3**

**Dose 1**

**Dose 2**

**Dose 3**

**Dose 1**

**Dose 2**

**Dose 3**

**Notes:**
ISS: 9.26-9.28
A second question we examined was if there was an increase in local reactogenicity by dose. Importantly, we did not see an increase in local reactogenicity after each subsequent dose in the infant series for local redness, swelling or tenderness.

## Infant Series: Solicited Local Swelling, Days 0-3, Comparison to Controls† by Dose

**†****Percentages are based on the most severe reaction at any of the vaccination sites for the individual control vaccines**

**10**

**20**

**30**

**40**

**50**

**Percent**

**Dose 1**

**Dose 2**

**Dose 3**

**Dose 1**

**Dose 2**

**Dose 3**

**Dose 1**

**Dose 2**

**Dose 3**

**Dose 1**

**Dose 2**

**Dose 3**

**PENTACEL****494-01, P3T06**

**SC**

**Controlled Studies**

**0**

| Any | 5.3 | 3.9 | 2.7 | 6.0 | 5.2 | 7.8 | 7.1 | 4.0 | 3.3 | 6.5  | 3.3  | 3.1 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Mild | 3.2 | 3.1 | 2.0 | 3.6 | 4.3 | 6.5 | 5.8 | 3.4 | 3.0 | 3.3 | 2.1 | 2.3 |
| Moderate | 1.6 | 0.8 | 0.7 | 2.0 | 0.9 | 1.2 | 1.2 | 0.5 | 0.3 | 2.4 | 0.6 | 0.7 |
| Severe | 0.4 | 0.0 | 0.0 | 0.4 | 0.1 | 0.1 | 0.1 | 0.1 | 0.0 | 0.8 | 0.5 | 0.1 |

**3.1**

**3.3 **

**6.5 **

**3.3**

**4.0**

**7.1**

**7.8**

**5.2**

**6.0**

**2.7**

**3.9**

**5.3**

**PENTACEL****494-03**

**FE**

**Notes:**
ISS: 9.26-9.28
I will now review the data for local injection site swelling. The rates for local swelling were similar or lower after Pentacel vaccination compared to control vaccines, both in the infant series...
(brief pause)

## 4th Dose: Solicited Local Swelling, Days 0-3, Comparison to Controls†

**PENTACEL ****494-01, P3T06**

**SC**

**FE**

**PENTACEL ****494-03, 5A9908**

**0**

**10**

**20**

**30**

**40**

**50**

**Percent**

**†****Percentages are based on the most severe reaction at any of the vaccination sites for the individual control vaccines**

| Any | 11.3 | 11.6 | 13.9 | 16.0 |
| --- | --- | --- | --- | --- |
| Mild | 6.9 | 7.7 | 9.2 | 6.6 |
| Moderate | 3.2 | 2.6 | 3.5 | 7.9 |
| Severe | 1.2 | 1.3 | 1.3 | 1.6 |

**16.0**

**13.9**

**11.6**

**11.3**

**Controlled Studies**

**Notes:**
ISS: 9.30
...and also after the 4th dose. Most reactions were mild or moderate.
We reached the same conclusion for local redness and injection site tenderness, data included in the briefing document.
(Pause)

## 4th Dose: Change in Limb Circumference,Days 0-3, Comparison to Control†

**PENTACEL ****494-01, P3T06**

**SC**

**HCPDT**

**PENTACEL ****494-03, 5A9908**

**0**

**10**

**20**

**30**

**40**

**50**

**Percent**

**†****Percentages are based on the most severe reaction at any of the vaccination sites for the individual control vaccines**

| Any | 27.0 | 37.5 | 21.7 | 34.4 |
| --- | --- | --- | --- | --- |
| Mild | 22.3 | 28.2 | 18.5 | 26.6 |
| Moderate | 4.5 | 8.2 | 3.1 | 7.0 |
| Severe | 0.3 | 1.1 | 0.0 | 0.8 |

**34.4**

**21.7**

**37.5**

**27.0**

**Controlled Studies**

**Notes:**
ISS: 9.30
After the toddler dose, we also examined any change in limb circumference. Rates were similar across studies and between Pentacel and control vaccines.

## Infant Series and 4th Dose: Safety Profile

**Immediate Reactions **
**Solicited ****Local and**** Systemic Reactions**
**Fever, less active, crying, fussiness, vomiting, diarrhea, anorexia and rash (presence or absence) collected on diary cards, days 0-7, severity documented **
**Non-Serious Unsolicited Adverse Events**
**Events of Special Interest**
**Serious Adverse Events**

**Notes:**
The pre-established list of solicited systemic reactions contained fever, infant being less active, crying, fussiness, vomiting, diarrhea, anorexia and rash. 
Information on presence and severity of these reactions was collected daily for 7 days on a diary card.
The safety comparison objective for systemic reactions in pivotal trials P3T06 and 494-01 was to demonstrate that Pentacel is non inferior to control vaccines with regard to the proportion of participants reporting any fever.

## Infant Series: Solicited Fever After PENTACEL, Day 0-7, Any Dose

**Notes:**
ISS: 9.44
Increased rates of fever compared to baseline were observed in the first 2 days after vaccination during the infant series, regardless if after Pentacel or control vaccines’ administration.

## Infant Series: Solicited Fever, Days 0-3, Comparison to Controls by Dose

**10**

**20**

**30**

**40**

**50**

**Percent**

**0**

**Mild**

**PENTACEL****494-01, P3T06**

**SC**

**FE**

**PENTACEL****494-03**

**Controlled Studies**

| Any | 7.7 | 13.7 | 18.7 | 9.3 | 16.1 | 15.8 | 13.8 | 15.7 | 20.6 | 11.5  | 16.5  | 18.4 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Mild | 6.2 | 10.4 | 12.9 | 7.7 | 11.8 | 10.7 | 11.5 | 10.8 | 16.0 | 10.0 | 12.7 | 13.9 |
| Moderate | 1.1 | 3.1 | 5.1 | 1.5 | 3.9 | 4.8 | 2.2 | 4.3 | 3.9 | 1.5 | 3.4 | 4.0 |
| Severe | 0.4 | 0.2 | 0.7 | 0.1 | 0.4 | 0.3 | 0.1 | 0.6 | 0.7 | 0.0 | 0.4 | 0.5 |

**Dose 1**

**Dose 2**

**Dose 3**

**Dose 1**

**Dose 2**

**Dose 3**

**Dose 1**

**Dose 2**

**Dose 3**

**Dose 1**

**Dose 2**

**Dose 3**

**18.4**

**16.5 **

**11.5 **

**20.6**

**15.7**

**13.8**

**15.8**

**16.1**

**9.3**

**18.7**

**13.7**

**7.7**

**PENTACEL****494-03**

**Notes:**
ISS: 9.31.9.33
Historically, there has been a concern about increased fever rates associated with combination vaccines as compared to their components during the infant series.
Fever rates observed after the administration  of Pentacel in the Infant Series were generally similar or lower compared to the control groups.  
Fever rates did slightly increase, but the majority of reported fevers were mild or moderate.

## Infant Series: Non-Inferiority of Fever Rates, Days 0-3, 90% CI of Difference (PENTACEL minus Control) by Dose

**Within Limit**

**Outside Limit**

**-10**

**-8**

**0**

**10**

**12**

**14**

**-2**

**2**

**4**

**-4**

**-6**

**6**

**8**

**P3T06**

**Notes:**
Non-inferiority for fever rates in Pentacel recipients in the 2 controlled studies was shown after each dose in the infant series.

## 4th Dose: Solicited Fever After PENTACEL, Days 0-7 

**Notes:**
ISS: 9.45
When looking at fever rates after the 4th dose, the large majority of cases were reported within 2 days after vaccination, similar to the infant series.
Rates of fever...

## 4th Dose: Solicited Fever, Days 0-3,Comparison to Controls

**PENTACEL ****494-01, P3T06**

**SC**

**FE**

**PENTACEL ****494-03, 5A9908**

**0**

**10**

**20**

**30**

**40**

**50**

**Percent**

| Any | 11.2 | 8.7 | 13.1 | 14.5 |
| --- | --- | --- | --- | --- |
| Mild | 8.1 | 5.5 | 9.1 | 9.3 |
| Moderate | 2.5 | 2.4 | 3.5 | 4.3 |
| Severe | 0.6 | 0.8 | 0.5 | 0.8 |

**14.5**

**13.1**

**8.7**

**11.2**

**Controlled Studies**

**Notes:**
ISS: 9.35
....were comparable across Pentacel and control groups. Most episodes of fever were mild or moderate.

## 4th Dose: Non-Inferiority of Fever Rates, Days 0-3, 90% CI of Difference (PENTACEL minus Control)

**Within Limit**

**Outside Limit**

**-10**

**-8**

**0**

**10**

**12**

**14**

**-2**

**2**

**4**

**-4**

**-6**

**6**

**8**

**Notes:**
The upper limit of the 90% CI of the difference in rates of any fever between Pentacel and control was lower than 10 for both controlled studies. The higher rate in P3T06, seen after Pentacel was solely caused by mild fever.  
There were no differences observed between Pentacel and control for the other solicited systemic reactions.  Data were provided in the briefing document.

## Infant Series and 4th Dose: Safety Profile

**Immediate Reactions**
**Solicited Local and Systemic Reactions**
**Non-Serious Unsolicited Adverse Events**
**Any non-serious ****unsolicited ****event, ****days 0-7, ****severity documented**
**Any non-serious**** event requiring healthcare provider contact,**** days 8-60, severity documented**
**Events of Special Interest**
**Serious Adverse Events**

**Notes:**
Non-serious unsolicited adverse events were collected from days 0 to7 after vaccination in the diary cards and during telephone contacts or site visits through day 60 after vaccination for those events requiring a medical contact. 

## Infant Series and 4th Dose: Non-serious Unsolicited Adverse Events

**No difference in rates between PENTACEL ****and control groups for frequently reported ****and rare events**
**Most events were common childhood conditions such as URI, otitis media, teething and nasal congestion**
**Majority assessed as non-related by ****the investigators**

**Notes:**
Overall rates were similar between Pentacel and control groups.
Most non-serious unsolicited adverse events were common childhood conditions, the majority of which were assessed as non-related to vaccination by the investigators.

## Infant Series and 4th Dose: Safety Profile

**Immediate Reactions**
**Solicited Local and Systemic Reactions**
**Non-Serious Unsolicited Adverse Events**
**Events of Special Interest**
**Hypotonic-hyporesponsive episode (HHE), hypotonia, ****non-febrile seizure, febrile seizure, and possible seizure ****collected days 0-60, severity documented**
**Serious Adverse Events**

**Notes:**
Among the Unsolicited adverse events, specific events of special interest were analyzed separately. 
These were hypotonic-hyporesponsive episodes, hypotonias, and seizures
Overall rates were....

## Infant Series: Events of Special Interest, Days 0-7, Comparison to Controls After Any Dose

|  |    P3T06 |  |  |  |    494-01 |  |  |  | 494-03 |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | PENTACELN=485 |  | Standardof CareN=1454 |  | PENTACELN=2506 |  | Formulation EquivalentN=1032 |  | PENTACELN=1207 |  |
|  | n | % | n | % | n | % | n | % | n | % |
| HHE | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
| Hypotonia | 0 | 0.0 | 1 | 0.1 | 3 | 0.1 | 0 | 0.0 | 1 | 0.1 |
| Non-Febrile Seizure  | 0 | 0.0 | 1 | 0.1 | 1 | <0.1 | 1 | 0.1 | 0 | 0.0 |
| Febrile Seizure | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
| Possible Seizure | 0 | 0.0 | 0 | 0.0 | 1 | <0.1 | 0 | 0.0 | 0 | 0.0 |

**Notes:**
ISS: 9.109
.....very low and similar between the Pentacel and control groups wihin seven days during the Infant Series.
There were no reports of HHE or febrile seizures.
Rates of hypotonia, non-febrile and possible seizures were low and comparable between Pentacel and control groups.
After the 4th dose....

## 4th Dose: Events of Special Interest, Days 0-7, Comparison to Control

|  | P3T06 |  |  |  | 494-01 |  |  |  | 494-03 |  | 5A9908 |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | PENTACELN=431 |  | Standard of CareN=418 |  | PENTACELN=1862 |  | Formulation EquivalentN=739 |  | PENTACELN=958 |  | PENTACELN=1782 |  |
|  | n | % | n | % | n | % | n | % | n | % | n | % |
| HHE | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
| Hypotonia | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
| Non-Febrile Seizure | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
| Febrile Seizure | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 2 | 0.3 | 0 | 0.0 | 2 | 0.1 |
| Possible Seizure | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |

**Notes:**
ISS: 9.110
...as seen on this table, no HHE’s, hypotonia’s, non-febrile or possible seizures were reported.
Rates for febrile seizures were similar between Pentacel and control vaccines.

