Vaccines and Related Biological Products Advisory Committee

March 7, 2001

FDA Briefing Document for

SmithKline Beecham Biologicals'

DTPa-HepB-IPV Vaccine

BLA Ref. No. 99-0800

STN# 103907

Clinical Review

Prepared by: Leslie K. Ball, MD

Office of Vaccines Research and Review

Center for Biologics Evaluation and Research

Food and Drug Administration

Table of Contents

1.  Questions for the VRBPAC (Draft) p. 4

    Question #1: Efficacy

Question #2: Safety

Discussion Point #3: Concurrent Immunizations

Discussion Point #4: Post-licensure Studies

2.  Overview of BLA p. 5

> 2.1 Proposed Indication p. 6
>
> 2.2 Formulation p. 6
>
> 2.3 Manufacturing Change During Product Development p. 7
>
> 2.4 Abbreviated U.S. Regulatory Timeline p. 7

3.  Clinical Studies

**3.1 Overview of Clinical Studies**

1.  **Objectives p. 7**

2.  **Pivotal Trial Summary p. 7**

3.  **Inclusion/Exclusion Criteria for Pivotal Trials p. 8**

> **3.1.4 Supportive Trial Summary p. 9**
>
> **3.1.5 Clinical Trial Summary Table (Pivotal +Supportive) p. 10**

**3.2 Efficacy Data (Immunogenicity)**

> **3.2.1 Characterization of the Immune Response p. 12**
>
> **3.2.2 Assessment of Immunogenicity p. 12**

**3.2.3 Pivotal Study: DTPa-HepB-IPV- 015 (Comparative**

> **Immunogenicity of DTPa-HepB-IPV vs. Separate**
>
> **Vaccines p. 14**
>
> **3.2.4 Pivotal Study: DTPa-HepB-IPV- 044)**
>
> **(Lot Consistency and Manufacturing Bridge) p. 16**

5.  **Hepatitis B Vaccine Schedule Change p. 25**

**3.3 Safety Data**

**3.3.1 Safety Database p. 28**

**3.3.2 Assessment of Safety p. 29**

3.  **Pivotal Study: DTPa-HepB-IPV-011 (Large**

> **Scale Safety Study) p. 31**
>
> **3.3.4 Pivotal Study: DTPa-HepB-IPV-015 p. 38**
>
> **3.3.5 Pivotal Study: DTPa-HepB-IPV-044 p. 42**

6.  **Safety of DTPa-HepB-IPV Following a**

> **Birth Dose of Hepatitis B Vaccine p. 45**

7.  **Summary Safety Data .p. 47**

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4.  **Concurrent Immunizations (Safety and Immunogenicity)**

    1.  ***Haemophilus influenzae* type b (Hib) Vaccine p. 53**

    2.  **7-V Pneumococcal Conjugate Vaccine (Prevnar) p. 55**

5.  **4^th^ Dose DTPa (Infanrix®) following**

> **Primary Series of DTPa-HepB-IPV p. 54**

4.  **Summary of Available Data p. 56**

5.  **Appendices**

> **Appendix 1: 7-valent Pneumococcal Conjugate Vaccine (Prevnar) and
> Concurrent DTPa or DTPa combination**
>
> **Appendix 2: Summary of Studies on 4^th^ Dose Infanrix® DTPa and
> Infanrix®-based DTPa combinations following primary series of
> DTPa-HepB-IPV**
>
> **Appendix 3: FDA Guidance for Industry. Evaluation of Combination
> Vaccines for Preventable Diseases: Production, Testing and Clinical
> Studies, April 1997**

**Appendix 4: Package Insert: Infanrix®**

**Appendix 5: Package Insert: Engerix-B®**

**Appendix 6: Package Insert: Prevnar™**

> **Appendix 7: Recommended Childhood Immunization Schedule United
> States, January-December 2001**
>
> **Appendix 8: Combination Vaccines for Childhood Immunizations. MMWR.
> 1999:48(RR-05); 1-15**
>
> **Appendix 9: Public Health Service Recommendations for the Use of
> Vaccines Manufactured with Bovine-Derived Materials. MMWR.
> 2000:49;1137-8**

1.  **Questions for the VRBPAC (DRAFT)**

**The questions below have been used to provide a framework for the
briefing document. The finalized questions will be presented at the
March meeting.**

**Question #1 (VOTE): The following questions pertain to
[efficacy]{.underline}:**

> **A) Are the available data adequate to support the efficacy of
> DTPa-HepB-IPV vaccine when given to infants in a primary series at 2,
> 4, and 6 months of age?**

B)  If the data are not adequate to address efficacy, what additional
    information should be requested?

    **Question #2 (VOTE): The following questions pertain to
    [safety]{.underline}:**

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A)  **Are the available data adequate to demonstrate the safety of the
    DTPa-HepB-IPV combination vaccine when given to infants in a primary
    series at 2, 4, and 6 months of age? Please comment on the increased
    rates of fever.**

B)  **If the data are not adequate to demonstrate safety, what
    additional information should be requested?**

    **Discussion Point #3:**

> **Please discuss the data submitted in support of the concurrent
> administration of other routinely recommended childhood immunizations
> with the DTPa-HepB-IPV vaccine in infants, i.e., *Haemophilus
> influenzae* type b vaccine and 7-valent pneumococcal conjugate vaccine
> (Prevnar).**

**Discussion Point #4:**

> **Please identify any issues that should be addressed in
> post-licensure studies. Please specifically include a discussion of
> the safety and immunogenicity of concurrent administration of other
> routinely recommended vaccines (e.g., Prevnar); safety and
> immunogenicity of 4^th^ and 5^th^ dose of Infanrix® DTPa following a
> primary series of DTPa-HepB-IPV; and safety of a primary series of
> DTPa-HepB-IPV following a birth dose of hepatitis B vaccine.**
>
> **VRPBAC Briefing Document**

**Infanrix~DTPa~ HepB-IPV™**

**SmithKline Beecham Biologicals (GlaxoSmithKline)**[^1]

**BLA 99-0800/STN# 103907**

**2.0 Overview of BLA**

SmithKline Beecham Biological's (SBB) DTPa-HepB-IPV vaccine is a liquid
combination vaccine formulated by pooling purified bulk preparations of
diphtheria and tetanus toxoids (DT); acellular pertussis (pertussis
toxoid \[PT\], filamentous hemagglutinin \[FHA\], and pertactin);
hepatitis B surface antigen (HBs) and inactivated poliovirus (IPV) types
1, 2, and 3. The DT toxoids adsorbed combined bulk is manufactured by
Chiron-Behring GmbH and Co., Marburg, Germany. The acellular pertussis
components are manufactured by SBB, Rixensart, Belgium. The combined
DTPa components (Infanrix®) were approved for use in the U.S. on January
29, 1997. The hepatitis B surface antigen is similar to that found in
Engerix-B approved by the U.S. FDA on August 29, 1989. The IPV component
is not licensed in the U.S.

In licensing combination vaccines the FDA is directed by the Code of
Federal Regulations (CFR). A new license is required when already
licensed products are combined or when unlicensed components are added
to a licensed vaccine \[21CFR 610.17\]. In addition, safe and effective
products may be combined if each component makes a contribution to the
claimed effects and combining does not decrease the purity, potency,
safety, or effectiveness of individual components \[21CFR 601.25\]. In
applying the latter regulation, the FDA has relied on the concept that
clinical studies of combination vaccines should be designed to rule out
clinically meaningful differences, as described in the 1997 guidance
document, "Guidance for Industry for the Evaluation of Combination
Vaccines for Preventable Diseases: Product, Testing and Clinical Issues"
(Appendix 3).

The approach to licensure of DTPa-HepB-IPV has been to demonstrate
non-inferiority of the combination vaccine with respect to efficacy and
safety when compared to separate administration of U.S. licensed
component vaccines. As mentioned above, the DTPa and hepatitis B
components of SBB's DTPa-HepB-IPV vaccine are already licensed in the
U.S. as Infanrix® (Appendix 4) and Engerix-B® (Appendix 5),
respectively. The IPV component is not currently licensed in the U.S.
Licensure of Infanrix® and Engerix-B® was based clinical endpoint
efficacy studies (see Appendices 4 and 5). Although there exists no
generally accepted immunologic correlate(s) of protection against
pertussis, demonstration of a comparable (non-inferior) antibody
response between the acellular pertussis components of the combination
vaccine to the licensed acellular pertussis vaccine of established
efficacy has been used to support efficacy in this application. For
antigens with identified correlates of protection (i.e., D, T, HBs, and
polio types 1, 2, and 3), evidence for efficacy has been provided by
demonstrating that the immune response to these antigens surpasses the
level previously established as a protective response. Additional
evidence for efficacy of the D, T, HBs and polio types 1, 2, and 3
components has been sought by demonstrating non-inferiority of the
immune responses to the combination vaccine compared with separately
administered components. However, even if the immune response to an
antigen in the combination product is decreased compared to separately
administered vaccines, it may still be possible to conclude that the
immune response to this component in the new combination is acceptable.

The overall objective of the clinical plan for DTPa-HepB-IPV has been to
demonstrate safety and immunogenicity of this vaccine when administered
as a [3 dose primary series]{.underline} in infants. Additionally, the
manufacturer has sought to demonstrate that the vaccine can be
manufactured consistently and produce consistent results with respect to
reactogenicity and immunogenicity. Finally, additional studies looked at
the effect of concurrent administration of *Haemophilus influenzae* type
b (Hib) vaccine. Of note, no data have been submitted to the FDA to date
evaluating DTPa-HepB-IPV with concurrent Prevnar, Wyeth-Lederle's 7
valent pneumococcal conjugate vaccine, as this product was not licensed
until after submission of the BLA.

**2.1 Proposed Indication:**

Marketing authorization is sought for the following:

**Indication**: "Infanrix ~DTPa~ HepB-IPV™ is indicated for active
immunization against diphtheria, tetanus, pertussis (whooping cough),
all known subtypes of hepatitis B virus and poliomyelitis caused by
poliovirus types 1, 2, and 3 as a three-dose primary series in infants
and children 6 weeks to 7 years (prior to the 7^th^ birthday)."

**Dose**: 0.5mL injections containing: 25 Lf diphtheria toxoid; 10 Lf
tetanus toxoid; 25

g PT; 25 g FHA; 8 g pertactin; 10 g HBs; 40 D-antigen units (DU) type

1 poliovirus; 8 DU type 2 poliovirus; 32 DU type 3 poliovirus.

**Schedule**: three injections at 4 to 8 week intervals (2, 4, 6 months
of age, customary)

administered intramuscularly.

**How Supplied:** turbid, white suspension in single-dose (0.5mL) vials
and single-dose,

pre-filled, disposable syringes.

**2.2 Vaccine formulation**

The DTPa-HepB-IPV combination consists of the following components in
each 0.5 mL dose:

+------------------------------------------------+---------------------+
| ###### **Composition**                         | **Quantity**        |
|                                                |                     |
|                                                | **(per 0.5 ml       |
|                                                | dose)**             |
+------------------------------------------------+---------------------+
| ### ***Active Substances***                    |                     |
+------------------------------------------------+---------------------+
| # Pertussis toxoid (PT), adsorbed (ads.)       | 25 g                |
+------------------------------------------------+---------------------+
| ## Filamentous haemagglutinin                  | 25 g                |
|                                                |                     |
| (FHA), adsorbed                                |                     |
+------------------------------------------------+---------------------+
| Pertactin (69kDa Outer Membrane Protein, PRN), | 8 g                 |
| ads.                                           |                     |
+------------------------------------------------+---------------------+
| Diphtheria toxoid (D), ads.                    | [\>]{.underline} 2  |
|                                                | U/ml or 25 Lf       |
+------------------------------------------------+---------------------+
| Tetanus toxoid (T), ads.                       | [\>]{.underline} 2  |
|                                                | U/ml or 10 Lf       |
+------------------------------------------------+---------------------+
| r-DNA Hepatitis B surface antigen, ads.        | 10 g (HBs)          |
+------------------------------------------------+---------------------+
| Inactivated Poliovirus Type 1                  | 40 DU               |
+------------------------------------------------+---------------------+
| Inactivated Poliovirus Type 2                  | 8 DU                |
+------------------------------------------------+---------------------+
| Inactivated Poliovirus Type 3                  | 32 DU               |
+------------------------------------------------+---------------------+
| #### *Excipients*                              |                     |
+------------------------------------------------+---------------------+
| 2-phenoxyethanol                               | 2.5 mg              |
+------------------------------------------------+---------------------+
| Sodium Chloride                                | 4.5 mg              |
+------------------------------------------------+---------------------+
| Water for Injection                            | 0.5 ml              |
+------------------------------------------------+---------------------+
| #### *Adjuvants*                               |                     |
+------------------------------------------------+---------------------+
| Aluminum salts (Aluminum hydroxide 0.5 mg and  | 0.7 mg              |
| aluminum phosphate 0.2 mg)                     |                     |
+------------------------------------------------+---------------------+

The diphtheria and tetanus toxoids, adsorbed combined bulk are produced
by Chiron Behring, GmbH and Co., Marburg, Germany. The acellular
pertussis antigens, hepatitis B surface antigen, and trivalent
inactivated polio virus vaccine are produced by SmithKline Beecham
Biologicals (SBB). SBB performs the formulation, filling, testing,
packaging and release of the final product.