## Infant Series and 4th Dose: Safety Profile

**Immediate Reactions**
**Solicited Local and Systemic Reactions**
**Non-Serious Unsolicited Adverse Events**
**Events of Special Interest**
**Serious Adverse Events**
**Any serious adverse event during the study through Day 60 post-dose 3 or post-dose 4 (Day 180 for P3T06), ****severity documented**

**Notes:**
Serious adverse events were collected during the whole study period and analyzed up to 60 days after each dose. 

## Infant Series: Serious Adverse Events, Days 0-60, Comparison to Control After Any Dose

|  | P3T06 |  |  |  | 494-01 |  |  |  | 494-03 |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | PENTACELN=485 |  | Standard of CareN=1454 |  | PENTACELN=2506 |  | Formulation EquivalentN=1032 |  | PENTACELN=1207 |  |
|  | n | % | n | % | n | % | n | % | n | % |
| Total participants with at least one SAE | 25 | 5.2 | 75 | 5.2 | 38 | 1.5 | 17 | 1.6 | 49 | 4.1 |
| Total participants with at least one related SAE  | 0 | 0.0 | 1 | 0.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |

**Notes:**
ISS: 9.9
Rates were similar between Pentacel and control groups.
All but 1 SAE were considered unrelated to vaccination by the investigator. This one SAE was observed in the control group...

## Infant Series: Related Serious Adverse Events After Any Dose

**No SAEs were reported as related to PENTACEL**
**A 7-week-old female (Study P3T06) experienced non-febrile seizure with apnea 12 hours post-Dose 1 of Daptacel, ActHIB, IPOL. Recombivax and Prevnar were ****co-administered. The event was considered probably related to vaccination**

**Notes:**
...and was a febrile seizure with apnea that occurred 12 hours post dose 1 and was considered probably related. The participant was not hospitalized for this episode and recovered fully without sequelae.

## Infant Series: Deaths

**A total of 3 deaths occurred during the Infant Series:**
**A 2-month-old female (Study 494-03, PENTACEL) died following an automobile accident, 22 days post-Dose 1**
**A 4-month-old male (Study 494-03, PENTACEL) died 52 days post-Dose 1. Cause of death reported as Sudden Infant ****Death Syndrome**
**An 8-month-old female (Study P3T06, SC) developed symptoms 54 days post-Dose 3 and was diagnosed with ependymoma. Death occurred 222 days post-Dose 3; primary cause of death reported as aspiration**
**All deaths were considered unrelated to vaccination**

**Notes:**
There were three deaths reported across the US licensure trials in infants. All were considered unrelated to vaccination. One was a case of a car accident 22 days after vaccination with Pentacel, one was a SIDs 52 days after vaccination with Pentacel, and 1 was a case of ependymoma diagnosed 54 days post-vaccination with control vaccines in study P3T06. 

## 4th Dose: Serious Adverse Events

|  | P3T06 |  |  |  | 494-01 |  |  |  | 494-03 |  | 5A9908 |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | PENTACELN=431 |  | Standard of CareN=418 |  | PENTACELN=1862 |  | FormulationEquivalentN=739 |  | PENTACELN=958 |  | PENTACELN=1782 |  |
|  | n | % | n | % | n | % | n | % | n | % | n | % |
| 0-60 days | 9 | 2.1 | 7 | 1.7 | 7 | 0.4 | 4 | 0.5 | 11 | 1.1 | 29 | 1.6 |
| 61-180 days | 9† | 2.1 | 2 | 0.5 | NA |  | NA |  | NA |  | NA |  |

**No SAEs were reported as related to PENTACEL or Control vaccines**

**†****Upper respiratory infections (3), congenital malformations (2), reaction to antibiotic, reaction to insect bite, post-infection cerebellar ataxia, seizure**

**Notes:**
P3T06 SII: 9.10
All SAE’s reported after the 4th dose were considered not related to vaccination by the investigators.
In the controlled studies, rates of SAE’s were similar between groups in the first 2 months after vaccination.
The 9 SAE’s in Study P3T06 occurring  between 2 and 6 months post-vaccination were mainly upper respiratory infections and pre-existing congenital malformations. 

## 4th Dose: Deaths

**One death occurred after Day 60 of the Infant Series and before the administration of the 4****th**** dose**
**A 9-month-old male (Study 494-01, PENTACEL) developed symptoms 95 days post-Dose 3.  Subject was later diagnosed with neuroblastoma, which eventually led to death 256 days post-Dose 3**
**One death occurred after administration of the 4th dose**
**A 15-month-old male (Study P3T06, PENTACEL) died 9 days post-Dose 4. Cause of death reported as suffocation**
**Both deaths were considered unrelated to vaccination**

**Notes:**
Two deaths were reported around the 4th dose of the pivotal studies. 
The first occurred between the infant series and toddler dose. It was a case of neuroblastoma first diagnosed in a 9 month old male leading to his death at age 15 months.
The second was a case of suffocation 9 days after the 4th dose of Pentacel. 
Both deaths were considered unrelated to vaccination.

In addition to the valuable clinical data collected. . . 

## Canadian Post-Marketing Safety Experience with PENTACEL 

**Notes:**
. . .we have access to extensive post-marketing safety data through the exclusive use of Pentacel in Canada for more 9 years.

## Canadian Post-Marketing Safety Experience 

**Introduced in May 1997, exclusively used ****since 1998**
**More than 12 million doses distributed**
**Similar dosing schedule as proposed for US**
**Passive surveillance data from spontaneous reports to sanofi pasteur**

**Notes:**
Pentacel was introduced in Canada in May 1997 and has been used exclusively since 1998. Approximately 12.5 million doses have been administered, using a schedule similar to the US.
Post-marketing data from passive surveillance has inherent limitations including under reporting and lack of denominator data. However, such systems are very valuable in detecting safety signals for clinically significant events.

## Canadian Post-Marketing Safety Experience: Reported Events 

**288 reports received from May 1997 through April 2006**
**221 were non-serious**
**Most commonly reported adverse events were injection site reactions **

**Notes:**
From May 1997 through April 2006, 288 reports were received. 
Most reports received, 221, were non-serious.  67 were reported as serious adverse events. 
The most commonly reported Adverse Event was an injection site reaction. In addition...

## Post-marketing Experience: Most Frequently Reported Adverse Events Following PENTACEL Vaccination

| MedDRA AE Preferred Term1 | Number of AEs 2 |
| --- | --- |
| Injection site reaction | 65 |
| Pyrexia | 64 |
| Crying | 51 |
| Injection site inflammation | 35 |
| Irritability | 31 |
| Urticaria | 25 |
| Vomiting | 24 |
| Rash | 20 |
| Convulsion3 | 19 |
| Injection site mass | 16 |

**1****MedDRA coding dictionary version 9.0****2****AE: adverse event. Includes both medically-confirmed and consumer cases****3****Includes MedDRA PT terms of Convulsion, Febrile convulsion, Status epilepticus and Convulsion local**

**Notes:**
...other frequently reported adverse events were in line with what has been observed in the controlled clinical trials and did not indicate any unexpected safety signal.

## Distribution of Spontaneously Reported Events of Special Interest*

| Total reports received 
N=288** | Post-
Dose 1 | Post-
Dose 2 | Post-
Dose 3 | Post-
Dose 4 | Post-
Any Dose |
| --- | --- | --- | --- | --- | --- |
|  | n | n | n | n | n |
| HHEs1,4 | 8 | 4 | 0 | 0 | 12 |
| All Seizures2,4  | 3 | 6 | 2 | 8 | 19 |
| Febrile Seizures4  | 0 | 0 | 0 | 2 | 2 |
| Encephalopathy4 | 1 | 1 | 0 | 1 | 3 |
| Fatal Reports3,4 | 10 | 1 | 0 | 3 | 14 |

*** For the period 1 May 1997 and 30 April 2006.******Medically-confirmed and consumer reports****1****Reported as HHE, or where the symptoms reported corresponded to the definition used for an HHE****2****MedDRA PT terms of Convulsion, Febrile convulsion, Status epilepticus and Convulsion local****3****Includes SIDS, Death Due to Unknown cause, and Death Due to Known Cause****4****For instances where dose information was not provided, the dose number was assumed based on the patient’s age and the latency to the event.**

**Notes:**
We did also analyze the same categories of events of special interest as studied in the clinical trials.
The number of reported events of HHE, seizures and deaths over a period of 9 years were low and well below the number of expected cases based on the literature for such events.

## Safety Conclusions

**Safety profile of PENTACEL is similar to that of the separate administration of standard of care vaccines (Daptacel, IPOL, and ActHIB) or formulation-equivalent component vaccines (HCPDT, Poliovax, and ActHIB) **
**PENTACEL is safe when administered alone or concomitantly with other age-recommended vaccines**
**No unexpected safety signals were identified in the Canadian post-marketing safety experience, which confirms conclusions from clinical trials**

**Notes:**
In conclusion,
In clinical trials, Pentacel was safe and well tolerated among infants and toddlers and its safety profile was similar to the standard of care vaccines.
As demonstrated by the data presented in the briefing doucment, Pentacel can be given either simultaneously or separately from hepatitis B, pneumo conjugate, MMR or varicella vaccines.
The safety profile of Pentacel in Canada where more than 12.5 million doses have been distributed since 1997 confirms the data from the clinical trials.
PAUSE
At this point I would like to invite Dr. Michael Decker to the podium. Michael will review the immunogenicity data of our studies.

## PENTACEL - Agenda

| Introduction | Luc Kuykens, MD, MPHVP Regulatory Affairs |
| --- | --- |
| Safety | Luc Kuykens, MD, MPHVP Regulatory Affairs |
| Immunogenicity  | Michael Decker, MD, MPH VP Scientific and Medical Affairs |
| Canadian Post-Marketing Effectiveness | Scott Halperin, MDProfessor of PediatricsDalhousie University, Halifax, Canada |
| US Perspective | David Greenberg, MDDirector Scientific and Medical Affairs |
| Conclusion | Luc Kuykens, MD, MPHVP Regulatory Affairs |

**Notes:**
Thank you Dr. Kuykens.  I’m Dr. Michael Decker and I will review for you the immunogenicity data from the Pentacel licensure file. 

## Immunological Endpoints and Analyses

**Geometric Mean Titers (GMT)**
**A primary endpoint for all antigens**
**4-Fold Rise (from pre-Dose 1)**
**A primary endpoint for pertussis antigens**
**Seroprotection (********post-Dose threshold)**
**A primary endpoint for Diphtheria, Tetanus, Hib, Polio**
**Vaccine Response (********cutoff point and ********baseline)**
**All pertussis antigens**
**Reverse Cumulative Distribution Curves (RCDC)**
**All antigens**
**Serological bridge to efficacy**
**All pertussis antigens**

**Notes:**
There are a number of different types of data that I can review with you.  We will be looking at geometric mean titers, which are normalized averages of antibody levels, and those are primary endpoints for all the antigens.  We’ll look at four-fold rises, which are the proportion of persons whose postimmunization antibody level is at least four times the preimmunization antibody level, and that is a primary endpoint for the pertussis antigens.  We’ll look at seroprotection rates for those antigens with predefined seroprotection levels, which includes diphtheria, tetanus, HIB and polio, and that’s the proportion of participants whose postimmunization antibody levels at least achieve those predefined thresholds.  We’ll look at vaccine response rates for the pertussis antigens.  For pertussis antigens, no seroprotective levels are defined but the vaccine response rate is an analogous measure for the pertussis antigens.  For all the antigens, we have available reverse cumulative distribution curves, which are graphical displays of the range of antibody levels in the entire population.  And then, we’ll look at the data for the serological bridge to efficacy for the pertussis antigens – a bridge between the antibody data from the U.S. kids in the licensing trials versus the Swedish kids in the Swedish efficacy trial. 

## Immunogenicity Presentation Sequence 

**Pertussis Immunogenicity**
**Hib (PRP) Immunogenicity**
**Diphtheria and Tetanus Immunogenicity**
**Polio Immunogenicity**
**Co-Administration with Other Licensed Vaccines**

**Notes:**
We’ll look at the data in the following order.  First, pertussis, then HIB, then diphtheria and tetanus, then polio, and finally, coadministration of Pentacel with other licensed vaccines. 

## P3T06: PENTACEL vs US Standard of Care Vaccines Study Characteristics

**Multi-center, randomized, controlled, ****open-label study**** **
**1939 infants **
**Vaccinated at 2, 4, 6, and 15-16 months of age**
**PENTACEL vaccine (n=484) vs Daptacel (3 lots), IPOL, ActHIB (n=1455)**
**All subjects received concomitant Recombivax HB ****and Prevnar**
**Objective**
**Demonstrate non-inferiority of PENTACEL vs US****standard of care vaccines Daptacel, IPOL, ActHIB**

**Notes:**
So, let’s begin with Study P3T06.  This was a multicenter randomized controlled open label study in nearly 2000 infants who were vaccinated at 2, 4, 6 and 15 to 16 months of age with either Pentacel or with the U.S. licensed standard of care regimen – Daptacel, IPOL and ActHIB.  About one-quarter of the kids received Pentacel, and each of the remaining three-quarters received one of three different lots of Daptacel, because this was also a Daptacel lot consistency trial. 
All the subjects received hepatitis B vaccine at birth, 2 and 6 months of age, and most received Prevnar at 2, 4 and 6 months of age. 

## P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 3: Pertussis GMTs

| PENTACEL | 90.0 | 73.7 | 36.1 | 268.2 |
| --- | --- | --- | --- | --- |
| Control | 63.8 | 29.2 | 43.3 | 267.2 |

**Notes:**
Now, I’m going to show you a number of slides that look like this.  A graphical display of the pertussis antibody results.  We’ve got four pairs of two bars each.  In each pair, the blue bar is Pentacel, the yellow bar is the antibody results of the kids that received Daptacel, IPOL and ActHIB.  The four bars represent PT, FHA, and pertactin in the left hand graph on the scale shown to the left; and then FIM in the right hand graph on the scale shown to the right.  And, always below these graphs we have a table that shows the actual numerical results.  So, here we’re looking at the post-dose three GMTs for pertussis, and what you see is that for PT and FHA, the antibody levels are higher for the Pentacel group, for FIM they’re the same, for pertactin they are a little bit higher than the Daptacel group. 

## P3T06: PENTACEL vs US Standard of Care VaccinesPost-Dose 3: Pertussis 4-Fold Rise Rates

| PENTACEL | 93.6 | 81.9 | 74.2 | 91.7 |
| --- | --- | --- | --- | --- |
| Control | 86.1 | 60.9 | 75.4 | 86.3 |

**0**

**20**

**40**

**60**

**80**

**100**

**PT**

**FHA**

**PRN**

**FIM**

**Percent**

**Notes:**
Here are the four-fold rise rates.  They are pretty similar across the four antigens, somewhat higher for Pentacel and PT and FHA. 

## P3T06: PENTACEL vs US Standard of Care VaccinesPost-Dose 3: Pertussis Non-Inferiority Comparisons

**Non-inferiority is based on 90% confidence intervals.**

**Notes:**
I’m going to show you a number of figures that look like this.  These are graphical displays of the results of the statistical non-inferiority testing.  Along the left axis we have arrayed the names of the evaluations being made.  To the right, we have a vertical line that shows the limited non-inferiority, and that aligns with 1.5 on the white X-axis scale, a GMT ratio of 1.5, but also aligns with 10% on the yellow X-axis scale, which is a difference in rates; for example, in seroprotection rates of 10%.  Then each comparison is shown with a horizontal bar within the figure, a tick mark showing the point estimate, and it’s the value of that point estimate numerically over it, and then the 90 or the 95% confidence limit, whichever was predefined, shown by the extent of the bar.  If the whole bar lies to the left of, or if there are two limits within the two limits, then the statistical test is met.  As you see here, where all 12 of these comparisons passed non-inferiority. 

## P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 4: Pertussis GMTs

| PENTACEL | 174.0 | 107.9 | 93.6 | 553.4 |
| --- | --- | --- | --- | --- |
| Control | 168.5 | 64.0 | 186.1 | 513.5 |

**0**

**40**

**80**

**120**

**160**

**200**

**PT**

**FHA**

**PRN**

**0**

**100**

**200**

**300**

**400**

**500**

**600**

**FIM**

**GMT (EU/mL)**

**GMT (EU/mL)**

**Notes:**
Now, here are the GMTs following the fourth dose given to toddlers; somewhat higher for Pentacel for FHA, somewhat higher for the Daptacel group for pertactin, pretty similar in the two groups for PT and FIM. 

## P3T06: PENTACEL vs US Standard of Care VaccinesPost-Dose 4: Pertussis 4-Fold Rise Rates

| PENTACEL | 97.4 | 88.4 | 92.7 | 93.5 |
| --- | --- | --- | --- | --- |
| Control | 97.1 | 79.3 | 98.3 | 91.6 |

**0**

**20**

**40**

**60**

**80**

**100**

**Percent**

**PT**

**FHA**

**PRN**

**FIM**

**Notes:**
Four-fold rise rates – are really pretty similar across all four comparisons. 

## P3T06: PENTACEL vs US Standard of Care VaccinesPost-Dose 4: Pertussis Non-Inferiority Comparisons

**Non-inferiority is based on 90% confidence intervals.**

**Notes:**
And, here are the results of the statistical non-inferiority testing.  Non-inferiority was met for 11 of the 12 comparisons.  It was not met for the comparison of pertactin GMTs, where the point estimate was 2.0 versus a limit of 1.5. 

## P3T06: PENTACEL vs US Standard of Care VaccinesPost-Dose 4: 4-Fold Rise Responses to Multiple Pertussis Antigens

| PENTACEL | 0.9 | 99.1 | 98.2 | 94.3 | 79.8 |
| --- | --- | --- | --- | --- | --- |
| Control | 0.4 | 99.6 | 98.7 | 94.8 | 73.3 |

**None**

**Any 1 of 4**

**Any 2 of 4**

**Any 3 of 4**

**All 4**

**0**

**20**

**40**

**60**

**80**

**100**

**Percent**

**Notes:**
Because the Canadian five component vaccine used in Daptacel, Pentacel and so on is a multicomponent vaccine, and each component is believed to contribute to the protective benefit of the vaccine, it’s relevant to ask what proportion of the children responded to one component, to two, to three, or to all four components.  This slide compares the answer to that question for the Pentacel group and the group receiving Daptacel, IPOL and ActHIB.  And, you see the results are very similar across all five comparisons here, with the exception that a somewhat higher proportion of the kids receiving Pentacel responded to all four antigens.  I say four antigens – by the way, because FIM2 and FIM3 are co-determined in the assay.  So, for the serological results, we just show four.  A higher proportion of the Pentacel kids responded to all four antigens. 

## PENTACEL Bridge to EfficacyP3T06 vs Sweden I Efficacy Trial

- PENTACEL Bridge to EfficacyP3T06 vs Sweden I Efficacy Trial

**NIH-sponsored efficacy trial in Sweden 1992-1995**
**Infants received Daptacel at 2, 4, 6 months of age**
**85% efficacy vs WHO-defined classic pertussis**
**78% efficacy vs any pertussis (lab-confirmed, ********1 day of cough)**
**Pertussis antibody levels in Sweden I Efficacy Trial were compared to those following 4 doses of PENTACEL in US pivotal trials P3T06 and 494-01**
**Sera from P3T06, 494-01 and the Sweden I Efficacy Trial were tested contemporaneously in same laboratory, under same conditions, using the same validated assay**

**Notes:**
I mentioned this serological bridge to efficacy.  From 1992 to 1995 the NIH sponsored a prospective randomized comparative efficacy trial in Sweden that evaluated several acellular pertussis vaccines, including Daptacel, which was administered at 2, 4 and 6 months of age.  After two years followup, the study showed 85% efficacy of Daptacel against WHO-defined, classic pertussis – whooping cough; and 78% efficacy against pertussis – lab-confirmed pertussis of any severity, having at least one day of cough.  Serum was drawn from some of the participants in the Swedish efficacy trial and the antibody levels among those Swedish children was compared to the antibody levels among the U.S. children in the clinical trials P3T06 and 49401.  The Swedish sera and the sera from the U.S. trials were tested contemporaneously in the same lab, under the same conditions, and using the same validated assay. 

## P3T06: PENTACEL vs Sweden I (Bridge to Efficacy) GMTs

| PENTACEL | 174.0 | 107.9 | 93.6 | 553.4 |
| --- | --- | --- | --- | --- |
| Sweden I | 87.5 | 40.7 | 111.3 | 339.3 |

**0**

**40**

**80**

**120**

**160**

**200**

**PT**

**FHA**

**PRN**

**0**

**100**

**200**

**300**

**400**

**500**

**600**

**FIM**

**GMT (EU/mL)**

**GMT (EU/mL)**

**Notes:**
In blue here we have the results from the Pentacel recipients in Study P3T06.  In green we have the results from the Swedish participants in the Sweden efficacy trial.  And, what you see here is that the results for Pentacel in the U.S. kids are substantially higher for PT, FHA and FIM, a little bit lower for pertactin. 

## P3T06: PENTACEL vs Sweden I (Bridge to Efficacy) Non-Inferiority Analyses

**Non-inferiority is based on 90% confidence intervals for GMTs and VR; 95% for 4-fold rise.**

**Notes:**
Here are the results of the statistical non-inferiority testing – 11 of the 12 comparisons were met.  The four-fold rise rate comparison for pertactin was borderline – with the upper bound just crossing the non-inferiority limit. 

## 494-01: Lot ConsistencyPENTACEL vs Control

**Multi-center, randomized, controlled, open-label ****lot-consistency study**
**3538 infants **
**Vaccinated at 2, 4, 6, and 15 months of age**
**PENTACEL (3 lots, n=2506) vs HCPDT, Poliovax, ActHIB given separately (n=1032)**
**All subjects received concomitant Recombivax HB**
**Most subjects received concomitant Prevnar**
**Objectives**
**Lot consistency**
**Non-inferiority**

**Notes:**
Study 49401 was a multicenter randomized controlled and open label lot consistency trial involving over 3500 infants who were vaccinated at 2, 4, 6 and 15 months of age.  Sixty-percent of these infants received one of three lots of Pentacel and 40% received HCPDT, which is the DTAP component of Pentacel.  It’s not a standalone vaccine anywhere in the world.  Poliovax, which is the poliovirus component of Pentacel – this is a licensed vaccine, but it’s not used as a standalone vaccine anywhere in the world, only as a component of the Canadian combination vaccines, and ActHIB given separately.  All the subjects also received hepatitis B vaccine at birth, 2 and 6 months of age, and most of the subjects received concomitant Prevnar. 

## 494-01: Lot Consistency, Post-Dose 3, Pertussis 

**Lot consistency is based on 90% confidence intervals.**

**Notes:**
As I mentioned, the primary purpose of the study was a lot consistency trial.  Here are the results of the 36 lot consistency comparisons, and lot consistency was met for all comparisons. 

## 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 3: Pertussis GMTs

| PENTACEL | 99.7 | 76.2 | 39.6 | 270.3 |
| --- | --- | --- | --- | --- |
| Control | 84.5 | 69.2 | 38.6 | 246.0 |

**0**

**20**

**40**

**60**

**80**

**100**

**PT**

**FHA**

**PRN**

**FIM**

**0**

**50**

**100**

**150**

**200**

**250**

**300**

**GMT (EU/mL)**

**GMT (EU/mL)**

**Notes:**
The study also involved, as I mentioned, the comparison between Pentacel and its constituent components given separately.  Here are the pertussis results following the first three doses given in infancy.  We see that the results are very similar across the two groups, a little bit higher for the Pentacel groups for PT, FHA and FIM, essentially identical for pertactin.  Here are the four-fold rise rates – essentially identical all the way across. 

## 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 3: Pertussis 4-Fold Rise Rates

| PENTACEL | 90.3 | 80.3 | 73.2 | 86.2 |
| --- | --- | --- | --- | --- |
| Control | 89.7 | 78.0 | 78.6 | 87.0 |

**0**

**20**

**40**

**60**

**80**

**100**

**Percent**

**PT**

**FHA**

**PRN**

**FIM**

**Notes:**
And, the results of the statistical non-inferiority testing. 

## 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 3: Pertussis Non-Inferiority Analyses

**Non-inferiority is based on 90% confidence intervals.**

**Notes:**
Criteria were met for all comparisons. 

## 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 4: Pertussis GMTs

| PENTACEL | 202.2 | 134.6 | 94.9 | 514.2 |
| --- | --- | --- | --- | --- |
| Control | 188.6 | 128.3 | 129.9 | 350.3 |

**0**

**25**

**50**

**75**

**100**

**125**

**150**

**175**

**200**

**225**

**0**

**50**

**100**

**150**

**200**

**250**

**300**

**350**

**400**

**450**

**500**

**550**

**GMT (EU/mL)**

**PT**

**FHA**

**PRN**

**FIM**

**GMT (EU/mL)**

**Notes:**
Following the toddler dose, we see the comparisons here.  PT and FHA very similar between the Pentacel recipients and the recipients of the separately-administered constituent components; higher for Pentacel for FIM; higher for the components for pertactin. 