**2.3 Manufacturing Changes During Development of DTPa-HepB-IPV: See
FDA's Confidential Briefing Document**

4.  **Abbreviated U.S. Regulatory Timeline**

02/29/96 Original Submission IND 6542: Safety and immunogenicity
"equivalence" study (DTPaHepB-IPV-015, U.S.)

06/25/96 Letter to Sponsor (Advice/IR)

07/19/96 6542/5, Submission of large scale safety trial
(DTPa-HepB-IPV-011, Germany)

06/12/97 IPV Meeting with Sponsor

12/02/97 Pre-phase 3 Meeting with Sponsor:

-   Manufacturing Issues: Process Modifications

-   Clinical Issues: Discussion of pivotal studies

01/27/98 6542/20 -- Submission of revised lot consistency/bridging study
(DTPa-HepB-IPV-044U.S.)

10/28/98 End of Phase III/Pre-Biologics License Application (BLA)
Meeting

02/23/99 Pre-BLA Meeting

07/02/99 BLA submission

09/99 Pre-Approval Inspection

02/09/00 FDA Information Request Letter

05/01/00 FDA Complete Response Letter

12/18/00 Submission of Complete Response

3.  **Clinical Studies**

    **3.1 Overview of Clinical Studies**

    **3.1.1 Objectives of Clinical Studies**

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1.  Establish the [safety]{.underline} of DTPa-HepB-IPV

-   To rule out important differences in the safety and reactogenicity
    of the combination vaccine compared to separately administered
    components.

2.  Establish the [efficacy]{.underline} of DTPa-HepB-IPV

-   Efficacy to be established via immunogenicity of each component in
    the combination.

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-   Rule out important differences between the immune response to each
    antigen elicited by DTPa-HepB-IPV compared to the separately
    administered components.

3.  Establish the safety and efficacy with [concurrent
    immunizations]{.underline}

-   Evaluate immunogenicity of DTPa-HepB-IPV when administered
    concurrently with routinely recommended U.S. licensed vaccines
    anticipated to be given on the same schedule (i.e., *Haemophilus
    influenzae* type b).

4.  Demonstrate [clinical consistency]{.underline} of production lots of
    DTPa-HepB-IPV.

5.  Demonstrate [clinical bridging]{.underline} (comparative
    immunogenicity) between two sequential series of production lots
    following a [manufacturing change]{.underline}.

6.  Compare the [immunogenicity of the hepatitis B]{.underline} surface
    antigen (HBs) when given in the combination at [2, 4, and 6 months
    of age]{.underline} versus the U.S. licensed regimen for hepatitis B
    (Engerix B) vaccination of 0, 1 and 6 months.

    **3.1.2 Pivotal Trial Summary**

Three clinical trials, **Study DTPa-HBV-IPV-011 (011), Study
DTPa-HBV-IPV-015 (-015), and Study DTPa-HBV-IPV-044 (-044)**, were
submitted as pivotal studies in support of the requested indication for
DTPa-HepB-IPV as a three dose primary series. Because the DTPa and
hepatitis B components of this vaccine are already licensed in the US
(as Infanrix® and Engerix-B®, respectively), and generally accepted
correlates of immunity exist for the IPV component, evidence of efficacy
was based on demonstrating non-inferiority of DTPa-HepB-IPV with respect
to immunogenicity of each component compared to separate administration
of U.S. licensed component vaccines (Infanrix®, Engerix-B®, and oral or
inactivated polio vaccines \[OPV or IPV\]). Immunogenicity data were
obtained from Studies -015 and -044; safety data were obtained from all
three pivotal studies. Safety of concurrent immunization with Hib
vaccine was studied in all three pivotal studies and immunogenicity of
concurrent Hib was studied in -015 and -044. Data on concurrent
administration of Prevnar, Wyeth Lederle's 7-valent pneumococcal
conjugate vaccine licensed in February 2000, were not part of the
DTPa-HepB-IPV BLA (submitted in July 1999).

**Study DTPa-HepB-IPV- 011**,a large scale comparative safety trial of
DTPa-HepB-IPV was conducted in Germany under a 3, 4, 5 month primary
immunization schedule with concurrent *Haemophilus influenzae* type b
(Hib) vaccine. This trial was amended after initiation to expand
enrollment and include a control group receiving separately administered
U.S. licensed vaccines, i.e., DTPa, OPV, and Hib. The separate
administration control group did not receive hepatitis B vaccine during
the study period.

**Study DTPa-HepB-IPV-015**, conducted in the U.S. under a 2, 4, and 6
month primary schedule, compared the safety and immunogenicity of 3-dose
primary series of DTPa-HepB-IPV and Hib with either a sequential IPV/OPV
schedule or separately administered U.S. licensed vaccines, e.g., DTPa,
hepatitis B, OPV and Hib.

**Study DTPa-HepB-IPV-044**, conducted in the U.S. under a 2, 4, 6 month
schedule, evaluated lot consistency and manufacturing bridge from the
1^st^ to the 2^nd^ lot series. Hib was administered concurrently in each
group.

**3.1.3 Inclusion/Exclusion Criteria for Pivotal Studies**

In general, criteria for inclusion were consistent across pivotal
studies with minor differences. Study DTPa-HepB-IPV-011 enrolled
subjects who were 8-16 weeks of age while Studies --015 and --044
enrolled subjects who were 6-12 weeks of age at study entry. Study
DTPa-HepB-IPV-011 did not exclude subjects born following a preterm (\<
36 week) gestation; Studies -015 and -044 excluded former preterm
infants. On entry (all pivotal studies) subjects were to be free of
obvious health problems, and born to mothers seronegative for HBsAg.
Subjects were excluded if they had a known hypersensitivity to any
vaccine component, had previously received any vaccines or any blood or
blood product (including Hepatitis B Immune Globulin), were born to
mothers known to be HIV positive, had temperatures [\>]{.underline} 38ºC
(100.4F) rectally at first study visit. In addition, Study --044
specifically excluded subjects with acute disease at the time of
enrollment, defined as "presence of a moderate or severe illness with or
without fever." In Study-044, vaccines could be administered to persons
with minor illness such as diarrhea or mild-upper respiratory infection
with or without low-grade febrile illness.

Pivotal Trial Summary

+------+-----------+----------+------+-------+----------+------------+
| # St | **Obj     | **End    | **   | **    | **N      | **N in     |
| udy/ | ectives** | points** | Sche | Concu | r        | Control    |
|      |           |          | dule | rrent | eceiving | Group**    |
| #    |           |          | (m   | vacci | D        |            |
| Loca |           |          | o)** | nes** | TPa-HepB | **(        |
| tion |           |          |      |       | -IPV\*** | Separately |
|      |           |          |      |       |          | Ad         |
|      |           |          |      |       |          | ministered |
|      |           |          |      |       |          | Vac        |
|      |           |          |      |       |          | cines)\*** |
+------+-----------+----------+------+-------+----------+------------+
| *    | Large     | Safety   | 3,   | Hib   | 4695     | 776\*\*    |
| *011 | scale     | only     | 4, 5 |       |          |            |
| G    | co        |          |      |       |          |            |
| erma | mparative |          |      |       |          |            |
| ny** | safety vs |          |      |       |          |            |
|      | separate  |          |      |       |          |            |
|      | vaccines  |          |      |       |          |            |
+------+-----------+----------+------+-------+----------+------------+
| **0  | Co        | Safety   | 2,   | Hib   | 200      | 200        |
| 15** | mparative | and      | 4, 6 |       |          |            |
|      | vs        | immuno   |      |       |          |            |
| **U  | separate  | genicity |      |       |          |            |
| SA** | vaccines  |          |      |       |          |            |
|      | (U.S.     |          |      |       |          |            |
|      | schedule) |          |      |       |          |            |
+------+-----------+----------+------+-------+----------+------------+
| **0  | Lot       | Safety   | 2,   | Hib   | 484      | §          |
| 44** | con       | and      | 4, 6 |       |          |            |
|      | sistency; | immuno   |      |       |          |            |
| **U  | Manu      | genicity |      |       |          |            |
| SA** | facturing |          |      |       |          |            |
|      | bridge    |          |      |       |          |            |
|      | from      |          |      |       |          |            |
|      | 1^st^ to  |          |      |       |          |            |
|      | 2^nd^ lot |          |      |       |          |            |
|      | series    |          |      |       |          |            |
+------+-----------+----------+------+-------+----------+------------+

\*Total cohort (number enrolled)

\*\* Study-011 was amended after initial enrollment to include a control
group receiving separately administered US licensed vaccines.

§There was no control group receiving separately administered vaccines
in Study-044.

**Study Designs: DTPa-HepB-IPV-011, DTPa-HepB-IPV-015, and
DTPa-HepB-IPV-044**

**(adapted from BLA Table 8.II.9- 1)**

+-------+------------+-----+-------------+---------+----------------+
| *     |            | **D |             | **DTPa- |                |
| *DTPa |            | TPa |             | HepB-IP |                |
| -HepB |            | -He |             | V-044** |                |
| -IPV- |            | pB- |             |         |                |
| 011** |            | IPV |             |         |                |
|       |            | -01 |             |         |                |
|       |            | 5** |             |         |                |
+-------+------------+-----+-------------+---------+----------------+
| *     | Germany    | **  | USA         | **Co    | USA            |
| *Coun |            | Cou |             | untry** |                |
| try** |            | ntr |             |         |                |
|       |            | y** |             |         |                |
+-------+------------+-----+-------------+---------+----------------+
| **    | 3, 4, 5    | **S | 2, 4, 6     | **Sch   | 2, 4, 6 months |
| Sched | months of  | che | months of   | edule** | of age         |
| ule** | age        | dul | age         |         |                |
|       |            | e** |             |         |                |
|       |            |     |             |         |                |
|       |            | *   |             |         |                |
|       |            | *Gr |             |         |                |
|       |            | oup |             |         |                |
|       |            | 1** |             |         |                |
+-------+------------+-----+-------------+---------+----------------+
| **G   | DTP        |     | DT          | **Group | DTPa-HepB-IPV  |
| roups | a-HepB-IPV |     | Pa-HepB-IPV | 1**     | (Lot A 2^nd^   |
| 1 -   | +          |     |             |         | lot series)+   |
| 4**   |            |     | \+ PM Hib   |         | PM Hib         |
|       | Various    |     |             |         |                |
| **poo | Hib\*      |     |             |         |                |
| led** |            |     |             |         |                |
+-------+------------+-----+-------------+---------+----------------+
|       |            | *   | DTPa        | **Group | DTPa-HepB-IPV  |
|       |            | *Gr | -HepB-IPV + | 2**     | (Lot B 2^nd^   |
|       |            | oup | Hib (2, 4   |         | lot series ) + |
|       |            | 2** | months)     |         | PM Hib         |
+-------+------------+-----+-------------+---------+----------------+
|       |            |     | DTPa-HepB + | **Group | DTPa-HepB-IPV  |
|       |            |     | PM Hib +    | 3**     | (Lot C 2^nd^   |
|       |            |     | Lederle OPV |         | lot series ) + |
|       |            |     | (6 months)  |         | PM Hib         |
+-------+------------+-----+-------------+---------+----------------+
|       |            | *   | DTPa-HepB + |         |                |
|       |            | *Gr | PM IPV + PM |         |                |
|       |            | oup | Hib         |         |                |
|       |            | 3** |             |         |                |
+-------+------------+-----+-------------+---------+----------------+
| **    | SBB DTPa + | *   | SBB DTPa +  | **Group | DTPa-HepB-IPV  |
| Group |            | *Gr |             | 4**     | (1st lot       |
| 5**   | PM Hib +   | oup | SBB HepB +  |         | series ) + PM  |
|       |            | 4** | PM Hib +    |         | Hib            |
|       | Lederle    |     |             |         |                |
|       | OPV        |     | Lederle OPV |         |                |
+-------+------------+-----+-------------+---------+----------------+

\*Group 1 = SBB Hib; Group 2 = Pasteur Merieux Connaught (PM-now Aventis
Pasteur) Hib; Group 3 = Lederle Hib; Group 4 = Merck Hib

**3.1.4 Supportive Studies**

# Primary series

In addition to the pivotal trials, safety and immunogenicity data from
additional studies were submitted in support of the BLA. These
included 1) additional studies of DTPa-HepB-IPV [not]{.underline}
conducted under US IND; and 2) studies of other Infanrix®-based
combination vaccines providing supportive data on safety and
immunogenicity. The latter category included Study DTPa-HepB-030 which
provided immunogenicity data from SBB's DTPa-HepB combination to support
the change in hepatitis B vaccination schedule from 0, 1, and 6 months
(Engerix-B®) to the 2, 4, 6 months schedule of DTPa-HepB-IPV. In
addition, supportive data on safety of a primary series of DTPa-HepB-IPV
following a birth dose of hepatitis B vaccine was submitted in the form
of Study DTPa-HepB-IPV-030 and Study DTPa-HepB-IPV/Hib-003.
DTPa-HepB-IPV/Hib-003 provided data on SBB's DTPa-HepB-IPV mixed
extemporaneously prior to injection with SBB's PRP-T vaccine (not
licensed in the U.S.)