## 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 4: Pertussis 4-Fold Rise Rates

| PENTACEL | 95.4 | 90.2 | 89.3 | 91.3 |
| --- | --- | --- | --- | --- |
| Control | 94.4 | 86.3 | 92.8 | 87.9 |

**0**

**20**

**40**

**60**

**80**

**100**

**Percent**

**PT**

**FHA**

**PRN**

**FIM**

**Notes:**
Four-fold rise rates were very essentially identical all the way across. 

## 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 4: Pertussis Non-Inferiority Analyses

**Non-inferiority is based on 90% confidence intervals.**

**Notes:**
And, here are the results of the statistical non-inferiority testing; 11 of the 12 comparisons met non-inferiority, the GMT comparison for pertactin was borderline. 

## 494-01: PENTACEL vs Sweden I (Bridge to Efficacy) GMTs

- 494-01: PENTACEL vs Sweden I (Bridge to Efficacy) GMTs

**0**

**40**

**80**

**120**

**160**

**200**

**0**

**100**

**200**

**300**

**400**

**500**

**600**

**GMT (EU/mL)**

**GMT (EU/mL)**

**PT**

**FHA**

**PRN**

**FIM**

| PENTACEL | 195.1 | 129.9 | 90.8 | 506.6 |
| --- | --- | --- | --- | --- |
| Sweden I | 87.5 | 40.7 | 111.3 | 339.3 |

**Notes:**
This is the bridge to efficacy now for the 49401 participants, shown in blue are the Pentacel recipients in that study; shown in green again are the Sweden 1 kids.  And, what you see is that the responses to PT, FHA and FIM were substantially higher than in the kids who received Pentacel, response to pertactin was a little bit higher in the kids in the Sweden 1 efficacy trial, who had received Daptacel. 

## 494-01: PENTACEL vs Sweden I (Bridge to Efficacy) 4-Fold Rise Rates

| PENTACEL | 94.9 | 91.7 | 89.2 | 91.5 |
| --- | --- | --- | --- | --- |
| Sweden I | 86.3 | 68.8 | 98.8 | 86.3 |

**0**

**20**

**40**

**60**

**80**

**100**

**Percent**

**PT**

**FHA**

**PRN**

**FIM**

**Notes:**
Four-fold rise rates follow a similar pattern, but the differences are less. 

## 494-01: PENTACEL vs Sweden I (Bridge to Efficacy) Non-Inferiority Analyses

**Non-inferiority is based on 90% confidence intervals for GMTs and VR; 95% for 4-fold rise.**

**Notes:**
And, here are the results of the statistical non-inferiority comparisons.  Eleven of the 12 comparisons met non-inferiority.  The one that did not was four-fold rise rate for pertactin.  Now, if the postimmunization GMTs are similar, but the four-fold rise rates are not, that suggests that the difference lies in the pre-titers.  So, seeing these results, we looked at that – and what we found was that the...

## 494-01: PENTACEL vs Sweden I (Bridge to Efficacy) Box Plot of 2-Month Baseline PRN Antibody Levels

**Notes:**
... pre-titers in the U.S. group included a number of persons with elevated titers, as compared to the Sweden 1 group.  In fact, if you draw a cutoff around 20 ELISA units, what you find is that there is only one kid in the Swedish cohort who had a value higher than that and it is only slightly above that.  Whereas there is nearly a dozen in the U.S. cohort who had titers higher than that.  If these values are removed, the four-fold rise non-inferiority is met.  So, from this we conclude that the difference in four-fold rise rates doesn’t reflect the performance of the vaccine – actually, the kids with these values ended up with quite high rises – just three-fold instead of four-fold, it rather reflects a difference in the distribution of pre-antibody titers. 

## PENTACEL Post-Dose 4 vs Sweden I RCDCs: PT

**PENTACEL, P3T06**
**PENTACEL, M5A07**
**PENTACEL, 494-01**
**PENTACEL, 494-03**
**PENTACEL, 5A9908**
**Daptacel, SWEDEN I**

**Notes:**
This is a reverse cumulative distribution curve – a graphical display of the antibody distribution in the entire population; on the Y-axis you’ve got arrayed the proportion of subjects who have some given antibody level; along the X-axis, the antibody level that they have.  And then, the curve connects the point.  So, for example – 100% of the participants have at least one unit of antibody, no one has 10,000 units of antibody.  Shown in the heavy white line is the PT antibody distribution in the Sweden 1 cohort, the kids who received Daptacel in that efficacy trial.  Shown in the thin colored lines are the various U.S. licensure trials for Pentacel for their PT antibody results.  And, what you see here is that all of the U.S. trials have got antibody distribution curves that are very similar – close together, quite parallel, and all of them exceed – or in the terminology used for these graphs, dominate the curve for Sweden 1. 

## PENTACEL Post-Dose 4 vs Sweden I RCDCs: FHA

**PENTACEL, P3T06**
**PENTACEL, M5A07**
**PENTACEL, 494-01**
**PENTACEL, 494-03**
**PENTACEL, 5A9908**
**Daptacel, SWEDEN I**

**Notes:**
Those are the results for PT. Here are the results for FHA. 

## PENTACEL Post-Dose 4 vs Sweden I RCDCs: PRN

**PENTACEL, P3T06**
**PENTACEL, M5A07**
**PENTACEL, 494-01**
**PENTACEL, 494-03**
**PENTACEL, 5A9908**
**Daptacel, SWEDEN I**

**Notes:**
Pertactin.  The results bracket the Sweden 1 curve. 

## PENTACEL Post-Dose 4 vs Sweden I RCDCs: FIM

**FIM Antibody (EU/mL)**

**PENTACEL, P3T06**
**PENTACEL, M5A07**
**PENTACEL, 494-01**
**PENTACEL, 494-03**
**PENTACEL, 5A9908**
**Daptacel, SWEDEN I**

**Notes:**
And, FIM.

## 5th Dose Follow-up Studies to 494-01, P3T06:  P3T10 and P3T11 (Studies Currently Underway)

**Both studies were multi-center, randomized, ****open-label**
**Solicited all PENTACEL or Daptacel recipients in P3T06 and 494-01 to participate**
**Sample size for pertussis immunogenicity**
**259 in P3T10**
**363 in P3T11 (89 primed with PENTACEL, ****274 primed with Daptacel)**
**Blood obtained for serology immediately prior to 5****th**** dose**

**Notes:**
Now, the children who participated in P3T06 and 49401, of course, have continued to grow and right now they are at the age where it’s appropriate to give them their fifth dose of acellular pertussis vaccine, given normally preschool ages 4 to 6.  So, we’ve organized two studies – P3T10 and P3T11 to follow these children up and to enroll them in fifth dose studies.  We solicited all the kids who participated in 49401 and in P3T06 to participate.  Blood was obtained prior to giving this fifth dose, and although these two studies are currently underway, we now have the results for that pre-fifth dose bleed, which of course represents the persistence of antibody following the toddler dose. 

## Percent Seropositive* at Pre-Dose 5, By Study and Pertussis Antigen

***********LOQ: PT, 5;  FHA, 3;  PRN, 3;  FIM, 17 **

**75.3**

**89.6**

**89.6**

**77.6**

**74.2**

**74.2**

**87.6**

**68.5**

**58.8**

**59.3**

**95.3**

**54.7**

**Percent ******** LOQ**

**0**

**20**

**40**

**60**

**80**

**100**

**PT**

**FHA**

**PRN**

**FIM**

**Notes:**
So, here are those results.  The left hand bar, the blue bar and the middle bar represent the Pentacel recipients in the two studies.  The yellow bar represents the Daptacel recipients.  And, what you see is that the persistence of antibody is at least as good for the Pentacel recipients as it is for the Daptacel recipients, with quite high proportions still having detectable antibody at ages 4 to 6 years. 

## Immunogenicity Presentation Sequence 

**Pertussis Immunogenicity**
**Hib (PRP) Immunogenicity**
**Diphtheria and Tetanus Immunogenicity**
**Polio Immunogenicity**
**Co-Administration with Other Licensed Vaccines**

**Notes:**
Let me turn now to the HIB antibody results. 

## P3T06: PENTACEL vs US Standard of Care VaccinesPost-Doses 3 and 4: Hib Seroprotection Rates 

| PENTACEL | 92.3 | 72.1 | 97.8 |
| --- | --- | --- | --- |
| Control | 93.3 | 70.8 | 95.9 |

**Percent**

**Post-Dose 4**

**Post-Dose 3**

**0**

**20**

**40**

**60**

**80**

**100**

******0.15 ****μg/mL**

******1.0 ****μg/mL**

******1.0 ****μg/mL**

**Notes:**
We’ll start again with Study P3T06.  These HIB slides are organized so that on this first slide I’m showing you the proportion achieving predefined seroprotective levels.  Post-dose three we have two levels we compare to, to the furthest left  0.15 mcg/mL, and then in the middle of the graph the proportion who are at least 1.0 mcg/mL post-dose three, and then to the right, the proportion who are at least 1.0 post-dose four.  Again, in blue are the Pentacel recipients, in yellow are the kids who received the U.S. licensed standard of care vaccines – Daptacel, IPOL and ActHIB.  And, you see the proportion seroprotected – both at the end of the infant series and after the toddler dose, are essentially identical in the two groups. 

## P3T06: PENTACEL vs US Standard of Care VaccinesPost-Doses 3 and 4: Hib GMTs 

| PENTACEL | 2.31 |  | 17.71 |
| --- | --- | --- | --- |
| Control | 2.29 |  | 20.49 |

**GMT (μg/mL)**

**Post-Dose 3**

**Post-Dose 4**

**0**

**1**

**2**

**3**

**0**

**5**

**10**

**15**

**20**

**25**

**GMT (μg/mL)**

**Notes:**
Here are the geometric mean titers – to the left following the first three doses given in infancy; to the right following the fourth dose given to toddlers.  Identical GMTs after the infant series, and very high GMTs – very similar, after the toddler booster; 18 in the Pentacel group and 20 in the separate vaccines group. 

## P3T06: Non-inferiority Testing of Hib Seroprotection Rates (Control-PENTACEL) and GMT Ratios (Control/PENTACEL)

**% ********0.15 ****μg/mL**

**% ********1.0 ****μg/mL**

**% ********1.0 ****μg/mL**

**Notes:**
All non-inferiority comparisons were met. 

## 494-01: Lot Consistency, Post-Dose 3: Hib

- 494-01: Lot Consistency, *Post-Dose 3*: Hib

**Lot consistency is based on 90% confidence intervals.**

**Notes:**
49401, you recall, was primarily a lot consistency study.  Here are the lot consistency results for the HIB component; 8 of the 9 lot consistency comparisons met predefined criteria; one was borderline. 

## 494-01: GMTs and Seroprotection Rates, PENTACEL Lots at Post-Dose 3: Hib

- 494-01: GMTs and Seroprotection Rates, PENTACEL Lots at *Post-Dose 3*: Hib

**0**

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

**3.0**

**3.5**

**4.0**

**GMT (****μ****g/mL)**

**0**

**20**

**40**

**60**

**80**

**100**

**Percent**

**94.5**

**78.5**

**95.0**

**77.2**

**96.7**

**81.7**

******0.15 ****μ****g/mL**

******1.0 ****μ****g/mL**

**3.1**

**2.9**

**3.6**

**Notes:**
Here are the data that lie behind that statistical test.  It was this comparison between these two lots here that was borderline.  But you see for those two lots, seroprotection rates were very high, really quite similar. 

## 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Doses 3 and 4: Hib Seroprotection Rates 

| PENTACEL | 95.4 | 79.1 | 98.2 |
| --- | --- | --- | --- |
| Control | 98.3 | 88.8 | 99.0 |

**0**

**20**

**40**

**60**

**80**

**100**

**Percent**

******0.15 ****μg/mL**

******1.0 ****μg/mL**

**Post-Dose 3**

**Post-Dose 4**

******1.0 ****μg/mL**

**Notes:**
Here are the comparisons between the Pentacel recipients and the recipients of the separate licensed or unlicensed components – constituent components of Pentacel, post-dose three and post-dose four.  Seroprotection rates essentially identical between the two groups. 

## P3T06 and 494-01: Comparison of Hib GMTs Post-Doses 3 and 4

| PENTACEL |  | 3.19 |
| --- | --- | --- |
| Control |  | 6.23 |

**PENTACEL**

**Control**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**494-01**

**Post-Dose 3**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**494-01**

**Post-Dose 4**

|  | 24.12 |
| --- | --- |
|  | 35.90 |

**GMT (****μ****g/mL)**

**GMT (****μ****g/mL)**

**Notes:**
Here are the geometric mean titers, and you’ll see here that the geometric mean titers in the group who received the separate constituent components are substantially higher than in the group that received Pentacel. 

## P3T06 and 494-01: Comparison of Hib GMTs Post-Doses 3 and 4

| PENTACEL | 2.31 | 3.19 |
| --- | --- | --- |
| Control | 2.29 | 6.23 |

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**P3T06**

**494-01**

**GMT (****μ****g/mL)**

**P3T06**

**494-01**

| 17.71 | 24.12 |
| --- | --- |
| 20.49 | 35.90 |

**GMT (****μ****g/mL)**

**Post-Dose 3**

**Post-Dose 4**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**Notes:**
This was very interesting, because as you see – the Pentacel group achieved GMTs that equaled or exceeded both the Pentacel and the separate U.S. licensed standard of care vaccines in Study P3T06; but nonetheless the group receiving HCPDT, Poliovax and ActHIB given separately were higher yet. 

## 494-01: Non-inferiority Testing of Hib Seroprotection Rates (Control-PENTACEL) and GMT Ratios (Control/PENTACEL)

**Non-inferiority is based on 90% confidence intervals.**

**Notes:**
Accordingly, the non-inferiority criteria were met for the seroprotection rates at 0.15 after post-dose three and 1.0 post-dose four, but not met for the other comparisons. 

## P3T06 and 494-01: Comparison of Hib GMTs Post-Doses 3 and 4

| PENTACEL | 2.31 | 3.19 |
| --- | --- | --- |
| Control | 2.29 | 6.23 |

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**P3T06**

**494-01**

**GMT (****μ****g/mL)**

**P3T06**

**494-01**

| 17.71 | 24.12 |
| --- | --- |
| 20.49 | 35.90 |

**GMT (****μ****g/mL)**

**Post-Dose 3**

**Post-Dose 4**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**Notes:**
This was very interesting, because as you see – the Pentacel group achieved GMTs that equaled or exceeded both the Pentacel and the separate U.S. licensed standard of care vaccines in Study P3T06; but nonetheless the group receiving HCPDT, Poliovax and ActHIB given separately were higher yet. 

## US and Canadian PENTACEL Licensure Trials: Post-Dose 3: Hib GMTs by Trial

**PENTACEL Studies: 494-01, P3T06, M5A07, 494-03, M5A03, PB9502, PB9601****ActHIB Studies: P3T07, 494-01, P3T06, PB9502**

**Notes:**
Now, when we received these results, it put us in a quandary because we had no context in which to understand or analyze these results.  As I mentioned, HCPDT is not a licensed vaccine; it is not used anywhere in the world.  In fact, the regimen of HCPDT, Poliovax and ActHIB given separately is not used anywhere in the world, nor has it every been studied in any other study by us or anyone else.  So, it makes it very hard to interpret what’s going on with these elevated antibody responses in the group receiving the separate constituent components.  To try to understand this, we looked at our data in a number of ways.  What you’re seeing here is one way to look at this.  Those of us who have been doing HIB studies for a long time know that HIB results have tended more than most of their antibody results, to be variable, to see different HIB results in different studies.  What you see on this graph are all of the U.S. and Canadian licensure trials HIB results.  To the left, the results for kids receiving Pentacel; to the right,  the results for those who received the controlled vaccines whether separately licenses vaccines or separate components.  And, what you see is there is a substantial variation from 2 to 7 in the Pentacel group from 2 to 6 in the separate vaccines group.  The range of results is virtually identical in the two, and the distribution is virtually identical.  49401 is a high outlier, if you will, in the separate vaccines group, but there is a similar result for a Pentacel group in a different study. 

## US and Canadian PENTACEL Licensure Trials: Post-Dose 4: Hib GMTs by Trial

- US and Canadian PENTACEL Licensure Trials: *Post-Dose 4: *Hib GMTs by Trial

**494-01**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**45**

**GMT (****μ****g/mL)**

**PENTACEL**

**ActHIB**

**Notes:**
The slide I just showed you is post-dose three.  We see the same thing post-dose four.  Very similar distribution of antibody results between the Pentacel recipients historically in all the trials we’ve done, and the separate vaccines or separate components groups. 

## P3T06: Hib GMTs by Study Site (10 Subjects), Post-Dose 3

**PENTACEL**

**ActHIB**

**GMT (****μ****g/mL)**

**Notes:**
The variability that we see in HIB results is really illustrated I think on this slide.  You recall that in Study P3T06, the HIB results for the Pentacel recipients as compared to the recipients of Daptacel, IPOL, ActHIB given separately, were identical.  This was a multicenter nationwide study, and here what you see is the distribution of GMTs by center, including only those centers with at least 10 participants, so the GMTs are reasonably stable.  And, you see an enormous variation from 1 to 6 – a six-fold variation in the results.  You see it for the Pentacel recipients, you see it for the ActHIB recipients.  Now, you might think – well, okay – but at one site we’ve got this result and this result, and these two numbers probably came from the same site, and these two numbers came from the same site, and so on; but that’s not the case. 

## P3T06: Hib GMTs by Study Site Post-Dose 3: PENTACEL vs Control by Site

**Shows only sites with ********10 PENTACEL subjects per group**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**PENTACEL**

**ActHIB**

**GMT (****μ****g/mL)**

**Notes:**
Here, you see the dots connected.  Most of the HIB studies in the literature, particularly the ones done in the 1980s and early 1990s when these vaccines were first getting going, are fairly small studies.  The number of kids in each study is about similar to the number of kids that are given at a single site for some of our sites.  Had we done P3T06 or 49401 just at this site, you’d have one impression about the comparative immunogenicity of Pentacel versus separately administered ActHIB.  If we’d done it at this site, you’ve have the opposite impression; because we did it at many sites – you know that the results are the same.  Is this the explanation for what’s going on with 49401?  I don’t know.  It shouldn’t be.  But, I don’t know. 

## Hib GMTs at Post-Dose 3, By Study

- Hib GMTs at *Post-Dose 3*, By Study

**4.4**

**7.1**

**3.2**

**2.8**

**2.3**

**3.0**

**3.5**

**3.8**

**6.2**

**2.3**

**3.0**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**PENTACEL**

**Control**

**GMT (****μ****g/mL)**

**PB9502**

**PB9601**

**494-01**

**494-03**

**P3T06**

**M5A03**

**M5A07**

**494-01**

**P3T06**

**P3T07**

**PB9502**

**Notes:**
Here’s another way to look at the entire body of data that we have concerning Pentacel’s performance as compared to separate vaccines.  These are all of the U.S. and Canadian licensure trials – in blue for Pentacel, in yellow for the separate vaccines or separate components, arrayed in chronological order.  So, the earliest studies are to the left, the most recent studies are to the right.  And, you can see not only the magnitude, but the temporal pattern of the results.  This is HIB GMTs post-dose three.  And, you see that the range and the pattern of results is very similar between Pentacel and separate components or separate vaccines.  Post-dose three...

## Hib GMTs at Pre-Dose 4, By Study

**0.42**

**0.60**

**0.38**

**0.31**

**0.56**

**0.29**

**0.30**

**0.37**

**0.56**

**0.25**

**0.25**

**0.50**

**0.75**

**1.00**

**GMT (****μ****g/mL)**

**Control**

**0.32**

**PB9502**

**PB9601**

**5A9908**

**494-01**

**494-03**

**P3T06**

**M5A03**

**PB9502**

**494-01**

**P3T06**

**M5A07**

**PENTACEL**

**0**

**Notes:**
...pre-dose four...

## Hib GMTs at Post-Dose 4, By Study

**10**

**20**

**30**

**40**

**30.1**

**PB9502**

**39.8**

**PB9601**

**32.5**

**5A9908**

**24.1**

**494-01**

**36.7**

**494-03**

**17.7**

**P3T06**

**25.6**

**M5A03**

**27.1**

**PB9502**

**35.9**

**494-01**

**20.5**

**P3T06**

**GMT (****μ****g/mL)**

**24.1**

**M5A07**

**Control**

**PENTACEL**

**0**

**Notes:**
...post-dose four, and at age 4 to 6 years pre-dose five. 

## Hib GMTs at Pre-Dose 5, By Study

- Hib GMTs at *Pre-Dose 5*, By Study

**2.06**

**1.48**

**1.39**

**GMT (****μ****g/mL)**

**0**

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

**2.52**

**ActHIB**

**TD508**

**P3T10**

**P3T11**

**PENTACEL**

**Control**

**Notes:**
Pentacel compares vary favorably to separate vaccines for the HIB GMTs. 

## Hib Seroprotection (1.0 μg/mL) at Post-Dose 3, By Study

**84.7**

**95.5**

**79.1**

**75.6**

**72.1**

**78.5**

**78.4**

**88.9**

**88.8**

**70.8**

**75.7**

**Percent**

**0**

**20**

**40**

**60**

**80**

**100**

**PB9502**

**PB9601**

**494-01**

**494-03**

**P3T06**

**M5A03**

**M5A07**

**494-01**

**P3T06**

**P3T07**

**PB9502**

**PENTACEL**

**Control**

**Notes:**
HIB seroresponse rates are perhaps more important than GMTs and they tend to be less variable.  If we look at those though, we see exactly the same pattern post-dose three...

## Hib Seroprotection (0.15 μg/mL) at Pre-Dose 4, By Study

- Hib Seroprotection (0.15 μg/mL) at *Pre-Dose 4*, By Study

**75.4**

**84.8**

**73.0**

**68.6**

**83.8**

**65.4**

**67.7**

**73.1**

**80.8**

**60.7**

**69.1**

**PB9502**

**PB9601**

**5A9908**

**494-01**

**494-03**

**P3T06**

**M5A03**

**PB9502**

**494-01**

**P3T06**

**M5A07**

**Percent**

**0**

**20**

**40**

**60**

**80**

**100**

**Control**

**PENTACEL**

**Notes:**
...pre-dose four...

## Hib Seroprotection (1.0 μg/mL) at Post-Dose 4, By Study

- Hib Seroprotection (1.0 μg/mL) at *Post-Dose 4*, By Study

**99.0**

**100.0**

**98.8**

**98.2**

**99.1**

**97.8**

**97.3**

**100.0**

**99.0**

**95.9**

**97.9**

**Percent**

**0**

**20**

**40**

**60**

**80**

**100**

**PB9502**

**PB9601**

**5A9908**

**494-01**

**494-03**

**P3T06**

**M5A03**

**PB9502**

**494-01**

**P3T06**

**M5A07**

**Control**

**PENTACEL**

**Notes:**
...post-dose four, and pre-dose five. 

## Hib Seroprotection (≥0.15 μg/mL) at Pre-Dose 5, By Study

**96.5**

**91.7**

**94.3**

**P3T11**

**0**

**20**

**40**

**60**

**80**

**100**

**98.4**

**TD508**

**P3T10**

**P3T11**

**PENTACEL**

**Control**

**Percent**

**Notes:**
Now, one other way we thought to compare Pentacel and U.S. standard of care results for HIB was to look at two studies called P3T07 and M5A07.  Virtually identical studies, except one involved Pentacel and one involved Daptacel. 

## P3T07: Daptacel+IPOL+ActHIB - No Concomitant Prevnar M5A07: PENTACEL - No Concomitant Prevnar Post-Dose 3: Hib Seroprotection Rates and GMTs

**≥****0.15 ****μ****g/mL**

**≥****1.0 ****μ****g/mL**

| PENTACEL | 95.3 | 79.6 | 3.6 |
| --- | --- | --- | --- |
| Daptacel, IPOL, ActHIB | 93.5 | 73.2 | 2.7 |

**0**

**1**

**2**

**3**

**4**

**5**

**0**

**20**

**60**

**80**

**100**

**40**

**Percent**

**GMT (****μ****g/mL)**

**Notes:**
They were conducted during overlapping periods of time at overlapping sites throughout the United States – sometimes even the same site.  P3T07 was a Daptacel post-marketing commitment trial designed to investigate whether there was any interference or interaction between Prevnar and Daptacel.  M5A07 was exactly the same study designed to look for interaction between Prevnar and Pentacel, but it was conducted pre-licensure as part of the BLA.  So, what we’ve done here is we’ve taken the kids from P3T07 and M5A07 who did not get Prevnar at the same time as their Pentacel or their Daptacel and put them on this slide, and on the next slide taking the kids who did get Prevnar at the same time and compared them.  So, the blue bars here are Pentacel recipients who did not get Prevnar with the Pentacel.  The yellow bars are the Daptacel recipients who did not get Prevnar with the Daptacel.  And, you see the HIB responses are very similar across the two groups – indeed perhaps a little bit better for the Pentacel recipients than the Daptacel recipients. 