# DTPa Booster

The license application for DTPa-HepB-IPV requests an indication for
primary series immunization. Overall clinical development of
DTPa-HepB-IPV included studies evaluating a toddler booster of DTPa
(Infanrix®) or a fourth consecutive dose of DTPa-HepB-IPV following a
primary series of DTPa-HepB-IPV. While not formally considered under
this BLA, SBB has submitted summary safety and immunogenicity data on
4^th^ (toddler) dose of Infanrix® or Infanrix®-based combinations
following a primary series with DTPa-HepB-IPV. (See Section 3.5 and
Appendix 2 of this review.)

**3.1.5 Clinical Trial Summary (Pivotal + Supportive)**

+-----+--------+-------+----+------------+---+----+----+-------------+
| **S | **Vac  | **O   | *  | **Study    | * | ** | *  | **Comment** |
| tud | cine** | bject | *C | Arms:**    | * | N= | *S |             |
| y** |        | ive** | ou |            | N | ** | ch |             |
|     | **(Lot |       | nt | **DTa      | = |    | ed |             |
| *   | Ser    |       | ry | P-HepB-IPV | r | *  | -u |             |
| *Nu | ies)** |       | ** | vs         | e | *C | le |             |
| mbe |        |       |    | Co         | c | om | ** |             |
| r** |        |       |    | mparator** | e | pa |    |             |
|     |        |       |    |            | i | r. | ** |             |
|     |        |       |    |            | v | ** | (m |             |
|     |        |       |    |            | i |    | o) |             |
|     |        |       |    |            | n |    | ** |             |
|     |        |       |    |            | g |    |    |             |
|     |        |       |    |            | D |    |    |             |
|     |        |       |    |            | T |    |    |             |
|     |        |       |    |            | P |    |    |             |
|     |        |       |    |            | a |    |    |             |
|     |        |       |    |            | - |    |    |             |
|     |        |       |    |            | H |    |    |             |
|     |        |       |    |            | e |    |    |             |
|     |        |       |    |            | p |    |    |             |
|     |        |       |    |            | B |    |    |             |
|     |        |       |    |            | - |    |    |             |
|     |        |       |    |            | I |    |    |             |
|     |        |       |    |            | P |    |    |             |
|     |        |       |    |            | V |    |    |             |
|     |        |       |    |            | # |    |    |             |
|     |        |       |    |            | * |    |    |             |
|     |        |       |    |            | * |    |    |             |
+-----+--------+-------+----+------------+---+----+----+-------------+
| 001 | D      | F     | Tu | DTa        | 2 | 20 | 3, | Research    |
| (   | TPa-He | easib | rk | P-HepB-IPV | 0 |    | 4, | lot         |
| Pil | pB-IPV | ility | ey |            |   |    | 5  |             |
| ot) |        |       |    | vs         |   |    |    |             |
|     | (1^st^ |       |    |            |   |    |    |             |
|     | Lot)   |       |    | DTP        |   |    |    |             |
|     |        |       |    | a-HepB+IPV |   |    |    |             |
+-----+--------+-------+----+------------+---+----+----+-------------+
| 002 | D      | F     | F  | DTa        | 3 | 0  | 2, |             |
| (   | TPa-He | easib | in | P-HepB-IPV | 0 |    | 4, |             |
| Pil | pB-IPV | ility | la |            |   |    | 6  |             |
| ot) |        |       | nd |            |   |    |    |             |
|     | (1^st^ |       |    |            |   |    |    |             |
|     | Lot)   |       |    |            |   |    |    |             |
+-----+--------+-------+----+------------+---+----+----+-------------+
| 004 | D      | F     | Ca | DTa        | 5 | 0  | 2, |             |
| (   | TPa-He | easib | na | P-HepB-IPV | 0 |    | 4, |             |
| Pil | pB-IPV | ility | da |            |   |    | 6  |             |
| ot) |        |       |    |            |   |    |    |             |
|     | (1^st^ |       |    |            |   |    |    |             |
|     | Lot)   |       |    |            |   |    |    |             |
+-----+--------+-------+----+------------+---+----+----+-------------+
| 005 | D      | Lot   | B  | DTa        | 5 | 0  | 3, |             |
| (Su | TPa-He | c     | el | P-HepB-IPV | 6 |    | 4, |             |
| ppo | pB-IPV | onsis | gi |            | 7 |    | 5  |             |
| rti |        | tency | um | (3         |   |    |    |             |
| ve) | (1^st^ |       |    | c          |   |    |    |             |
|     | Lot)   |       |    | onsistency |   |    |    |             |
|     |        |       |    | lots)      |   |    |    |             |
+-----+--------+-------+----+------------+---+----+----+-------------+
| **  | **DTP  | **    | *  | **DTaP-He  | * | *  | ** | **-Original |
| 011 | a-HepB | Large | *G | pB-IPV+SBB | * | *7 | 3, | objective   |
| (P  | -IPV** | scale | er | Hib (1)**  | 4 | 76 | 4, | to compare  |
| ivo |        | saf   | ma |            | 6 | ** | 5  | different   |
| tal | **(1st | ety** | ny | **vs**     | 9 |    | ** | Hib         |
| )** | Lot)** |       | ** |            | 5 | ** |    | for         |
|     |        |       |    | **DTa      | * | (G |    | mulations** |
|     |        |       |    | P-HepB-IPV | * | ro |    |             |
|     |        |       |    | +PMC Hib   |   | up |    | **-Amended  |
|     |        |       |    | (2)**      | * | 5) |    | to compare  |
|     |        |       |    |            | * | ** |    | to US       |
|     |        |       |    | **vs**     | ( |    |    | licensed    |
|     |        |       |    |            | G |    |    | separate    |
|     |        |       |    | **DTa      | r |    |    | i           |
|     |        |       |    | P-HepB-IPV | o |    |    | njections** |
|     |        |       |    | +Led Hib   | u |    |    |             |
|     |        |       |    | (3)**      | p |    |    | **[-No      |
|     |        |       |    |            | s |    |    | serology    |
|     |        |       |    | **vs**     | 1 |    |    | pe          |
|     |        |       |    |            | - |    |    | rformed]{.u |
|     |        |       |    | **DTa      | 4 |    |    | nderline}** |
|     |        |       |    | P-HepB-IPV | ) |    |    |             |
|     |        |       |    | +Merck Hib | * |    |    | \-**Not on  |
|     |        |       |    | (4)**      | * |    |    | US schedule |
|     |        |       |    |            |   |    |    | of 2, 4, 6  |
|     |        |       |    | **vs.**    |   |    |    | months**    |
|     |        |       |    |            |   |    |    |             |
|     |        |       |    | **DT       |   |    |    |             |
|     |        |       |    | Pa+Hib+OPV |   |    |    |             |
|     |        |       |    | (5)**      |   |    |    |             |
+-----+--------+-------+----+------------+---+----+----+-------------+
| 012 | D      | Hib   | L  | DTaP-He    | 5 | 0  | 3, |             |
|     | TPa-He | co    | it | pB-IPV+SBB | 4 |    | 4. |             |
| (Su | pB-IPV | -admi | hu | Hib        | 9 |    | 5, |             |
| ppo |        | nistr | an |            |   |    | 6  |             |
| rti | (1st   | ation | ia | vs         |   |    |    |             |
| ve) | Lot)   |       |    |            |   |    |    |             |
|     |        |       |    | DTa        |   |    |    |             |
|     |        |       |    | P-HepB-IPV |   |    |    |             |
|     |        |       |    | +PMC Hib   |   |    |    |             |
|     |        |       |    |            |   |    |    |             |
|     |        |       |    | vs         |   |    |    |             |
|     |        |       |    |            |   |    |    |             |
|     |        |       |    | DTa        |   |    |    |             |
|     |        |       |    | P-HepB-IPV |   |    |    |             |
|     |        |       |    | +Led Hib   |   |    |    |             |
|     |        |       |    |            |   |    |    |             |
|     |        |       |    | vs         |   |    |    |             |
|     |        |       |    |            |   |    |    |             |
|     |        |       |    | DTa        |   |    |    |             |
|     |        |       |    | P-HepB-IPV |   |    |    |             |
|     |        |       |    | +Merck Hib |   |    |    |             |
+-----+--------+-------+----+------------+---+----+----+-------------+
| **  | **DTP  | **1)  | *  | **DTPa-He  | * | *  | ** |             |
| 015 | a-HepB | C     | *U | pB-IPV+Hib | * | *2 | 2, |             |
| (P  | -IPV** | ompar | SA | \@2,4, 6   | 2 | 00 | 4, |             |
| ivo |        | ative | ** | mo (Group  | 0 | ** | 6  |             |
| tal | **(1st | immu  |    | 1)**       | 0 |    | ** |             |
| )** | Lot)** | nogen |    |            | * |    |    |             |
|     |        | icity |    | **vs**     | * |    |    |             |
|     |        | vs    |    |            |   |    |    |             |
|     |        | sep   |    | **DTPa-He  |   |    |    |             |
|     |        | arate |    | pB-IPV+Hib |   |    |    |             |
|     |        | in    |    | \@2,4, and |   |    |    |             |
|     |        | jecti |    | DTPa-He    |   |    |    |             |
|     |        | ons** |    | pB+OPV+Hib |   |    |    |             |
|     |        |       |    | \@6mo      |   |    |    |             |
|     |        | **2)  |    | (Group     |   |    |    |             |
|     |        | S     |    | 2)**       |   |    |    |             |
|     |        | afety |    |            |   |    |    |             |
|     |        | (c    |    | **vs**     |   |    |    |             |
|     |        | ommon |    |            |   |    |    |             |
|     |        | A     |    | *          |   |    |    |             |
|     |        | Es)** |    | *DTPa-HepB |   |    |    |             |
|     |        |       |    | +IPV+ Hib  |   |    |    |             |
|     |        | *     |    | (Group     |   |    |    |             |
|     |        | *3)Si |    | 3)**       |   |    |    |             |
|     |        | multa |    |            |   |    |    |             |
|     |        | neous |    | **vs**     |   |    |    |             |
|     |        | imm.  |    |            |   |    |    |             |
|     |        | (H    |    | **DTPa +   |   |    |    |             |
|     |        | ib)** |    | HepB+OPV+  |   |    |    |             |
|     |        |       |    | Hib (Grp   |   |    |    |             |
|     |        |       |    | 4)**       |   |    |    |             |
+-----+--------+-------+----+------------+---+----+----+-------------+
| 016 | **DTP  | 1)S   | G  | DTPa-He    | 1 | 3  | 3, |             |
| (Su | a-HepB | afety | er | pB-IPV/Hib | 8 | 68 | 4, |             |
| ppo | -IPV** |       | ma |            | 4 |    | 5  |             |
| rti |        | 2     | ny | vs         |   |    |    |             |
| ve) | **(1st | )Immu |    |            |   |    |    |             |
|     | Lot)** | nogen |    | DTPa-IP    |   |    |    |             |
|     |        | icity |    | V/Hib+HepB |   |    |    |             |
+-----+--------+-------+----+------------+---+----+----+-------------+

Manufacturer abbreviation: SBB=SmithKline Beecham Biologicals;
PMC=Pasteur Merieux Connaught, now known as Aventis Pasteur; Led=Wyeth
Lederle