## P3T07: Daptacel+IPOL+ActHIB - with Concomitant Prevnar M5A07: PENTACEL - with Concomitant Prevnar Post-Dose 3: Hib Seroprotection Rates and GMTs

| PENTACEL, Prevnar | 95.8 | 77.1 | 3.3 |
| --- | --- | --- | --- |
| Daptacel, IPOL, ActHIB, Prevnar | 94.4 | 80.3 | 3.8 |

**0**

**1**

**2**

**3**

**4**

**5**

**0**

**20**

**60**

**80**

**100**

**40**

**Percent**

**≥****0.15 ****μ****g/mL**

**≥****1.0 ****μ****g/mL**

**GMT (****μ****g/mL)**

**Notes:**
And, similarly for the kids who did receive Prevnar with their product at the same time – very similar results across the two groups. 

## PENTACEL vs Standard of CarePost-Dose 3: Hib RCDCs

**Hib Antibody (****μg/mL)**

**Notes:**
Finally, the reverse cumulative distribution curves for the HIB antibody for all the U.S. licensure trials as compared to the U.S. standard of care – separately administered Daptacel, IPOL and ActHIB, you see that the RCD curves for the Pentacel recipients are very uniform – parallel, closely clustered, and all equal or superior to the curve for the U.S. standard of care. 

## Immunogenicity Presentation Sequence 

**Pertussis Immunogenicity**
**Hib (PRP) Immunogenicity**
**Diphtheria and Tetanus Immunogenicity**
**Polio Immunogenicity**
**Co-Administration with Other Licensed Vaccines**

**Notes:**
Turning now to diphtheria and tetanus immunogenicity. 

## P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 3: Diphtheria, Tetanus Seroprotection Rates

| PENTACEL | 100.0 | 98.8 | 100.0 | 99.7 |
| --- | --- | --- | --- | --- |
| Control | 100.0 | 98.5 | 100.0 | 100.0 |

******0.01 IU/mL**

******0.1 IU/mL**

**Diphtheria**

**Tetanus**

******0.01 IU/mL**

******0.1 IU/mL**

**0**

**20**

**40**

**60**

**80**

**100**

**Percent**

**Notes:**
The left two pairs of bars are diphtheria, the right two pairs are tetanus, within each group the first pair of bars looks at seroprotection against a cutoff of 0.01, the second pair against 0.1.  In blue, the Pentacel; in yellow, the Daptacel, IPOL and ActHIB recipients – and it looks identical. 

## P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 4: Diphtheria, Tetanus Seroprotection Rates

| PENTACEL | 100.0 | 96.5 | 100.0 | 92.9 |
| --- | --- | --- | --- | --- |
| Control | 100.0 | 95.7 | 100.0 | 99.4 |

******0.1 IU/mL**

******1.0 IU/mL**

**Diphtheria**

**Tetanus**

******0.1 IU/mL**

******1.0 IU/mL**

**0**

**20**

**40**

**60**

**80**

**100**

**Percent**

**Notes:**
That was post-dose three.  Here’s post-dose four.  Same result. 

## 494-01: PENTACEL vs HCPDT, Poliovax, ActHIBPost-Dose 3: Diphtheria, Tetanus Seroprotection Rates

| PENTACEL | 99.8 | 92.1 | 100.0 | 99.9 |
| --- | --- | --- | --- | --- |
| Control | 99.7 | 92.2 | 100.0 | 100.0 |

******0.01 IU/mL**

******0.1 IU/mL**

**Diphtheria**

**Tetanus**

******0.01 IU/mL**

******0.1 IU/mL**

**0**

**20**

**40**

**60**

**80**

**100**

**Percent**

**Notes:**
49401 – post-dose three... 

## 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 4: Diphtheria, Tetanus Seroprotection Rates

| PENTACEL | 100.0 | 95.5 | 100.0 | 93.4 |
| --- | --- | --- | --- | --- |
| Control | 99.7 | 95.1 | 100.0 | 98.6 |

**0**

**20**

**40**

**60**

**80**

**100**

**Percent**

******0.1 IU/mL**

******1.0 IU/mL**

**Diphtheria**

**Tetanus**

******0.1 IU/mL**

******1.0 IU/mL**

**Notes:**
...post-dose four. 

## PENTACEL Non-inferiority, P3T06 and 494-01:Diphtheria and Tetanus Seroprotection Rates

**Non-inferiority is based on 90% confidence intervals.**

**% ********0.1 ****IU/mL**

**% ********0.01 ****IU/mL**

**% ********0.1 ****IU/mL**

**% ********0.01 ****IU/mL**

**% ********0.1 ****IU/mL**

**% ********0.01 ****IU/mL**

**% ********0.1 ****IU/mL**

**% ********0.01 ****IU/mL**

**% ********0.1 ****IU/mL**

**% ********0.01 ****IU/mL**

**% ********0.1 ****IU/mL**

**% ********0.01 ****IU/mL**

**% ********0.1 ****IU/mL**

**% ********0.01 ****IU/mL**

**% ********0.1 ****IU/mL**

**% ********0.01 ****IU/mL**

**Notes:**
All non-inferiority comparisons met criteria. 

## Immunogenicity Presentation Sequence 

**Pertussis Immunogenicity**
**Hib (PRP) Immunogenicity**
**Diphtheria and Tetanus Immunogenicity**
**Polio Immunogenicity**
**Co-Administration with Other Licensed Vaccines**

**Notes:**
For polio...

## P3T06 and 494-01: PENTACEL vs ControlPolio Seroprotection Rates (1:8)

| PENTACEL | 99.4 | 100.0 | 100.0 | 99.7 | 100.0 | 100.0 | 100.0 | 100.0 | 100.0 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Control | 100.0 | 100.0 | 100.0 | 100.0 | 100.0 | 100.0 | 100.0 | 100.0 | 100.0 |

**Polio 1**

**Polio 2**

**Polio 3**

**0**

**20**

**40**

**60**

**80**

**100**

**Percent**

**Polio 1**

**Polio 2**

**Polio 3**

**Polio 1**

**Polio 2**

**Polio 3**

**494-01 Post-Dose 3**

**494-01 Post-Dose 4**

**P3T06 Post-Dose 3**

**Notes:**
We have a rate here – all the results on one slide.  Three pairs of bars in each section for the three serotypes of polio.  The first three pairs of bars are P3T06 post-dose three, the middle three pairs of bars – 49401 post-dose three, the last three pairs of bars – 49401 post-dose four.  Seroprotection is uniformly high, nearly 100% or 100% for all the comparisons.  All non-inferiority criteria were met.

## PENTACEL Non-inferiority, P3T06 and 494-01:Polio Seroprotection Rates

**Polio 1 % ********1:8**

**Polio 2 % ********1:8**

**Polio 3 % ********1:8**

**Polio 1 % ********1:8**

**Polio 2 % ********1:8**

**Polio 3 % ********1:8**

**Polio 1 % ********1:8**

**Polio 2 % ********1:8**

**Polio 3 % ********1:8**

- PENTACEL Non-inferiority, P3T06 and 494-01:Polio Seroprotection Rates

**Non-inferiority is based on 90% confidence intervals.**

**Notes:**
Finally, coadministration of Pentacel with other licensed vaccines. 

## Immunogenicity Presentation Sequence 

**Pertussis Immunogenicity**
**Hib (PRP) Immunogenicity**
**Diphtheria and Tetanus Immunogenicity**
**Polio Immunogenicity**
**Co-Administration with Other Licensed Vaccines**

**Notes:**
Most of this information is in the briefing documents.  In the interest of time, I can’t show it all to you, but I’ll show you selected results for Prevnar, which is perhaps the most interesting. 

## P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 3: Pneumococcal Seroprotection Rates

| PENTACEL | 100.0 | 98.1 | 92.5 | 81.0 | 99.7 | 94.4 | 100.0 | 96.3 | 100.0 | 98.1 | 97.5 | 94.7 | 98.1 | 92.8 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Control | 100.0 | 98.9 | 91.4 | 80.7 | 99.3 | 96.7 | 99.3 | 97.4 | 99.5 | 97.8 | 97.9 | 95.6 | 96.9 | 91.3 |

**0**

**20**

**40**

**60**

**80**

**100**

******0.15**

******0.50**

**4**

**6B**

**9V**

**14**

**18C**

**19F**

**23F**

**Percent**

******0.15**

******0.50**

******0.15**

******0.50**

******0.15**

******0.50**

******0.15**

******0.50**

******0.15**

******0.50**

******0.15**

******0.50**

**Notes:**
Here’s Study P3T06.  As you recall, these kids received Prevnar at the same time as their Pentacel or their Daptacel, IPOL and ActHIB.  Shown on this slide are the antibody responses to the Prevnar – 7 components, each component evaluated at two cutoffs – 0.15 and 0.50.  In blue, the Pentacel; and in yellow, the Daptacel, IPOL, ActHIB. 

## 494-03: Co-Administration With Other Recommended Vaccines

**Multi-center, randomized, open-label study**
**PENTACEL 4****th**** dose****†**** given at 15 to 16 months of age concomitantly with, or separately from, MMR, Varivax, and Prevnar**
**Only 4****th**** dose data are presented (n=958)**
**Objective: **
**Determine the effect of PENTACEL on ****co-administered vaccines**

**†****PENTACEL was previously administered at 2, 4, and 6 months of age**

**Notes:**
Prevnar makes the same amount of antibody whether you give it with Daptacel, IPOL and ActHIB, or you give it with Pentacel.  This is post-dose three.  We’ll come to post-dose four here in Study 49403, which looks at the same question – following the toddler dose. 

## 494-03: Effect of PENTACEL on Concomitant VaccinesPrevnar 4th Dose

| PENTACEL+Prevnar | 100.0 | 98.7 | 97.4 | 95.5 | 100.0 | 98.7 | 100.0 | 99.4 | 100.0 | 98.7 | 100.0 | 97.4 | 98.7 | 95.5 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| MMR+Varivax+Prevnar | 100.0 | 99.4 | 99.4 | 97.5 | 100.0 | 99.4 | 100.0 | 100.0 | 99.4 | 98.7 | 99.4 | 96.2 | 98.7 | 95.6 |

**0**

**20**

**40**

**60**

**80**

**100**

******0.15**

******0.50**

**4**

**6B**

**9V**

**14**

**18C**

**19F**

**23F**

**Percent**

******0.15**

******0.50**

******0.15**

******0.50**

******0.15**

******0.50**

******0.15**

******0.50**

******0.15**

******0.50**

******0.15**

******0.50**

**Notes:**
And, we see that whether you get Prevnar with your Pentacel, or the Prevnar is given separately from the Pentacel, the Prevnar makes the same amount of pneumo-antibody either way. 

## M5A07: PENTACEL+Prevnar vs PENTACELPost-Dose 3: Pertussis GMTs

**0**

**25**

**50**

**75**

**100**

**125**

**150**

**0**

**50**

**100**

**150**

**200**

**250**

**300**

**PT**

**FHA**

**PRN**

**FIM**

**GMT (EU/mL)**

**GMT (EU/mL)**

- M5A07: PENTACEL+Prevnar vs PENTACEL*Post-Dose 3:* Pertussis GMTs

| PENTACEL+Prevnar | 103.6 | 82.4 | 45.7 | 272.5 |
| --- | --- | --- | --- | --- |
| PENTACEL | 102.8 | 77.8 | 44.3 | 281.0 |

**Notes:**
M5A07, I’ve already mentioned to you, was designed to look more completely at the possible interaction between Pentacel and Prevnar.  So, here we see that the kids who received Pentacel with Prevnar – shown in blue, have exactly the same antibody responses as the kids who received Pentacel with no Prevnar, shown in white. 

## M5A07: PENTACEL+Prevnar vs PENTACELPost-Dose 4 Pertussis GMTs

**0**

**40**

**80**

**120**

**160**

**200**

**0**

**100**

**200**

**300**

**400**

**500**

**GMT (EU/mL)**

**GMT (EU/mL)**

**PT**

**FHA**

**PRN**

**FIM**

| PENTACEL+Prevnar | 189.7 | 116.2 | 98.2 | 456.3 |
| --- | --- | --- | --- | --- |
| PENTACEL | 189.3 | 107.6 | 93.3 | 486.9 |

**Notes:**
That was post-dose three.  We see it again post-dose four.  The FDA briefing document – by the way, mentioned that the post-dose four M5A07 results were not available and raised a number of questions about the possible interpretation of the Canadian epidemiology, because Canada was not using Prevnar; but you see here that those questions are mute because those data, which just became available, show that Prevnar has no impact on Pentacel. 