**Clinical Trial Summary (Pivotal + Supportive -- cont.)**

+-----+--------+-------+---+------------+---+----+----+-------------+
| **S | **V    | **O   | * | **Study    | * | ** | *  | **Comment** |
| tud | accine | bject | * | Arms:**    | * | N= | *S |             |
| y** | /Lot   | ive** | C |            | N | ** | ch |             |
|     | Se     |       | o | **DTa      | = |    | ed |             |
| *   | ries** |       | u | P-HepB-IPV | r | ** | -u |             |
| *Nu |        |       | n | vs         | e | Co | le |             |
| mbe |        |       | t | Co         | c | mp | ** |             |
| r** |        |       | r | mparator** | e | ar |    |             |
|     |        |       | y |            | i | ** | ** |             |
|     |        |       | * |            | v |    | (m |             |
|     |        |       | * |            | i |    | o) |             |
|     |        |       |   |            | n |    | ** |             |
|     |        |       |   |            | g |    |    |             |
|     |        |       |   |            | D |    |    |             |
|     |        |       |   |            | T |    |    |             |
|     |        |       |   |            | P |    |    |             |
|     |        |       |   |            | a |    |    |             |
|     |        |       |   |            | - |    |    |             |
|     |        |       |   |            | H |    |    |             |
|     |        |       |   |            | e |    |    |             |
|     |        |       |   |            | p |    |    |             |
|     |        |       |   |            | B |    |    |             |
|     |        |       |   |            | - |    |    |             |
|     |        |       |   |            | I |    |    |             |
|     |        |       |   |            | P |    |    |             |
|     |        |       |   |            | V |    |    |             |
|     |        |       |   |            | # |    |    |             |
|     |        |       |   |            | * |    |    |             |
|     |        |       |   |            | * |    |    |             |
+-----+--------+-------+---+------------+---+----+----+-------------+
| 017 | D      | 1)S   | F | DTaP-He    | 2 | 1  | 2, |             |
| (Su | TPa-He | afety | r | pB-IPV+Hib | 9 | 80 | 3, |             |
| ppo | pB-IPV |       | a |            |   |    | 4  |             |
| rti |        | 2     | n | vs         |   |    |    |             |
| ve) | (1st   | )Immu | c |            |   |    |    |             |
|     | Lot)   | nogen | e | DTPa-He    |   |    |    |             |
|     |        | icity |   | pB-IPV/Hib |   |    |    |             |
|     |        |       |   |            |   |    |    |             |
|     |        |       |   | vs         |   |    |    |             |
|     |        |       |   |            |   |    |    |             |
|     |        |       |   | DTPa-IP    |   |    |    |             |
|     |        |       |   | V/Hib+HepB |   |    |    |             |
+-----+--------+-------+---+------------+---+----+----+-------------+
| 019 | D      | 1)S   | E | DTa        | 6 | 60 | 3  |             |
|     | TPa-He | afety | s | P-HepB-IPV | 0 |    | ,4 |             |
| (Su | pB-IPV |       | t |            |   |    | .5 |             |
| ppo |        | 2     | o | vs         |   |    | ,6 |             |
| rti | (1st   | )Immu | n |            |   |    |    |             |
| ve) | Lot)   | nogen | i | DTPa-HepB  |   |    |    |             |
|     |        | icity | a | +IPV       |   |    |    |             |
+-----+--------+-------+---+------------+---+----+----+-------------+
| 030 | D      | S     | M | birth dose | 1 | 1  | 6  | -All        |
|     | TPa-He | afety | o | HepB+      | 6 | 60 | ,1 | infants     |
| (Su | pB-IPV | after | l | DTP        | 0 |    | 0, | received    |
| ppo |        | birth | d | a-HepB-IPV |   |    | 14 | birth dose  |
| rti | (2nd   | dose  | o |            |   |    | w  | of hepB     |
| ve) | Lot)   | HepB  | v | @ 6, 10,   |   |    | ee |             |
|     |        |       | a | 14 wks     |   |    | ks | -Compressed |
|     |        |       |   |            |   |    |    | schedule    |
|     |        |       |   | vs         |   |    |    | (6, 10, 14  |
|     |        |       |   |            |   |    |    | wks)        |
|     |        |       |   | birth dose |   |    |    |             |
|     |        |       |   | HepB+DT    |   |    |    | -Comparator |
|     |        |       |   | Pw-IPV-Hib |   |    |    | includes    |
|     |        |       |   | +HepB @ 6, |   |    |    | whole cell  |
|     |        |       |   | 10, 14     |   |    |    | pertussis   |
|     |        |       |   | weeks      |   |    |    | vaccine     |
+-----+--------+-------+---+------------+---+----+----+-------------+
| *   | **DTP  | **    | * | **DTP      | * | *  | ** | **No        |
| *04 | a-HepB | 1)Lot | * | a-HepB-IPV | * | *0 | 2, | separate    |
| 4** | -IPV** | con   | U | (Groups    | 4 | ** | 4, | injection   |
|     |        | siste | S | 1-3) (3    | 8 |    | 6  | control     |
| *   | **(1st | ncy** | A | lots of    | 4 |    | ** | arm**       |
| *(P | Lot)   |       | * | 2^nd^ lot  | * |    |    |             |
| ivo | and**  | **2)B | * | series)**  | * |    |    |             |
| tal |        | ridge |   |            |   |    |    |             |
| )** | **DTP  | from  |   | **vs**     | * |    |    |             |
|     | a-HepB | 1^st^ |   |            | * |    |    |             |
|     | -IPV** | lot   |   | **DTP      | 1 |    |    |             |
|     |        | to    |   | a-HepB-IPV | : |    |    |             |
|     | **(2nd | 2^nd^ |   | (Group     | 1 |    |    |             |
|     | Lot)** | lot   |   | 4)**       | : |    |    |             |
|     |        | for   |   |            | 1 |    |    |             |
|     |        | s     |   | **(1 lot   | : |    |    |             |
|     |        | afety |   | of 1^st^   | 1 |    |    |             |
|     |        | and   |   | lot        | * |    |    |             |
|     |        | i     |   | series)**  | * |    |    |             |
|     |        | mmuno |   |            |   |    |    |             |
|     |        | genic |   |            |   |    |    |             |
|     |        | ity** |   |            |   |    |    |             |
+-----+--------+-------+---+------------+---+----+----+-------------+
| *D  | *      | *Lot  | * | *DTPa+He   | * | *  | *  | ***Note:    |
| TPa | DTPa-H | c     | U | pB+OPV+Hib | 1 | 35 | 2, | Study       |
| -He | epB-IP | onsis | S | (Group 1)* | 0 | 8* | 4, | evaluated   |
| pB- | V/Hib* | tency | A |            | 8 |    | 6* | DTPa-HepB   |
| IPV |        | (S    | * | *vs*       | 5 |    |    | -IPV/Hib*** |
| /Hi |        | afety |   |            | * |    |    |             |
| v-0 |        | and   |   | *DTPa-Hep  |   |    |    |             |
| 27* |        | i     |   | B-IPV/Hib* |   |    |    |             |
|     |        | mmuno |   |            |   |    |    |             |
| *(  |        | genic |   | *(3 lots   |   |    |    |             |
| Sup |        | ity)* |   | of         |   |    |    |             |
| por |        |       |   | DTP        |   |    |    |             |
| tiv |        |       |   | a-HepB-IPV |   |    |    |             |
| e)* |        |       |   | 2^nd^ lot  |   |    |    |             |
|     |        |       |   | series,    |   |    |    |             |
|     |        |       |   | same lots  |   |    |    |             |
|     |        |       |   | as -044)*  |   |    |    |             |
|     |        |       |   |            |   |    |    |             |
|     |        |       |   | *(Groups   |   |    |    |             |
|     |        |       |   | 2-4)*      |   |    |    |             |
+-----+--------+-------+---+------------+---+----+----+-------------+
| *   | *DTPa  | *Su   | * | *D         | * | *N | *  | ***Note:    |
| DTP | -HepB* | pport | U | TaP-HepB + | N | .A | 2, | Study       |
| a-H |        | sch   | S | Hib + OPV* | . | .* | 4, | evaluated   |
| epB |        | edule | A |            | A |    | 6* | D           |
| -0  |        | c     | * | *\@2, 4, 6 | . |    |    | TaP-HepB*** |
| 30* |        | hange |   | mo*        | * |    |    |             |
|     |        | HepB* |   |            |   |    |    |             |
| *(  |        |       |   | *vs*       |   |    |    |             |
| Sup |        |       |   |            |   |    |    |             |
| por |        |       |   | *DTaP +    |   |    |    |             |
| tiv |        |       |   | Hib +OPV   |   |    |    |             |
| e)* |        |       |   | \@2,4,6    |   |    |    |             |
|     |        |       |   | mo*        |   |    |    |             |
|     |        |       |   |            |   |    |    |             |
|     |        |       |   | *HepB \@0, |   |    |    |             |
|     |        |       |   | 1, 6 mo*   |   |    |    |             |
+-----+--------+-------+---+------------+---+----+----+-------------+
| *D  | *      | *S    | * | *DTPa-He   | * | *N | *  | ***Note:    |
| TPa | DTPa-H | afety | U | pB-IPV/Hib | N | .A | 2, | Study       |
| -He | epB-IP | after | S | (no birth  | . | .* | 4, | evaluated   |
| pB- | V/Hib* | birth | A | dose HepB) | A |    | 6* | DTPa-HepB   |
| IPV |        | dose  | * | (Group 1)* | . |    |    | -IPV/Hib*** |
| /HI |        | HepB* |   |            | * |    |    |             |
| B-0 |        |       |   | *vs*       |   |    |    |             |
| 03* |        |       |   |            |   |    |    |             |
|     |        |       |   | *DTPa-     |   |    |    |             |
| *(  |        |       |   | HepB-IPV + |   |    |    |             |
| Sup |        |       |   | birth dose |   |    |    |             |
| por |        |       |   | HepB       |   |    |    |             |
| tiv |        |       |   | (Group 2)* |   |    |    |             |
| e)* |        |       |   |            |   |    |    |             |
+-----+--------+-------+---+------------+---+----+----+-------------+
| **[ | **all  |       | * |            | * | ** |    |             |
| Tot | stu    |       | * |            | * | 17 |    |             |
| a]{ | dies** |       | P |            | 7 | 64 |    |             |
| .un |        |       | i |            | 0 | ** |    |             |
| der | **S    |       | v |            | 2 |    |    |             |
| lin | tudies |       | o |            | 8 |    |    |             |
| e}l | 0      |       | t |            | * |    |    |             |
| [   | 11+015 |       | a |            | * |    |    |             |
| Coh | +044** |       | l |            |   |    |    |             |
| ort |        |       |   |            | * |    |    |             |
| ]{. | **S    |       | + |            | * |    |    |             |
| und | tudies |       | S |            | 5 |    |    |             |
| erl | 015    |       | u |            | 3 |    |    |             |
| ine | +044** |       | p |            | 7 |    |    |             |
| }** |        |       | p |            | 9 |    |    |             |
|     |        |       | o |            | * |    |    |             |
| *   |        |       | r |            | * |    |    |             |
| *Sa |        |       | t |            |   |    |    |             |
| fet |        |       | i |            | * |    |    |             |
| y** |        |       | v |            | * |    |    |             |
|     |        |       | e |            | 6 |    |    |             |
| *   |        |       | * |            | 8 |    |    |             |
| *Im |        |       | * |            | 4 |    |    |             |
| mun |        |       |   |            | * |    |    |             |
| oge |        |       | * |            | * |    |    |             |
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| cit |        |       | P |            |   |    |    |             |
| y** |        |       | i |            |   |    |    |             |
|     |        |       | v |            |   |    |    |             |
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|     |        |       | t |            |   |    |    |             |
|     |        |       | a |            |   |    |    |             |
|     |        |       | l |            |   |    |    |             |
|     |        |       | * |            |   |    |    |             |
|     |        |       | * |            |   |    |    |             |
|     |        |       |   |            |   |    |    |             |
|     |        |       | * |            |   |    |    |             |
|     |        |       | * |            |   |    |    |             |
|     |        |       | P |            |   |    |    |             |
|     |        |       | i |            |   |    |    |             |
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+-----+--------+-------+---+------------+---+----+----+-------------+

#Numbers from Electronic Submission BLA 99-0800 Item 8.1.1 Summary of
Studies Table 8.I.6-1

**3.2 Efficacy Data (Immunogenicity)**

**3.2.1 Characterization of the Immune Response: Clinical Serology**

> All assays were performed blinded to vaccination status. Assays were
> conducted in either of two laboratories: SBB Laboratories in
> Rixensart, Belgium or in the labs of Dr. Michael Pichichero (MEP) at
> the University of Rochester. Data to support the comparability of the
> procedures employed and the results obtained from the two laboratories
> were reported in the BLA.

+----------------------------+--------------+-------------------------+
| **Antigen**                | ########     | **Endpoints\*\***       |
|                            |  Serological |                         |
|                            |              |                         |
|                            | **Method**   |                         |
+----------------------------+--------------+-------------------------+
| ###                        |              |                         |
| **DTPa-HepB-IPV antigens** |              |                         |
+----------------------------+--------------+-------------------------+
| Diphtheria Toxoid (D)      | ###### ELISA | 0.1 IU/mL               |
+----------------------------+--------------+-------------------------+
| Tetanus Toxoid (T)         | ELISA        | 0.1 IU/mL               |
+----------------------------+--------------+-------------------------+
| Pertussis Toxoid (PT)      | ELISA        | 5 EL.U/mL               |
+----------------------------+--------------+-------------------------+
| Filamentous Haemagglutinin | ELISA        | 5 EL.U/mL               |
| (FHA)                      |              |                         |
+----------------------------+--------------+-------------------------+
| Pertactin (PRN)            | ELISA        | 5 EL.U/mL               |
+----------------------------+--------------+-------------------------+
| Hepatitis B surface        | RIA          | 10 mIU/mL               |
| antigen (HBs)              |              |                         |
+----------------------------+--------------+-------------------------+
| Poliovirus types 1, 2, 3   | Cell culture | 1/8                     |
| (IPV)                      | ne           |                         |
|                            | utralization |                         |
+----------------------------+--------------+-------------------------+
| ### **Co                   |              |                         |
| ncurrent administration**  |              |                         |
+----------------------------+--------------+-------------------------+
| *Haemophilus influenzae*   | ELISA\*      | 0.15 and 1.0 mcg/mL     |
| type b (Hib)               |              |                         |
+----------------------------+--------------+-------------------------+

> **\***In studies DTPa-HepB-IPV-002, 004, -005, and -012, anti-PRP
> antibodies were measured using radiolabeled antigen-binding assay
> (RABA).
>
> **\*\***"For D, T, HBs, "seroprotection" rates (i.e., the % of infants
> with antibody titers equal or above the assay cut-off) were set such
> that subjects who had titers above the cut off could be considered
> protected from disease.
>
> For polio types 1, 3, and 3, subjects with detectable neutralizing
> antibody were considered protected from disease.
>
> For pertussis antigens, "vaccine response" rates (i.e., the % of
> infants showing a vaccine response to each pertussis antigen (PT, FHA
> and PRN) was defined as antibody titers equal to or above the assay
> cut-off in subjects who were seronegative prior to vaccination and at
> least maintenance of prevaccination antibody titers in those who were
> seropositive prior to vaccination.

2.  **Assessment of Immunogenicity**

Subjects evaluated for immunogenicity had serum samples for measurement
of antibody response obtained before vaccination and approximately one
month after the third vaccine dose.

**Study cohorts for immunogenicity:**

[Intent-to-treat (ITT) cohort for analysis of
immunogenicity]{.underline}: All subjects enrolled in the study for whom
assay results were available for antibodies against at least one study
antigen either pre- or post-vaccination.

[According-to-Protocol (ATP)]{.underline} cohort for analysis of
immunogenicity:

Studies DTPa-HepB-IPV-016, -030, and -044: All evaluable subjects (i.e,
those meeting all inclusion/exclusion criteria and complying with the
procedures defined in the protocol, and fulfilling requirements for
analysis) for whom assay results were available for antibodies against
at least one study vaccine antigen post-vaccination.

All other studies: same criteria as above but must have assay results
available for antibodies against at least one study antigen both pre-
and post-vaccination.

**Criteria for evaluation of immunogenicity:**

Primary endpoints for immunogenicity were defined as seroprotection
rates for D, T, HBsAg, and poliovirus (Types 1, 2, 3) and in terms of
vaccine response rates and GMTs for the pertussis components (PT, FHA,
and PRN). Seroprotection rates for PRP, seropositivity rates for PT, FHA
and PRN, and GMTs for D, T, HBsAg, poliovirus (Types 1, 2, 3) and PRP
were considered secondary endpoints.

**Endpoints:**

The following immunogenicity endpoints were evaluated.

-   **"**[Seroprotection" rates]{.underline}: i.e., the % of infants
    with antibody titers equal to or above the assay cut-off. D, T,
    HepB, Polio, Hib

```{=html}
<!-- -->
```
-   D, T, hepatitis B: % infants with antibody titers [\>]{.underline}
    the predefined levels (see table below)

-   Polio types 1, 2, 3 : % infants with neutralizing antibodies
    [\>]{.underline} 1:8

-   Hib: % infants with anti-PRP antibodies [\>]{.underline} 0.15 and
    1.0 mcg/mL

```{=html}
<!-- -->
```
-   [Vaccine response rates]{.underline}: Pertussis

```{=html}
<!-- -->
```
-   \% infants showing response to PT, FHA, PRN

-   Defined as: [\>]{.underline} 5 EL.U/mL in subjects who were
    seronegative prior to vaccination or at least maintenance of
    pre-vaccination antibody titers in those "seropositive" prior to
    vaccination

```{=html}
<!-- -->
```
-   [Geometric mean antibody titers (GMTs)]{.underline}: The anti-log of
    the mean of the log titer transformation.

```{=html}
<!-- -->
```
-   [Distribution of antibody responses by reverse cumulative
    distribution curves (RCD curves)]{.underline}

    **Statistical methodology: (From BLA 8.III.1.3)**

The statistical methodology used to evaluate the immunogenicity of the
study vaccine evolved during clinical development, from testing of the
null hypothesis of no vaccination difference in the earlier studies to
testing for non-inferiority or equivalence in later studies (ICH E-9
Statistical principles for clinical trials, Final, February, 1998:
Section 3.3.2).

Three statistical approaches were used:

1.  [Descriptive analyses]{.underline} within each vaccine group: all
    studies

For each treatment group, seroprotection rates and GMTs were calculated
with their 95% confidence intervals (CI) for all time points for which
serum was titrated. Vaccine response rates and their 95% CI were also
tabulated by treatment group.

Antibody titer distributions, approximately one month after the
vaccination course, were displayed by means of reverse cumulative
distribution curves.

2.  [Hypothesis testing of no difference]{.underline} between the SBB
    DTPa-HepB-IPV vaccine and control, or for lot-to-lot consistency
    (studies DTPa-HepB-IPV-005, -012).

Seroprotection/ vaccine response rates were compared between vaccine
groups using Fisher's Exact test, whereas GMTs were compared using
one-way ANOVA test. P-values less than 0.05 (two-sided test of the null
hypothesis of no difference) were considered as indicative of
statistical significance.

3.  [Equivalence testing]{.underline} between the SBB DTPa-HepB-IPV
    vaccine and commercial control or for lot-to-lot consistency
    (studies DTPa-HepB-IPV-015, -016,-030, -044, and -005 *\[a
    posteriori* analysis\]).

The clinical limits defining non-inferiority of the SBB DTPa-HepB-IPV
vaccine relative to a control, and consistency between lots of the SBB
DTPa-HepB-IPV vaccine, were as follows:

**Specified limits for non-inferiority of DTPa-HepB-IPV\* relative to a
control and consistency between lots of the SBB DTPa-HepB-IPV vaccine
(8.III.1.3.2)**

+------------------------------------------------+---------------------+
| # Seroprotection/vaccine response rate         | **Max difference**  |
+------------------------------------------------+---------------------+
| \% subjects with anti D[\>]{.underline}0.1     | 10%                 |
| IU/mL                                          |                     |
+------------------------------------------------+---------------------+
| \% subjects with anti T[\>]{.underline}0.1     | 10%                 |
| IU/mL                                          |                     |
+------------------------------------------------+---------------------+
| \% subjects with anti-PT vaccine response      | 10%                 |
+------------------------------------------------+---------------------+
| \% subjects with anti-FHA vaccine response     | 10%                 |
+------------------------------------------------+---------------------+
| \% subjects with anti-PRN vaccine response     | 10%                 |
+------------------------------------------------+---------------------+
| \% subjects with anti-HBS[\>]{.underline} 10   | 10%                 |
| mIU/ml                                         |                     |
+------------------------------------------------+---------------------+
| \% subjects with anti-polio 1 [\>]{.underline} | 10%                 |
| 1:8                                            |                     |
+------------------------------------------------+---------------------+
| \% subjects with anti-polio 2 [\>]{.underline} | 10%                 |
| 1:8                                            |                     |
+------------------------------------------------+---------------------+
| \% subjects with anti-polio 3 [\>]{.underline} | 10%                 |
| 1:8                                            |                     |
+------------------------------------------------+---------------------+
| **Geometric Mean Titers (GMTs)**               | **Max Ratio**       |
+------------------------------------------------+---------------------+
| Anti-PT GMT                                    | 1.5                 |
+------------------------------------------------+---------------------+
| Anti-FHA GMT                                   | 1.5                 |
+------------------------------------------------+---------------------+
| Anti-PRN GMT                                   | 1.5                 |
+------------------------------------------------+---------------------+
| Anti-HBs GMT                                   | 2.0\*               |
+------------------------------------------------+---------------------+

\*Secondary endpoint

According to the study objectives, non-inferiority was demonstrated
when, for all study primary endpoints, the upper limit of the 90% CI for
the vaccine difference was below the specified clinical limit of
non-inferiority (one-sided equivalence test; alpha = 5%).

Likewise, consistency was demonstrated when, for all study primary
endpoints, and for all pair-wise comparisons of vaccines (lots), the 90%
CI for the difference between vaccines (lots) was included in the
specified clinical limits of equivalence (two-sided equivalence test;
alpha =5%).

For the differences in seroprotection and vaccine response rates, exact
90% CIs were calculated using "StatXact 3.0". For GMT ratios, the 90%
CIs were derived from a one-way ANOVA model on the logarithm of the
titers, assuming that the logarithm of the titers were normally
distributed and had a common variance across groups. The robustness of
the GMT analysis with respect to the parametric assumptions was
evaluated using a Cox regression model. Both ANOVA and Cox models
included the group effect as the only regressor.

3.  **Pivotal Study for Immunogenicity: DTPa-HepB-IPV-015 (Comparative
    Immunogenicity vs. Separately Administered U.S. Licensed Vaccines)**

**Title:** An open study of the safety and immunogenicity of
DTPa-HepB-IPV vaccine administered as a three dose series or in a
sequential IPV/OPV schedule at 2, 4, and 6 months of age.

**Objectives:**

[Primary Objective]{.underline}: To evaluate the immune response and
potential interactions to each of the 10 antigens (D, T, PT, FHA,
Pertactin, PRP, Hepatitis B, and polio virus types 1, 2, and 3) in
infants who receive three doses of DTPa-HepB-IPV vaccine and Hib
(OmniHIB™) simultaneously at separate sites compared to DTPa-HepB (SBB)
administered with IPV (IPOL®) and Hib (OmniHIB™) simultaneously at
separate injection sites and compared to DTPa (Infanrix®), Hepatitis B
(Engerix-B®) and Hib (OmniHIB™) vaccines simultaneously at separate
sites along with OPV (ORIMUNE™).

[Secondary objective]{.underline}: To evaluate the safety and
immunogenicity of the IPV component of the DTPa-HepB-IPV administered as
a single injection relative to the safety and immunogenicity of OPV
(ORIMUNE®) or IPV (IPOL®) administered separately along with DTPa
(Infanrix®) Hepatitis B (Engerix-B®), Hib (OmniHIB™ or DTPa-HepB (SBB)
and Hib (OmniHIB™). Note SBB-s DTPa-HepB vaccine is not licensed in the
U.S.

To compare the safety and immunogenicity of the sequential
administration of DTPa-HepB-IPV vaccine at 2 and 4 months followed by
OPV (ORIMUNE®) at 6 months of age with a three dose series of
DTPa-HepB-IPV vaccine.

**Design:** Open, randomized

**Schedule:** 2, 4, 6 months

Group 1: DTPa-HepB-IPV + Hib at 2, 4, 6 mo

Group 2: DTPa-HepB-IPV at 2, 4 mo; DTPa-HepB + Hib + OPV at 6 months

Group 3: DTPa-HepB + Hib + IPV at 2, 4, 6 mo

### Group 4: DTPa + HepB + OPV + Hib at 2, 4, 6 mo

**Number of subjects**

Total enrolled (ITT cohort): 400 (100 per group)

Completed: 347

ATP for safety cohort: 399

### ATP immunogenicity cohort: 332

**Data analysis**

As defined by SBB, the primary objective was demonstrated if the upper
limits of all the 90% CIs for the difference in the primary endpoints
(see section 3.3.2: specified limits of non-inferiority) between Group 1
and Group 4, were below the limit defining clinical non-inferiority.

In the review of DTPa-HepB-IPV, Group 1 (DTPa-HepB-IPV + Hib at 2, 4,
and 6 months of age) and Group 4 (DTPa + HepB + Hib + OPV at 2, 4, and 6
months of age) considered. Group 2 included the sequential IPV/OPV
schedule which is no longer part of the U.S. Recommended Childhood
Immunization Schedule, and Group 3 evaluated SBB's DTPa-HepB combination
(unlicensed in the U.S). Therefore, data presented below concentrate on
groups 1 and 4.

**DTPa-HepB-IPV-015: Comparison of the immunogenicity of DTPa-HepB-IPV
and U.S. licensed vaccines administered separately, i.e., Group 1 vs
Group 4 (ATP cohort for immunogenicity)**

<table style="width:100%;">
<colgroup>
<col style="width: 7%" />
<col style="width: 13%" />
<col style="width: 4%" />
<col style="width: 6%" />
<col style="width: 4%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2" rowspan="3"><strong>Antigens</strong></td>
<td colspan="7"><h5
id="seroprotectionvaccine-response">Seroprotection/Vaccine Response‡
</h5></td>
<td colspan="5"><p id="gmts" class="heading">GMTs§</p></td>
</tr>
<tr class="even">
<td colspan="2"><strong>Group 1</strong></td>
<td colspan="2"><strong>Group 4</strong></td>
<td colspan="3"><strong>Difference (Group 4 minus Group 1)</strong></td>
<td rowspan="2"><strong>Group 1</strong></td>
<td rowspan="2"><strong>Group 4</strong></td>
<td colspan="3"><strong>Group 4 Divided by Group 1</strong></td>
</tr>
<tr class="odd">
<td colspan="2"><strong>N %</strong></td>
<td colspan="2"><strong>N %</strong></td>
<td colspan="3"><p><strong>90% CI</strong></p>
<p><strong>LL UL</strong></p></td>
<td colspan="3"><p><strong>90% CI</strong></p>
<p><strong>LL UL</strong></p></td>
</tr>
<tr class="even">
<td colspan="2">Diphtheria</td>
<td>90</td>
<td>98.9</td>
<td>78</td>
<td>100</td>
<td>1.1</td>
<td>-5.2</td>
<td>8.2*</td>
<td>1.294**</td>
<td>0.805</td>
<td>0.62</td>
<td>0.50</td>
<td>0.77</td>
</tr>
<tr class="odd">
<td colspan="2">Tetanus</td>
<td>90</td>
<td>100</td>
<td>78</td>
<td>100</td>
<td>0.0</td>
<td>-7.0</td>
<td>5.5*</td>
<td>3.730**</td>
<td>2.345</td>
<td>0.63</td>
<td>0.51</td>
<td>0.77</td>
</tr>
<tr class="even">
<td colspan="2">Hepatitis B</td>
<td>89</td>
<td>100</td>
<td>77</td>
<td>100</td>
<td>0.0</td>
<td>-7.1</td>
<td>5.5*</td>
<td>1661.2</td>
<td>804.9</td>
<td>0.48</td>
<td>0.35</td>
<td>0.67*</td>
</tr>
<tr class="odd">
<td colspan="2">PT</td>
<td>91</td>
<td>98.9</td>
<td>78</td>
<td>98.7</td>
<td>-0.2</td>
<td>-8.1</td>
<td>6.2*</td>
<td>97.1</td>
<td>47.5</td>
<td>0.49</td>
<td>0.41</td>
<td>0.58*</td>
</tr>
<tr class="even">
<td colspan="2"><strong>FHA</strong></td>
<td><strong>91</strong></td>
<td><strong>95.6</strong></td>
<td><strong>77</strong></td>
<td><strong>100</strong></td>
<td><strong>4.4</strong></td>
<td><strong>-2.6</strong></td>
<td><strong>12.8</strong></td>
<td>119.1</td>
<td>153.2</td>
<td>1.29</td>
<td>1.12</td>
<td>1.48*</td>
</tr>
<tr class="odd">
<td colspan="2">PRN</td>
<td>91</td>
<td>95.6</td>
<td>78</td>
<td>91.0</td>
<td>-4.6</td>
<td>-15.0</td>
<td>4.3*</td>
<td>150.4</td>
<td>108.6</td>
<td>0.72</td>
<td>0.58</td>
<td>0.90*</td>
</tr>
<tr class="even">
<td colspan="2">Polio 1</td>
<td>86</td>
<td>100</td>
<td>73</td>
<td>98.6</td>
<td>-1.4</td>
<td>-9.7</td>
<td>4.7*</td>
<td>415.3**</td>
<td>819.2</td>
<td>1.97</td>
<td>1.48</td>
<td>2.63</td>
</tr>
<tr class="odd">
<td colspan="2">Polio 2</td>
<td>86</td>
<td>98.8</td>
<td>73</td>
<td>100</td>
<td>1.2</td>
<td>-5.6</td>
<td>8.6*</td>
<td>514.2**</td>
<td>1261.8</td>
<td>2.45</td>
<td>1.83</td>
<td>3.29</td>
</tr>
<tr class="even">
<td colspan="2">Polio 3</td>
<td>86</td>
<td>100</td>
<td>73</td>
<td>100</td>
<td>0.0</td>
<td>-7.4</td>
<td>5.7*</td>
<td>1729.2**</td>
<td>452.6</td>
<td>0.26</td>
<td>0.20</td>
<td>0.34</td>
</tr>
<tr class="odd">
<td rowspan="2">PRP**</td>
<td><u>&gt;</u>1.0 mcg/ml</td>
<td>90</td>
<td>94.4</td>
<td>78</td>
<td>94.9</td>
<td>0.4</td>
<td>-8.5</td>
<td>10.1*</td>
<td rowspan="2">6.165**</td>
<td rowspan="2">7.822</td>
<td rowspan="2">1.27</td>
<td rowspan="2">0.95</td>
<td rowspan="2">1.69</td>
</tr>
<tr class="even">
<td><u>&gt;</u>0.15 mcg/ml</td>
<td>90</td>
<td>98.9</td>
<td>78</td>
<td>100</td>
<td>1.1</td>
<td>-8.2</td>
<td>5.2*</td>
</tr>
</tbody>
</table>