## M5A07: PENTACEL+Prevnar vs PENTACELPost-Dose 3: Hib Seroprotection Rates and GMTs 

| PENTACEL+Prevnar | 95.8 | 77.1 |
| --- | --- | --- |
| PENTACEL | 95.3 | 79.6 |

| 3.32 |
| --- |
| 3.60 |

**0**

**20**

**40**

**60**

**80**

**100**

******0.15 ****μ****g/mL **

******1.0 ****μ****g/mL**

**Percent**

**GMT (μg/mL)**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**Notes:**
With respect to HIB, we see the same thing.  Post-dose three – same HIB performance whether or not Prevnar is given at the same time.  Post-dose four – same performance. 

## M5A07: PENTACEL+Prevnar vs PENTACEL Post-Dose 4: Hib Seroprotection Rates and GMTs

- M5A07: PENTACEL+Prevnar vs PENTACEL *Post-Dose 4*: Hib Seroprotection Rates and GMTs

******1.0 ****μ****g/mL**

| PENTACEL+Prevnar | 97.7 |
| --- | --- |
| PENTACEL | 98.2 |

**0**

**20**

**40**

**60**

**80**

**100**

**Percent**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

| 21.7 |
| --- |
| 26.7 |

**GMT (μg/mL)**

**Notes:**
GMTs are very high in the post-dose four group. 

## Overall Immunogenicity Conclusions

**PENTACEL efficacy against Pertussis can be concluded based on favorable serological comparison to the ****Sweden I Efficacy Trial **
**PENTACEL produced Pertussis GMTs and seroresponse rates comparable to those seen with separately administered vaccines **
**Good similarity of responses demonstrated across all the US licensure trials (RCDCs)**
**Good antibody persistence up to 4-6 years of age**
**PENTACEL produced Diphtheria, Tetanus, and Poliovirus seroprotection rates comparable to those seen with separately administered vaccines**

**Notes:**
So, based on all these data, we conclude that Pentacel produced pertussis GMTs and seroresponse rates comparable to those seen with separately-administered vaccines.  There was a good similarity of Pentacel responses demonstrated across all the U.S. licensure trials, as shown by the reverse cumulative distribution curves.  Pentacel’s efficacy against pertussis can be concluded – based on the favorable serological comparison to the Sweden 1 efficacy trial.  There is very good antibody persistence up to 4 to 6 years of age, and Pentacel’s diphtheria, tetanus and poliovirus seroprotection rates compare favorably to those seen with separately-administered vaccines. 

## Overall Immunogenicity Conclusions

**PENTACEL produced Hib GMTs and seroprotection ****rates that were:**
**Comparable to separately administered US standard of ****care vaccines**
**Similar across the full range of PENTACEL studies**
**Very high following the 4****th**** dose**
**Persisted into the pre-school booster age **
**PENTACEL can be co-administered with other routinely recommended infant and toddler vaccines**
**With respect to immune responses, PENTACEL is a suitable replacement for separately administered Daptacel, IPOL, and ActHIB**

**Notes:**
With respect to HIB, Pentacel produced HIB, GMTs and seroprotection rates that were comparable to separately-administered U.S. licensed standard of care vaccines, GMTs and seroprotection rates that were similar across the full range of Pentacel studies and very high following the fourth dose, antibody levels for HIB persisted well into the preschool booster age.  Pentacel can be co-administered with other routinely recommended infant and toddler vaccines.  And so, with respect to immune responses, Pentacel is a suitable replacement for separately administered Daptacel, IPOL and ActHIB.  I’d like to ask Dr. Scott Halperin now to come to the podium and discuss with you the Canadian epidemiology data. 

## PENTACEL - Agenda

| Introduction | Luc Kuykens, MD, MPHVP Regulatory Affairs |
| --- | --- |
| Safety | Luc Kuykens, MD, MPHVP Regulatory Affairs |
| Immunogenicity  | Michael Decker, MD, MPH VP Scientific and Medical Affairs |
| Canadian Post-Marketing Effectiveness | Scott Halperin, MDProfessor of Pediatrics Dalhousie University, Halifax, Canada |
| US Perspective | David Greenberg, MDDirector Scientific and Medical Affairs |
| Conclusion | Luc Kuykens, MD, MPHVP Regulatory Affairs |

**Notes:**
Thank you Dr. Decker.  
The results from the clinical trials are compelling.  
However, clinical trial data can only tell part of the story.
In Canada, we have real-world experience that proves the safety and effectiveness of Pentacel.
Over the past 8 years, universal of use of Pentacel has controlled invasive Hib disease and pertussis. 

## Canadian Post-Marketing Experience

**Licensed May 1997**
**Introduced nationally 1997-1998**
**Universal and exclusive use**
**As of April 2006, more than 12 million doses**
**Canadian schedule: 2, 4, 6, and 18 months**
**Quadracel (DTaP-IPV; PENTACEL without Hib) at 4-6 years**

**Notes:**
Pentacel vaccine was licensed in Canada in May, 1997 and it was introduced nationally between July 1997 and April 1998
Pentacel is used universally and exclusively throughout Canada, where it is administered at 2, 4, 6, and 18 months of age
Quadracel, which is Pentacel without the Hib component, is administered at 4 to 6 years of age 
To date, over 12 million doses of Pentacel have been safely administered in Canada  
Serious events, such as seizures, HHEs, and SIDS, are rarely reported, and occur at rates below those observed in studies of whole-cell or other acellular pertussis vaccines
In addition, epidemiologic data demonstrate that Pentacel has controlled Hib and pertussis 

## Pertussis Incidence Rates, Canada, 1924 – 2000

**Source: Canadian Immunization Guide, 6****th**** ed., 2005:169.**

## Age-specific Rates of Pertussis, Canada, 1988 – 2005†

**†****Provisional data for 2003-2005.**
**Source: http://dsol-smed.hc-sc.gc.ca/dsol-smed/ndis/c_time_e.html and Notifiable Diseases Reporting System, Public Health Agency of Canada**

**Year**

**0**

**50**

**100**

**150**

**200**

**250**

**300**

**Rate per 100,000**

**88**

**90**

**92**

**94**

**96**

**98**

**00**

**02**

**04****†**

** ****PENTACEL Introduced**

**Notes:**
As in the US, the highest rates of pertussis have consistently occurred among infants less than 1 year of age in Canada
The majority of cases in this age group occur in infants less than 6 months of age, those too young to complete the infant vaccine series 
The next two curves represent children 1 to 4 and 5 to 9 years of age.  
Incidence rates of pertussis classically peak every 3-4 years.  Historically, this has been true in Canada, just as in other countries.  
We had peaks in 1990, 1993 to 1995 and 1998.  
Since the last peak in 1998, the rates among children aged 1 to 4 years decreased 84% and the rate among children aged 5 to 9 years decreased 89%.
Note that no peak was observed when expected in 2001 or 2002 based on the classic 3 to 4 year cycle.  Even as recently as 2004, no increase of cases had been seen.
The decline of pertussis cases in these age groups and the interruption of the usual cycling can be attributed to the introduction of Pentacel and Quadracel in 1997.  
Quadracel, that is, Pentacel but without the Hib component, is given as a booster dose at 4-6 years of age.

## Canadian IMPACT Surveillance Network

**12 pediatric hospitals throughout Canada**
**90% of tertiary care pediatric beds **
**Referrals from all provinces and territories**
**Children from birth through 16 years of age**
**Surveillance conducted by nurse monitor at each site**

## Annual Number of Hospitalized Cases of Pertussis, IMPACT Centers, 1993 – 2005

**Source: Bettinger et al., 6th Canadian Immunization Conference, Montreal, Quebec, Dec 5-8, 2004.****Bettinger et al., Pediatr Infect Dis J. 2007;26:31-5.**

**PENTACEL Era**

**PENTACEL Introduction**

**Whole Cell Era**

** ****PENTACEL****Used Nationally**

**0**

**50**

**100**

**150**

**200**

**250**

**300**

**350**

**93**

**94**

**95**

**96**

**97**

**98**

**99**

**00**

**01**

**02**

**03**

**04**

**05**

**Year**

**Number of Cases **

**Notes:**
Pertussis surveillance data were collected by the same investigators in the Canadian IMPACT hospital network, as described earlier for Hib.  
The period of 1993 to 1997 was called the whole-cell vaccine era and the period of 1998 to 2003 was called the acellular vaccine era.  
The period of time when Pentacel and Quadracel vaccines were being introduced, province-by-province, was called the transitional year, and the data from this period were not included in the analyses 
The annual number of children with pertussis, hospitalized in IMPACT centers, declined 41% during the acellular era relative to the whole-cell era.  
The 41% decline was associated with improved control of pertussis by Pentacel and Quadracel vaccines compared with the whole-cell vaccine we used previously

## Number of Pertussis Cases by Age Group, Northwest Territories

**Age (years)**

**Number of Cases **

**10**

**20**

**30**

**40**

**50**

**< 1**

**1-4**

**5-9**

**0**

**Source: Kandola K, et al. *****Can J Infect Dis Med Microbiol.***** 2005;16:271-4.**

**Notes:**
In addition to the national and IMPACT data, there are data available from a surveillance study conducted by Dr. Kandola in the Northwest Territories 
The distribution of pertussis cases during 1993 to 1996, when whole-cell pertussis vaccine was used, serves as the baseline
About 20 to 35 cases were reported in each of the age groups
After Pentacel was introduced a decline of cases was seen in these age groups

## Incidence of Invasive Hi* Disease in Children Aged <5 Years, Canada, 1989 – 2005

**Data for 2003-2005 are provisional.**
**Source: Public Health Agency of Canada, 2006.**
***Not all *****Haemophilus influenzae***** were confirmed as type b. **

**Year**

**PENTACEL Introduced**

## Invasive Hib Disease Among Children Admitted to Hospitals in the IMPACT† Surveillance Network, 1985 – 2005

- Invasive Hib Disease Among Children Admitted to Hospitals in the IMPACT† Surveillance Network, 1985 – 2005

**†****Immunization Monitoring Program, Active**
**Source: *****Can Med Assoc J.***** 1996;154:1041-1047 and 2005;172:53-6;*****Can Commun Dis Rep.***** 1998;24:105-108; 2000;26:93-96; 2001;27:149-150; *****Paediatr Child Health.***** 2005;10:314; and David Scheifele, IMPACT.**

**PENTACEL****Introduced**

**Notes:**
Since 1992, a group of Canadian investigators has monitored invasive Hib disease in a network of pediatric hospitals known as IMPACT.  
IMPACT is comprised of 12 centers, accounting for 90% of Canada’s tertiary-care pediatric hospital beds.  
The number of Hib cases decreased from 485 cases in 1985 to an average of fewer than 10 cases per year since 1997.  
Further, since 1997, about 95% of invasive Hib cases have occurred in children who are unimmunized, incompletely immunized or had severe underlying medical conditions including a variety of immunodeficiency states.  
The data from IMPACT demonstrate that Pentacel has maintained excellent control of Hib in Canada.