Group 1: DTPa-HepB-IPV + Hib at 2, 4, and 6 months of age

Group 4: DTPa + HepB + Hib + OPV at 2, 4, and 6 months of age

N = number of subjects tested

‡ Definition of seroprotection/vaccine response provided in Section
3.2.2.

§Clinical limit = GMT ratio of 1.5 for all anti-pertussis antibodies
(anti-PT, anti-FHA, and anti-PRN); 2.0 for anti-HBs

\*Upper limit of 90% CI below clinical limit for non-inferiority

\*\*supportive parameter of secondary interest (clinical limit for
non-inferiority was not specified for these antigens)

> *[Reviewer comment]{.underline}*: Differences in
> seroprotection/vaccine response rates between Group 1 and Group 4 as
> well as GMT ratios between Group 1 and Group 4 one month after
> completion of the three-dose primary vaccination course in subjects
> included in the according to protocol (ATP) immunogenicity analyses
> were within the pre-specified clinical limits for non-inferiority with
> the exception of vaccine response rates for FHA **(bolded)**.

**3.2.4 Pivotal Study: DTPa-HepB-IPV-044 (Lot Consistency and
Manufacturing Bridge)**

**Title:** A double-blind randomized primary vaccination study to
evaluate the lot-to-lot consistency of DTPa-HepB-IPV vaccine
manufactured according to the new manufacturing process and to bridge
the DTPa-HepB-IPV vaccine manufactured according to the new
manufacturing process with the DTPa-HepB-IPV vaccine manufactured by the
initial manufacturing process administered to infants at 2, 4, and 6
months of age co-administered with Hib vaccine (OmniHIB™) in a separate
injection.

**Location:** USA

**Study Period:** 2/11/98-2/3/99

**Investigators:**

Mark M. Blatter, MD: Pittsburgh Pediatric Research

Douglas Eisert, MD: Wenatchee Valley Clinic, WA

Gerald W. Bottenfield, MD: R/D Clinical Research, Inc., Lake Jackson, TX

James M. McCarty, MD: Hill Top Research, Inc., Fresno, CA

Kathryn M. Edwards, MD: Vanderbilt University School of Medicine, TN

Beth W. Nauert, MD: Center for Clinical Research, Austin, TX

**Objectives:**

**Primary Objective:**

-   To evaluate the lot-to-lot consistency in terms of immunogenicity
    for three production lots of DTPa-HepB-IPV vaccine manufactured
    according to the new manufacturing process (second lot series)

    **Secondary Objectives:**

```{=html}
<!-- -->
```
-   To evaluate the lot-to-lot consistency in terms of reactogenicity
    for three production lots of DTPa-HepB-IPV vaccine manufactured
    according to the new manufacturing process (second lot series)

```{=html}
<!-- -->
```
-   To evaluate whether DTPa-HepB-IPV vaccine manufactured according to
    the new manufacturing process (second lot series) results in
    decreased immunogenicity as compared to DTPa-HepB-IPV vaccine
    manufactured according to the initial manufacturing process (first
    lot series): Manufacturing bridge from first to second lot series
    for immunogenicity

-   To evaluate whether DTPa-HepB-IPV vaccine manufactured according to
    the new manufacturing process (second lot series) results in
    increased reactogenicity as compared to DTPa-HepB-IPV vaccine
    manufactured according to the initial manufacturing process (first
    lot series): Manufacturing bridge from first to second lot series
    for safety

    **Schedule:** 2, 4, 6 months of age

(6-12 weeks at time of first vaccination)

Group 1: DTPa-HepB-IPV, Lot A 2nd lot series + Hib (OmniHIB™)

Group 2: DTPa-HepB-IPV, Lot B 2nd lot series + Hib (OmniHIB™)

Group 3: DTPa-HepB-IPV, Lot C 2nd lot series + Hib (OmniHIB™)

Group 4: DTPa-HepB-IPV, 1st lot series + Hib (OmniHIB™)

**Number of subjects**

Number of subjects: Enrolled (ITT Cohort): 484 at five centers (Note:
six centers were initiated but one of the six centers did not enroll any
subjects)

According-to-Protocol (ATP) safety analysis: 477

ATP Immunogenicity analysis (primary analysis): 434

Population group: Healthy infants, 6 to 12 weeks of age at the time of
the first vaccination

# Data analysis for immunogenicity

For each treatment group, and for the pooled second series lots, the
seropositivity rates/seroprotection rates/vaccine response rates one
month after the third vaccination and their exact 95% CIs were
calculated. Antibody titers were summarized by GMTs with their 95% CIs
and Reverse Cumulative Distribution Curves.

[Primary objective:]{.underline} For evaluation of the lot-to-lot
consistency, the pairwise differences between Group 1 and Group 2, Group
1 and Group 3, and Group 2 and Group 3 were evaluated using 90% CIs for
primary and secondary parameters. The primary objective, i.e.,
consistency of the three second series production lots of DTPa-HepB-IPV
vaccine, was reached if for all primary parameters each set of 90%
confidence intervals for pairwise differences were within the clinical
limits defining equivalence for differences in vaccine response/
seroprotection rates \[-10%; +10%\] and for GMT ratios for anti-PT,
anti-PRN and anti-FHA \[0.67; 1.5\].

[Secondary objective:]{.underline} The non-inferiority of the second
series formulation (pooled Groups 1, 2 and 3) as compared to the first
series formulation (Group 4) was also evaluated using 90% CIs for
primary parameters and secondary parameters. If the primary objective
was reached, the second series formulation was considered at least as
immunogenic as the first series formulation, if the upper limits of the
exact 90% CI of treatment effect were below the clinical limits defining
non-inferiority for all primary parameters.

**Primary objective: Lot-to-lot consistency**

**DTPa-HepB-IPV-044: Seroprotection/vaccine response rates for Group 1,
Group 2 and Group 3 with maximum 90% CI limits of pairwise differences
for subjects (ATP cohort for immunogenicity)**

+---------------------+----+---+---+---+---+-----+-----------------+
| ##### Endpoints     | *  |   | * |   | * |     | **Maximum 90%   |
|                     | *G |   | * |   | * |     | CI**            |
|                     | ro |   | G |   | G |     |                 |
|                     | up |   | r |   | r |     | **limit of      |
|                     | 1  |   | o |   | o |     | pairwise**      |
|                     | ** |   | u |   | u |     |                 |
|                     |    |   | p |   | p |     | **              |
|                     |    |   | 2 |   | 3 |     | differences\*** |
|                     |    |   | * |   | * |     |                 |
|                     |    |   | * |   | * |     |                 |
+---------------------+----+---+---+---+---+-----+-----------------+
|                     | *  | * | * | * | * | **  |                 |
|                     | *N | * | * | * | * | Rat |                 |
|                     | ** | R | N | R | N | e** |                 |
|                     |    | a | * | a | * |     |                 |
|                     |    | t | * | t | * |     |                 |
|                     |    | e |   | e |   |     |                 |
|                     |    | * |   | * |   |     |                 |
|                     |    | * |   | * |   |     |                 |
+---------------------+----+---+---+---+---+-----+-----------------+
|                     |    | * |   | * |   | *   |                 |
|                     |    | * |   | * |   | *(% |                 |
|                     |    | ( |   | ( |   | )** |                 |
|                     |    | % |   | % |   |     |                 |
|                     |    | ) |   | ) |   |     |                 |
|                     |    | * |   | * |   |     |                 |
|                     |    | * |   | * |   |     |                 |
+---------------------+----+---+---+---+---+-----+-----------------+
| anti-D \> 0.1       | 1  | 1 | 1 | 1 | 1 | 9   | 7.0%\*\*        |
| IU/mL‡              | 07 | 0 | 1 | 0 | 0 | 9.1 |                 |
|                     |    | 0 | 2 | 0 | 9 |     |                 |
+---------------------+----+---+---+---+---+-----+-----------------+
| anti-T \> 0.1       | 1  | 1 | 1 | 1 | 1 | 100 | 5.5%\*\*        |
| IU/mL‡              | 07 | 0 | 1 | 0 | 0 |     |                 |
|                     |    | 0 | 2 | 0 | 9 |     |                 |
+---------------------+----+---+---+---+---+-----+-----------------+
| Vaccine response to | 1  | 1 | 1 | 9 | 1 | 100 | 6.8%\*\*        |
| PT‡                 | 07 | 0 | 1 | 9 | 0 |     |                 |
|                     |    | 0 | 2 | . | 9 |     |                 |
|                     |    |   |   | 1 |   |     |                 |
+---------------------+----+---+---+---+---+-----+-----------------+
| **Vaccine response  | ** | * | * | * | * | *   | **11.4%**       |
| to FHA‡**           | 97 | * | * | * | * | *10 |                 |
|                     | ** | 9 | 1 | 9 | 1 | 0** |                 |
|                     |    | 9 | 0 | 6 | 0 |     |                 |
|                     |    | . | 4 | . | 2 |     |                 |
|                     |    | 0 | * | 2 | * |     |                 |
|                     |    | * | * | * | * |     |                 |
|                     |    | * |   | * |   |     |                 |
+---------------------+----+---+---+---+---+-----+-----------------+
| **Vaccine response  | *  | * | * | * | * | **  | **17.8%**       |
| to PRN‡**           | *1 | * | * | * | * | 91. |                 |
|                     | 07 | 9 | 1 | 8 | 1 | 7** |                 |
|                     | ** | 1 | 1 | 3 | 0 |     |                 |
|                     |    | . | 2 | . | 9 |     |                 |
|                     |    | 6 | * | 9 | * |     |                 |
|                     |    | * | * | * | * |     |                 |
|                     |    | * |   | * |   |     |                 |
+---------------------+----+---+---+---+---+-----+-----------------+
| anti-HBs \> 10      | 1  | 9 | 1 | 9 | 1 | 100 | 8.2%\*\*        |
| mIU/mL‡             | 07 | 9 | 1 | 8 | 0 |     |                 |
|                     |    | . | 2 | . | 9 |     |                 |
|                     |    | 1 |   | 2 |   |     |                 |
+---------------------+----+---+---+---+---+-----+-----------------+
| anti-Polio 1 \> 8‡  | 1  | 1 | 1 | 1 | 1 | 100 | 5.6%\*\*        |
|                     | 07 | 0 | 1 | 0 | 0 |     |                 |
|                     |    | 0 | 1 | 0 | 8 |     |                 |
+---------------------+----+---+---+---+---+-----+-----------------+
| anti-Polio 2 \> 8‡  | 1  | 1 | 1 | 1 | 1 | 100 | 5.6%\*\*        |
|                     | 07 | 0 | 1 | 0 | 0 |     |                 |
|                     |    | 0 | 1 | 0 | 8 |     |                 |
+---------------------+----+---+---+---+---+-----+-----------------+
| anti-Polio 3 \> 8‡  | 1  | 1 | 1 | 1 | 1 | 100 | 5.6%\*\*        |
|                     | 07 | 0 | 1 | 0 | 0 |     |                 |
|                     |    | 0 | 0 | 0 | 8 |     |                 |
+---------------------+----+---+---+---+---+-----+-----------------+
| anti-PRP \> 1.0     | 1  | 9 | 1 | 8 | 1 | 9   | 12.5%           |
| mcg/mL†             | 07 | 2 | 1 | 9 | 0 | 0.8 |                 |
|                     |    | . | 2 | . | 9 |     |                 |
|                     |    | 5 |   | 3 |   |     |                 |
+---------------------+----+---+---+---+---+-----+-----------------+
| anti-PRP \> 0.15    | 1  | 1 | 1 | 1 | 1 | 100 | 5.5%            |
| mcg/mL†             | 07 | 0 | 1 | 0 | 0 |     |                 |
|                     |    | 0 | 2 | 0 | 9 |     |                 |
+---------------------+----+---+---+---+---+-----+-----------------+

Group 1: DTPa-HBV-IPV, second series Lot A + Hib

Group 2: DTPa-HBV-IPV, second series Lot B + Hib

Group 3: DTPa-HBV-IPV, second series Lot C + Hib

N = number of subjects tested

\* highest value among the limits of exact 90% CIs for all pairwise
differences between groups 1, 2, and 3

\*\*Maximum 90% CI limit of pairwise differences below clinical limit
for equivalence

Clinical limit = 10% difference in seroprotection rates except for
anti-PRP \> 0.15 mcg/mL where limit = 5% difference

Vaccine response to PT, FHA, and PRN was defined as appearance of
antibodies in subjects who were initially seronegative, and at least
maintenance of prevaccination antibody titers in those who were

initially seropositive.

‡: parameter of primary interest

† supportive parameter of secondary interest

> *Reviewer comment*: When the immune response in terms of
> seroresponse/vaccine response rates to lots A, B, and C in the second
> lot series underwent pairwise comparison, the difference in
> seroresponse/vaccine response rate was within the prespecified limit
> of 10% for equivalence (lot consistency), with the exception of the
> response rates to pertactin and FHA **(bolded)**.

**DTPa-HepB-IPV-044: Post-vaccination GMTs in Group 1, Group 2 and Group
3 with maximum 90% CI limits of pairwise ratios (ATP cohort for
immunogenicity)**

+------------+----+-----+----+-----+---+-----+---------------------+
| #          | *  |     | *  |     | * |     | ######## Maxi       |
|  Endpoints | *G |     | *G |     | * |     | mum 90% CI limit of |
|            | ro |     | ro |     | G |     |                     |
|            | up |     | up |     | r |     | **pairwise          |
|            | 1  |     | 2  |     | o |     | ratio\***           |
|            | ** |     | ** |     | u |     |                     |
|            |    |     |    |     | p |     |                     |
|            |    |     |    |     | 3 |     |                     |
|            |    |     |    |     | * |     |                     |
|            |    |     |    |     | * |     |                     |
+------------+----+-----+----+-----+---+-----+---------------------+
|            | *  | *   | *  | *   | * | *   |                     |
|            | *N | *GM | *N | *GM | * | *GM |                     |
|            | ** | T** | ** | T** | N | T** |                     |
|            |    |     |    |     | * |     |                     |
|            |    |     |    |     | * |     |                     |
+------------+----+-----+----+-----+---+-----+---------------------+
| anti-D†    | 1  | 1.  | 1  | 1.  | 1 | 1.  | 1.22                |
|            | 07 | 050 | 12 | 049 | 0 | 047 |                     |
|            |    |     |    |     | 9 |     |                     |
+------------+----+-----+----+-----+---+-----+---------------------+
| anti-T†    | 1  | 2.  | 1  | 2.  | 1 | 2.  | 1.34                |
|            | 07 | 651 | 12 | 561 | 0 | 910 |                     |
|            |    |     |    |     | 9 |     |                     |
+------------+----+-----+----+-----+---+-----+---------------------+
| anti-PT‡   | 1  | 9   | 1  | 9   | 1 | 10  | 1.30\*\*            |
|            | 07 | 3.1 | 12 | 9.1 | 0 | 5.3 |                     |
|            |    |     |    |     | 9 |     |                     |
+------------+----+-----+----+-----+---+-----+---------------------+
| anti-FHA‡  | 97 | 16  | 1  | 15  | 1 | 19  | 1.41\*\*            |
|            |    | 4.4 | 04 | 1.0 | 0 | 0.2 |                     |
|            |    |     |    |     | 2 |     |                     |
+------------+----+-----+----+-----+---+-----+---------------------+
| **a        | *  | **1 | *  | **  | * | **1 | **1.59**            |
| nti-PRN‡** | *1 | 15. | *1 | 95. | * | 26. |                     |
|            | 07 | 4** | 12 | 9** | 1 | 7** |                     |
|            | ** |     | ** |     | 0 |     |                     |
|            |    |     |    |     | 9 |     |                     |
|            |    |     |    |     | * |     |                     |
|            |    |     |    |     | * |     |                     |
+------------+----+-----+----+-----+---+-----+---------------------+
| anti-HBs§  | 1  | 156 | 1  | 157 | 1 | 193 | 1.73\*\*            |
|            | 07 | 3.8 | 12 | 5.5 | 0 | 0.4 |                     |
|            |    |     |    |     | 9 |     |                     |
+------------+----+-----+----+-----+---+-----+---------------------+
| anti-Polio | 1  | 29  | 1  | 32  | 1 | 37  | 1.60                |
| 1†         | 07 | 5.3 | 11 | 0.6 | 0 | 1.5 |                     |
|            |    |     |    |     | 8 |     |                     |
+------------+----+-----+----+-----+---+-----+---------------------+
| anti-Polio | 1  | 27  | 1  | 28  | 1 | 40  | 1.86                |
| 2†         | 07 | 7.7 | 11 | 8.3 | 0 | 6.4 |                     |
|            |    |     |    |     | 8 |     |                     |
+------------+----+-----+----+-----+---+-----+---------------------+
| anti-Polio | 1  | 84  | 1  | 80  | 1 | 105 | 1.69                |
| 3†         | 07 | 8.3 | 10 | 0.9 | 0 | 7.4 |                     |
|            |    |     |    |     | 8 |     |                     |
+------------+----+-----+----+-----+---+-----+---------------------+
| anti-PRP†  | 1  | 5.  | 1  | 4.  | 1 | 6.  | 1.67                |
|            | 07 | 107 | 12 | 955 | 0 | 431 |                     |
|            |    |     |    |     | 9 |     |                     |
+------------+----+-----+----+-----+---+-----+---------------------+

Group 1: DTPa-HBV-IPV, second series Lot A + Hib

Group 2: DTPa-HBV-IPV, second series Lot B+ Hib

Group 3: DTPa-HBV-IPV, second series Lot C + Hib

N = number of subjects tested

\* highest value among the limits of 90% CIs for all pairwise ratios
between groups 1, 2 and 3

\*\* Maximum 90% CI limit of pairwise ratios below clinical limit for
equivalence

Clinical limit = GMT ratio of 1.5 for all anti-pertussis antibodies
(anti-PT, anti-FHA, and anti-PRN); 2.0 for anti-HBs

‡: parameter of primary interest

§: main parameter of secondary interest

† supportive parameter of secondary interest (clinical limit for
non-inferiority was not specified for these endpoints)

> *Reviewer comment:* With respect to the pairwise ratios of GMTs, the
> prespecified endpoints for non-inferiority between the three lots were
> met, with the exception of the GMTs to pertactin **(bolded)**.
>
> To address the fact that the *a priori* clinical limits defining
> equivalence for lot-to-lot consistency were not met with respect to
> all pertussis antigens, the manufacturer hypothesized that high
> prevaccination titers affected the immune response to pertussis
> components. A reanalysis of the data was performed as follows:

Study DTPa-HepB-IPV-044: Re-analysis of the consistency of the Second
Lot Series of the SBB DTPa-HepB-IPV vaccine in terms of the immune
response to the pertussis antigens after adjustment for pre-vaccination
titer: vaccine response calculated after elimination of subjects with
high\* pre-vaccination titers; GMT analyzed after adjustment for
pre-vaccination titer (ANCOVA) (BLA Table 8.III.1.7)

  ------------- ------------- ---------- --------- ---------- --------- ---------- ------------ ---------- ----- ------- ----- ------- ----- ----------
  **Antigen**   **Vaccine                                                                       **GMT‡**                                     
                Response†**                                                                                                                  

                **\                      **\                  **\                  **Max 90% CI **\              **\           **\           **Max 90%
                Group 1**                Group 2**            Group 3**            limit for    Group 1**        Group         Group         CI limit
                                                                                   difference                    2**           3**           for ratio
                                                                                   between                                                   between
                                                                                   lots**                                                    lots**

                **N**         **%**      **N**     **%**      **N**     **%**                   **N**            **N**         **N**         

  PT            106           100        109       100        111       99.1       6.9§         107        93    109     104   112     101   1.3§

  **FHA**       **97**        **99.0**   **101**   **100**    **104**   **96.2**   **11.4**     97         165   102     187   104     152   1.4§

  **PRN**       **97**        **96.9**   **104**   **95.2**   **101**   **92.1**   **14.9**     107        116   109     121   112     100   1.4§
  ------------- ------------- ---------- --------- ---------- --------- ---------- ------------ ---------- ----- ------- ----- ------- ----- ----------

Group 1: DTPa-HBV-IPV, second series Lot A+ Hib

Group 2: DTPa-HBV-IPV, second series Lot B + Hib

Group 3: DTPa-HBV-IPV, second series Lot C+ Hib

\% = Percentage of subjects with VR

\*Anti-PT titer 54 EL.U/ml; Anti-FHA titer 119 EL.U/ml; Anti-PRN titer
56 EL.U/ml

†VR definition: for pertussis antibodies: initially seronegative
subjects with post-vaccination titer cut-off (5 EL.U/ml) or

initially seropositive subjects with post-vaccination titer
pre-vaccination titer

‡Units for Pertussis antibodies: EL.U/ml §Limit within clinical limits
of equivalence

*Reviewer comment*: SBB hypothesized that failure to meet the
equivalence criteria for demonstrating lot consistency with respect to
pertactin and FHA may be due to an imbalance in the groups in the number
of subjects with high prevaccination titers (from maternal antibodies)
to pertussis antigens. However, even after excluding subjects with high
pre-vaccination titers, the maximum difference between the lots still
falls outside the prespecified limit of 10% with respect to vaccine
response rates to FHA and pertactin **(bolded**). The adjusted GMTs,
however, are within prespecified limits.

**Supportive Data for Lot-to-lot Consistency of Second Lot Series**

Additional data to support the lot-to-lot consistency of the second lot
series were provided by studies DTPa-HepB-IPV/Hib-027 conducted in the
US under a 2, 4, 6 month schedule. This study evaluated the same lots of
DTPa-HepB-IPV used in DTPa-HepB-IPV-044 but evaluated SBB's
DTPa-HepB-IPV/Hib vaccine (DTPa-HepB-IPV admixed with SBB's PRP-T prior
to injection). DTPa-HepB-IPV/Hib is not licensed in the U.S. Lot-to-lot
consistency testing for the three pertussis antigens PT, FHA, and
pertactin was performed using an equivalence approach and the same
prespecified criteria as in Study DTPa-HepB-IPV-044. Results are shown
below.

**Study DTPa-HepB-IPV/Hib-027: Differences in [vaccine response
rates]{.underline} to PT, FHA and PRN with their**

**90% CIs between paired consistency lots (Group 2 and Group 3, Group 2
and Group 4, and Group 3 and Group 4) \-- ATP cohort for Immunogenicity
(BLA amendment 8/3/00, Table 23.b-1)**