## Invasive Hib Disease, Children Aged <5 YearsIMPACT Surveillance Network, 2001 – 2005

**Only 34 cases during 2001 ****– ****2005**
**Of these, 11 occurred among native children (Aboriginal – First Nation and Inuit)**
**2 unvaccinated**
**7 partially vaccinated (1 or 2 doses)**
**2 received 3 doses (1 with recurrent ****pneumonia history)**
**Only 2 breakthrough cases during 5-year period**

## International Circumpolar Surveillance PHAC, Canada and CDC, US

|  | Canada | US |  |
| --- | --- | --- | --- |
| Regions | Yukon, Northwest Territories, Nunavut, northern Labrador and Quebec | Alaska |  |
| Total population | 137,000 | 664,000 |  |
| Native population | 75,000 (55%) | 120,000 (18%) |  |
| Surveillance | 5 years (2000-2004) | 5 years (2002-2006) |  |
| Vaccine | PENTACEL | PRP-OMP |  |
| Hib cases <5 y/o  | 4 (3 Native) | 7 (6 Native) |  |
| Ages (Doses) | 1.6 mo (0)
3.7 mo (unknown)
3.9 mo (partial)
1.4 yr (partial) | 0.4 mo (2)
0.5 mo (0)
0.8 mo (2) | 1.1 yr (2)
2.4 yr (3)
2.6 yr (3)
3.6 yr (3) |

## 2007 NACI Recommendations for Use of Combination Vaccines in Canada

**“****Combination vaccines against diphtheria, pertussis, polio, tetanus and...Hib infections have become the standard for routine primary immunization of infants in Canada.”**
**“****Like its monovalent constituent vaccines, PENTACEL has been highly successful in controlling these infectious diseases in Canada but has the additional benefit of fewer injections.”**

**NACI = Canadian National Advisory Committee on Immunization****CCDR 2007;33(ASC-1):1-14**

## Conclusions: Effectiveness of PENTACEL Against Pertussis and Invasive Hib Disease

**9 years of clinical experience with more than ****12 million doses of PENTACEL in Canada**
**Multiple surveillance systems confirm very low rates of pertussis and Hib disease **
**PENTACEL provides sustained protection against pertussis through 9 years of age **
**PENTACEL provides excellent protection against invasive Hib disease**
**Hib cases are rare among vaccinated children, including high risk populations**

## PENTACEL - Agenda

| Introduction | Luc Kuykens, MD, MPHVP Regulatory Affairs |
| --- | --- |
| Safety | Luc Kuykens, MD, MPHVP Regulatory Affairs |
| Immunogenicity  | Michael Decker, MD, MPH VP Scientific and Medical Affairs |
| Canadian Post-Marketing Effectiveness | Scott Halperin, MDProfessor of Pediatrics Dalhousie University, Halifax, Canada |
| US Perspective | David Greenberg, MDDirector Scientific and Medical Affairs |
| Conclusion | Luc Kuykens, MD, MPHVP Regulatory Affairs |

**Notes:**
Thank you Dr. Kuykens  
Dr. Halperin has shown you how PENTACEL has successfully controlled pertussis and invasive Hib disease in Canada,
But you might be asking yourself whether the same performance can be expected in the US
Since PENTACEL consists of the same antigens contained in DAPTACEL and ActHIB vaccines,
It makes sense to show you how these vaccines have performed here
I will present comparative immunization coverage rates and pertussis and Hib disease rates in the two countries

## US Perspective

**US Experience**
**Pertussis and Hib epidemiology **
**Comparison to Canadian experience**
**Benefits of PENTACEL Vaccine**
**Patient, healthcare provider, public health**
**Immunization schedule**
**Coverage rates and timeliness**

## Epidemiology of Pertussis: United States, 1922 – 2005

- Epidemiology of Pertussis: United States, 1922 – 2005

**CDC. *****MMWR.***** 2002;51:73-76;**
**CDC. Summary of notifiable diseases, US, 2003. Published Apr 22, 2005, MMWR 2003:52(54):72-76;**
**CDC. Summary of notifiable diseases, US, 2004. Published June 16, 2006, MMWR 2004:53(53):19;**
**CDC. *****MMWR.***** 2005;55:890.**

**Notes:**
Dr. Halperin showed you a slide of pertussis disease incidence in Canada dating back to 1924
This slide of pertussis in the US, since 1922, is essentially the same as that for Canada
In addition, the rates of pertussis among pre-school and young school-aged children are nearly identical in the US and in Canada 
That is, pertussis is equally controlled among children who receive acellular pertussis vaccines, including DAPTACEL, in the US, and children who receive PENTACEL in Canada

## Pertussis Incidence, US, 2005

**Rates per 100,000 persons; **
**National Center for Immunization and Respiratory Diseases, CDC. Pertussis Surveillance Reports for 2005.**

**0**

**10**

**20**

**30**

**40**

**50**

**160**

**<6 mos**

**6-11 mos**

**1-4 yrs**

**5-9 yrs**

**10-19 yrs**

**20+ yrs**

**Incidence per 100,000**

**140**

## Hib: Invasive Disease in US Children <5 Years National Data, 1994 – 2005

**0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**94**

**95**

**96**

**97**

**98**

**99**

**00**

**01**

**02**

**03**

**04**

**05**

**Year**

- Hib: Invasive Disease in US Children <5 Years National Data, 1994 – 2005

**Note: Rates per 100,000 persons; Only cases confirmed as type b are shown.**
**Source: *****MMWR***** 1995;44:545-50; 1996;45:901-6; 1998;47:993-8; 2001;50:48; 2002:51:16; 2002;51:234-7; 2004;53:691; 2005;54:775; and 2006;55:887.  **

**Rate per 100,000**

**Notes:**
National Notifiable Disease Surveillance data, collected by the CDC, demonstrates a steady decline of Hib cases among young children in the US over the past dozen years
The decline of Hib cases in the US has occurred at the same time that the market share of ActHIB has risen 
In addition, the incidence rate of Hib disease among young children in the US is essentially the same as in Canada, shown to you earlier by Dr. Halperin

## Hib: Invasive Disease in US Children <5 Years ABCs Data, 1994 – 2005

- Hib: Invasive Disease in US Children <5 Years ABCs Data, 1994 – 2005

**Note: Rates per 100,000 persons; ****2005 data are provisional**
**Source: http://www.cdc.gov/ncidod/dbmd/abcs/reports.htm**

**Notes:**
A similar pattern can be seen from the data collected from the Active Bacterial Core, or ABC, sentinel surveillance program
Cases from ABCs also contributes to the data in the National Surveillance System
Very few cases of invasive Hib disease have been found among children in the ABC sentinel population, while the market share of ActHIB has increased
In addition, the majority of Hib cases in the US occur among infants and young children who are unvaccinated or only partially immunized, just as Dr. Halperin demonstrated for the Hib cases in Canada

## ActHIB Vaccine Market Share in the US, 1996 – 2005 

- ActHIB Vaccine Market Share in the US, 1996 – 2005

**Note: Assumed market of 15.2 million Hib conjugate vaccine doses per year; includes TriHIBit****®****.**
**Source: Data on file, sanofi pasteur.**

**Notes:**
Over the past 10 years, the market share of ActHIB and TriHIBit vaccines in the US have steadily climbed to about 60%
Therefore, control of invasive Hib disease in the US can be attributed, to a large extent, by the same Hib vaccine component contained in these vaccines and in PENTACEL

## Summary of US and Canadian Experiences

**Pertussis epidemiology is similar in US and Canada **
**In Canada, PENTACEL has led to sustained protection against pertussis through 9 years of age**
**The epidemiology of invasive Hib disease is similar in US and Canada**
**ActHIB is the dominant Hib vaccine used in the US**
**ActHIB, in PENTACEL, is the exclusive Hib vaccine used ****in Canada **
**In light of these data, PENTACEL is expected to perform as well in US as it has in Canada **

## 2007 Recommended Childhood Immunization Schedule: Birth – 18 Months

- 2007 Recommended Childhood Immunization Schedule: Birth – 18 Months

## ACIP, AAP, AAFP Recommendations:Combination Vaccines

**“****To minimize the number of injections children receive, parenteral combination vaccines should be used, if licensed and indicated for the patient’s age, instead of their equivalent component vaccines.”**
**“****The use of licensed combination vaccines is preferred over separate injection of their equivalent component vaccines.”**

**Centers for Disease Control and Prevention (CDC). *****MMWR.***** 1999;48(No. RR-5):1-2.**

## CDC: Timeliness of Childhood Immunizations, United States

**2003 National Immunization Survey (n=14,810)**
**Only 17% of 24-35 month old children were immunized on time for 6 vaccines**
**Undervaccinated by mean of 172 days**
**37% undervaccinated >6 months for ********1 vaccine**
**IPV ****	****  9%**
**DTaP ****	****16% **
**Hib****	****21%**

**Luman et al. *****JAMA.***** 2006;293:1204-11.**

## Improved Coverage Rates, 2 Years of Age Georgia Medicaid 2003

**Marshall et al. 40th National Immunization Conference, Atlanta, GA, March 2006.**

**All comparisons, P<0.001**

## Improved Coverage Rates, 15 Months of Age Germany, 1996 – 2003

**0**

**10**

**20**

**30**

**40**

**50**

**Percent  Fully Immunized ****by 15 Months of Age**

**Hib**

**IPV**

**Hepatitis B**

**Kailies et al. *****Pediatr Infect Dis J.***** 2006;25:507-12.****N=2701 children with immunization booklets available**

## 2007 Recommended Childhood Immunization Schedule: Birth – 18 Months

- 2007 Recommended Childhood Immunization Schedule: Birth – 18 Months

## Reduction of the Number of Injections Through 18 Months of Age with Combination Vaccines

**23**

**-10**

**-5**

**0**

**5**

**10**

**15**

**20**

**25**

**Total # of Shots**

**Single Entity**

**Notes:**
PENTACELTM would provide the maximum relief to the number of injections required per child through 18 months of age

## PENTACEL: First Candidate DTaP-IPV-Hib Combination Vaccine in the US

**Patient Benefits**
**Maximum shot reduction**
**Safety profile encourages compliance**
**Healthcare Provider Benefits**
**Optimizes implementation of immunization recommendations**
**Simplifies administration**
**Public Health Benefits**
**Expected to improve vaccination coverage rates and timeliness**
**Facilitates optimal HepB schedule**
**Improves combination vaccine supply for infant series**

**Notes:**
Optimizes immunization guidelines
	enables incorporation of new and additional vaccines
	facilitates HepB guidelines
Simplifies administration
	Pentacel is well aligned with DTaP, IPV and Hib schedule
Maximum shot reduction
	Pentacel provides the greatest shot reduction compared to any other single vaccine
	Safety profile of Pentacel addresses concerns among physicians of increased reactions with combination vaccines
Public health
	4 dose pentavalent vaccine will ensure maximize vaccination opportunity
	Disparity between DTaP and Hib vaccine coverage rates

## PENTACEL - Agenda

| Introduction | Luc Kuykens, MD, MPHVP Regulatory Affairs |
| --- | --- |
| Safety | Luc Kuykens, MD, MPHVP Regulatory Affairs |
| Immunogenicity  | Michael Decker, MD, MPH VP Scientific and Medical Affairs |
| Canadian Post-Marketing Experience | Scott Halperin, MDProfessor of Pediatrics Dalhousie University, Halifax, Canada |
| US Experience | David Greenberg, MDDirector Scientific and Medical Affairs |
| Conclusion | Luc Kuykens, MD, MPHVP Regulatory Affairs |

**Notes:**
Thank you David

Pentacel safety data have shown... 

## PENTACEL Clinical Safety Conclusions

**Safety profile of PENTACEL similar to that of separate administration of US standard of care vaccines (Daptacel, IPOL, and ActHIB)**
**PENTACEL is safe when administered alone or concomitantly with other age-recommended vaccines**

**Notes:**
...that it was safe and well tolerated among infants and toddlers with a safety profile similar to the current standard of care vaccines.
Pentacel  can be given safely either simultaneously or separate from hepatitis B, pneumo conjugate, MMR or varicella vaccines.
The immunogenicity data...

## PENTACEL Immunogenicity Conclusions

**PENTACEL efficacy against Pertussis can be concluded based on favorable serological comparison to the Sweden I Efficacy Trial**
**PENTACEL produced Hib GMTs and seroprotection rates that were comparable to separately administered US standard of ****care vaccines**
**Immune responses were similar when PENTACEL was administered alone or concomitantly with other vaccines**

**Notes:**
For Pertussis...seen after Pentacel administration compared favorably to the Sweden I Efficacy trial.
Hib GMT’s and seroprotection rates were comparable to the current US standard of care vaccines and...
Pentacel has shown similar immune responses when given alone or concomitantly with hepatitis B, Prevnar, MMR and Varivax vaccines.

## PENTACEL Benefits

**Proven safety record after 9 years of exclusive use ****in Canada**
**Proven effective in controlling pertussis and Hib disease in Canada**
**Similar epidemiology of pertussis and Hib in Canada and US predicts similar success with PENTACEL**
**Patient benefits with maximum shot reduction**
**Provider benefits with simplified administration**
**Public health benefits through potential improvement of vaccination timeliness and coverage**

**Notes:**
After 9 years of exclusive use in Canada, Pentacel has shown to be safe and effective in controlling pertussis and Hib disease.(NEXT SLIDE)Pentacel is expected to perform as well in the US as in Canada given the similar epidemiology of pertussis and Hib disease between the 2 countries.(NEXT SLIDE)Its adoption will reduce the number of injections for infants and toddlers and its fit with the US immunization schedule will facilitate the inclusion of new vaccines.(NEXT SLIDE)The introduction of PENTACEL has the potential to improve timeliness and coverage of vaccination.

## PENTACEL®

**Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus Vaccine and Haemophilus***** *****b Conjugate (Tetanus Toxoid Conjugate) Vaccine Combined ****(DTaP-IPV/Hib Combined)**

**Vaccine and Related Biological Products Advisory Committee**
**January 25, 2007**

**Notes:**
This concludes the presentation of sanofi pasteur and we will be happy to answer any clarifying questions from the committee.