+----------------------+------+-----+---+----+---------+----+-------+
| **Endpoints**        | **G  |     | * |    | **Diffe |    |       |
|                      | roup |     | * |    | rence** |    |       |
|                      | 3**  |     | G |    |         |    |       |
|                      |      |     | r |    | *       |    |       |
|                      |      |     | o |    | *(Group |    |       |
|                      |      |     | u |    | 2 minus |    |       |
|                      |      |     | p |    | Group   |    |       |
|                      |      |     | 2 |    | 3)**    |    |       |
|                      |      |     | * |    |         |    |       |
|                      |      |     | * |    |         |    |       |
+----------------------+------+-----+---+----+---------+----+-------+
|                      | ##   | **  | * | ** | **Dif   | *  |       |
|                      | ###  | Rat | * | Ra | ference | *9 |       |
|                      |      | e** | N | te | of**    | 0% |       |
|                      | ###  |     | * | ** |         | CI |       |
|                      | ## N | *   | * |    | **rates | ** |       |
|                      |      | *(% |   | *  | (%)**   |    |       |
|                      |      | )** |   | *( |         |    |       |
|                      |      |     |   | %) |         |    |       |
|                      |      |     |   | ** |         |    |       |
+----------------------+------+-----+---+----+---------+----+-------+
|                      |      |     |   |    |         | ** | *     |
|                      |      |     |   |    |         | LL | *UL** |
|                      |      |     |   |    |         | ** |       |
+----------------------+------+-----+---+----+---------+----+-------+
| Vaccine response to  | 227  | 97  | 2 | 9  | 1.41    | -  | 5     |
| PT                   |      | .80 | 5 | 9. |         | 1. | .09\* |
|                      |      |     | 2 | 21 |         | 48 |       |
+----------------------+------+-----+---+----+---------+----+-------+
| Vaccine response to  | 206  | 99  | 2 | 9  | -0.36   | -  | 2     |
| FHA                  |      | .03 | 2 | 8. |         | 3. | .85\* |
|                      |      |     | 6 | 67 |         | 88 |       |
+----------------------+------+-----+---+----+---------+----+-------+
| Vaccine response to  | 230  | 94  | 2 | 9  | 2.49    | -  | 7     |
| PRN                  |      | .35 | 5 | 6. |         | 1. | .13\* |
|                      |      |     | 3 | 84 |         | 53 |       |
+----------------------+------+-----+---+----+---------+----+-------+
|                      | **G  |     | * |    | **Diffe |    |       |
|                      | roup |     | * |    | rence** |    |       |
|                      | 4**  |     | G |    |         |    |       |
|                      |      |     | r |    | *       |    |       |
|                      |      |     | o |    | *(Group |    |       |
|                      |      |     | u |    | 2 minus |    |       |
|                      |      |     | p |    | Group   |    |       |
|                      |      |     | 2 |    | 4)**    |    |       |
|                      |      |     | * |    |         |    |       |
|                      |      |     | * |    |         |    |       |
+----------------------+------+-----+---+----+---------+----+-------+
| Vaccine response to  | 249  | 98  | 2 | 9  | 0.81    | -  | 3     |
| PT                   |      | .39 | 5 | 9. |         | 2. | .94\* |
|                      |      |     | 2 | 21 |         | 09 |       |
+----------------------+------+-----+---+----+---------+----+-------+
| Vaccine response to  | 241  | 99  | 2 | 9  | -0.50   | -  | 2     |
| FHA                  |      | .17 | 2 | 8. |         | 3. | .40\* |
|                      |      |     | 6 | 67 |         | 85 |       |
+----------------------+------+-----+---+----+---------+----+-------+
| Vaccine response to  | 251  | 95  | 2 | 9  | 1.22    | -  | 5     |
| PRN                  |      | .62 | 5 | 6. |         | 2. | .32\* |
|                      |      |     | 3 | 84 |         | 73 |       |
+----------------------+------+-----+---+----+---------+----+-------+
|                      | **G  |     | * |    | **Diffe |    |       |
|                      | roup |     | * |    | rence** |    |       |
|                      | 4**  |     | G |    |         |    |       |
|                      |      |     | r |    | *       |    |       |
|                      |      |     | o |    | *(Group |    |       |
|                      |      |     | u |    | 3 minus |    |       |
|                      |      |     | p |    | Group   |    |       |
|                      |      |     | 3 |    | 4)**    |    |       |
|                      |      |     | * |    |         |    |       |
|                      |      |     | * |    |         |    |       |
+----------------------+------+-----+---+----+---------+----+-------+
| Vaccine response to  | 249  | 98  | 2 | 9  | -0.59   | -  | 2     |
| PT                   |      | .39 | 2 | 7. |         | 4. | .59\* |
|                      |      |     | 7 | 80 |         | 40 |       |
+----------------------+------+-----+---+----+---------+----+-------+
| Vaccine response to  | 241  | 99  | 2 | 9  | -0.14   | -  | 2     |
| FHA                  |      | .17 | 0 | 9. |         | 3. | .70\* |
|                      |      |     | 6 | 03 |         | 56 |       |
+----------------------+------+-----+---+----+---------+----+-------+
| Vaccine response to  | 251  | 95  | 2 | 9  | -1.27   | -  | 2     |
| PRN                  |      | .62 | 3 | 4. |         | 6. | .98\* |
|                      |      |     | 0 | 35 |         | 06 |       |
+----------------------+------+-----+---+----+---------+----+-------+

Group 2: DTPa-HepB-IPV lot A mixed with Hib lot A

Group 3: DTPa-HepB-IPV lot B mixed with Hib lot B

Group 4: DTPa-HepB-IPV lot C mixed with Hib lot C

N = number of subjects with pre- and post-vaccination results available

Vaccine response defined as appearance of antibodies in initially
seronegative subjects and at least maintenance of pre-vaccination titers
in initially seropositive subjects

\*Upper and lower limits of 90% CIs within clinical limits for
equivalence

Clinical limits = -10%, +10% difference in vaccine response rates

**Study DTPa-HepB-IPV/Hib-027: Ratios of post-vaccination
[GMTs]{.underline} for anti-PT, anti-FHA, and anti-PRN**

**with their 90% CIs between paired consistency lots (Group 2 and Group
3, Group 2 and Group 4, and Group 3 and Group 4) \-- ATP cohort for
immunogenicity (BLA amendment 8/3/00-Table 23.b-2)**

+------------+-----+-------+-----+------+------------+-----+--------+
| ####       | *   |       | *   |      | **Group 2  |     |        |
| # Antibody | *Gr |       | *Gr |      | divided by |     |        |
|            | oup |       | oup |      | Group 3**  |     |        |
|            | 2** |       | 3** |      |            |     |        |
+------------+-----+-------+-----+------+------------+-----+--------+
|            |     |       |     |      |            | **  |        |
|            |     |       |     |      |            | 90% |        |
|            |     |       |     |      |            | C   |        |
|            |     |       |     |      |            | I** |        |
+------------+-----+-------+-----+------+------------+-----+--------+
|            | **  | **    | **  | **G  | **Ratio of | **L | **UL** |
|            | N** | GMT** | N** | MT** | GMTs**     | L** |        |
+------------+-----+-------+-----+------+------------+-----+--------+
| anti-PT    | 302 | 70.7  | 274 | 82.3 | 0.86       | 0   | 0.94\* |
|            |     |       |     |      |            | .79 |        |
+------------+-----+-------+-----+------+------------+-----+--------+
| anti-FHA   | 273 | 321.7 | 248 | 2    | 1.09       | 1   | 1.18\* |
|            |     |       |     | 96.2 |            | .00 |        |
+------------+-----+-------+-----+------+------------+-----+--------+
| anti-PRN   | 303 | 116.1 | 276 | 1    | 0.95       | 0   | 1.07\* |
|            |     |       |     | 22.8 |            | .84 |        |
+------------+-----+-------+-----+------+------------+-----+--------+
|            | *   |       |     | **G  |            |     | *      |
|            | *Gr |       |     | roup |            |     | *Group |
|            | oup |       |     | 4**  |            |     | 2      |
|            | 2** |       |     |      |            |     | d      |
|            |     |       |     |      |            |     | ivided |
|            |     |       |     |      |            |     | by     |
|            |     |       |     |      |            |     | Group  |
|            |     |       |     |      |            |     | 4**    |
+------------+-----+-------+-----+------+------------+-----+--------+
| anti-PT    | 302 | 70.7  | 289 | 70.7 | 1.00       | 0   | 1.09\* |
|            |     |       |     |      |            | .92 |        |
+------------+-----+-------+-----+------+------------+-----+--------+
| anti-FHA   | 273 | 321.7 | 281 | 3    | 1.00       | 0   | 1.08\* |
|            |     |       |     | 22.5 |            | .92 |        |
+------------+-----+-------+-----+------+------------+-----+--------+
| anti-PRN   | 303 | 116.1 | 290 | 1    | 1.01       | 0   | 1.14\* |
|            |     |       |     | 14.6 |            | .90 |        |
+------------+-----+-------+-----+------+------------+-----+--------+
|            | *   |       |     | **G  |            |     | *      |
|            | *Gr |       |     | roup |            |     | *Group |
|            | oup |       |     | 4**  |            |     | 3      |
|            | 3** |       |     |      |            |     | d      |
|            |     |       |     |      |            |     | ivided |
|            |     |       |     |      |            |     | by     |
|            |     |       |     |      |            |     | Group  |
|            |     |       |     |      |            |     | 4**    |
+------------+-----+-------+-----+------+------------+-----+--------+
| anti-PT    | 274 | 82.3  | 289 | 70.7 | 1.16       | 1   | 1.27\* |
|            |     |       |     |      |            | .07 |        |
+------------+-----+-------+-----+------+------------+-----+--------+
| anti-FHA   | 248 | 296.2 | 281 | 3    | 0.92       | 0   | 1.00\* |
|            |     |       |     | 22.5 |            | .84 |        |
+------------+-----+-------+-----+------+------------+-----+--------+
| anti-PRN   | 276 | 122.8 | 290 | 1    | 1.07       | 0   | 1.21\* |
|            |     |       |     | 14.6 |            | .95 |        |
+------------+-----+-------+-----+------+------------+-----+--------+

Group 2: DTPa-HepB-IPV lot A mixed with Hib lot A

Group 3: DTPa-HepB-IPV lot B mixed with Hib lot B

Group 4: DTPa-HepB-IPV lot C mixed with Hib lot C

N = number of subjects with available results

\*Upper and lower limits of 90% CIs within clinical limits for
equivalence

Clinical limits = GMT ratio between 0.67, 1.5

> *Reviewer comment:* Data from Study DTPa-HepB-IPV/Hib-027 utilized the
> same lots of DTPa-HepB-IPV as in DTPa-HepB-IPV. In these studies, all
> prespecified pertussis immunogenicity endpoints for demonstrating
> lot-to-lot consistency of the second lot series were met.
>
> In addition, DTPa-HepB-IPV/Hib-027 included a comparison with
> separately administered U.S. licensed vaccines DTPa, hepatitis B, OPV
> and Hib (Infanrix®, Engerix-B®, ORIUME®, and OmniHIB™, respectively),
> allowing a direct comparison of the pertussis immune responses of
> DTPa-HepB-IPV/Hib and separately administered Infanrix®.

**DTPa-HepB-IPV/Hib-027 -- Vaccine response rates and GMTs to pertussis
antigens-ATP cohort**

+-------+--------+-------+-------+-------+---+-------+-------+--------+
| **Va  |        |       |       |       |   | **    |       |        |
| ccine |        |       |       |       |   | GMT** |       |        |
| Respo |        |       |       |       |   |       |       |        |
| nse** |        |       |       |       |   |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
| **    | *      |       |       |       |   |       |       |        |
| Antib | *Group |       |       |       |   |       |       |        |
| ody** | 1**    |       |       |       |   |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
|       | **N**  | **%** | **95% |       |   |       | **95% |        |
|       |        |       | CI**  |       |   |       | CI**  |        |
|       |        |       |       |       |   |       |       |        |
|       |        |       | **LL  |       |   |       | **LL  |        |
|       |        |       | UL**  |       |   |       | UL**  |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
| An    | 260    | 100.0 | 98.6  | 100   | 5 |       | 50.3  | 58.3   |
| ti-PT |        |       |       |       | 4 |       |       |        |
|       |        |       |       |       | . |       |       |        |
|       |        |       |       |       | 2 |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
| Ant   | 245    | 100   | 98.5  | 100   | 3 |       | 309.5 | 358.1  |
| i-FHA |        |       |       |       | 3 |       |       |        |
|       |        |       |       |       | 2 |       |       |        |
|       |        |       |       |       | . |       |       |        |
|       |        |       |       |       | 9 |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
| Ant   | 260    | 100   | 98.6  | 38.0  | 1 |       | 100.5 | 124.7  |
| i-PRN |        |       |       |       | 1 |       |       |        |
|       |        |       |       |       | 2 |       |       |        |
|       |        |       |       |       | . |       |       |        |
|       |        |       |       |       | 0 |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
|       | *      |       |       |       |   |       |       |        |
|       | *Group |       |       |       |   |       |       |        |
|       | 2**    |       |       |       |   |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
| An    | 302    | 100   | 98.8  | 100   | 7 |       | 65.9  | 75.9   |
| ti-PT |        |       |       |       | 0 |       |       |        |
|       |        |       |       |       | . |       |       |        |
|       |        |       |       |       | 7 |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
| Ant   | 273    | 100   | 98.7  | 100   | 3 |       | 299.6 | 345.5  |
| i-FHA |        |       |       |       | 2 |       |       |        |
|       |        |       |       |       | 1 |       |       |        |
|       |        |       |       |       | . |       |       |        |
|       |        |       |       |       | 7 |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
| Ant   | 303    | 99.3  | 97.3  | 99.9  | 1 |       | 104.8 | 128.8  |
| i-PRN |        |       |       |       | 1 |       |       |        |
|       |        |       |       |       | 6 |       |       |        |
|       |        |       |       |       | . |       |       |        |
|       |        |       |       |       | 1 |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
|       | *      |       |       |       |   |       |       |        |
|       | *Group |       |       |       |   |       |       |        |
|       | 3**    |       |       |       |   |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
| An    | 274    | 100   | 98.7  | 100   | 8 |       | 76.7  | 88.4   |
| ti-PT |        |       |       |       | 2 |       |       |        |
|       |        |       |       |       | . |       |       |        |
|       |        |       |       |       | 3 |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
| Ant   | 248    | 100   | 98.5  | 100   | 2 |       | 275.4 | 318.6  |
| i-FHA |        |       |       |       | 9 |       |       |        |
|       |        |       |       |       | 6 |       |       |        |
|       |        |       |       |       | . |       |       |        |
|       |        |       |       |       | 2 |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
| Ant   | 276    | 100   | 98.7  | 100   | 1 |       | 110.8 | 136.0  |
| i-PRN |        |       |       |       | 2 |       |       |        |
|       |        |       |       |       | 2 |       |       |        |
|       |        |       |       |       | . |       |       |        |
|       |        |       |       |       | 8 |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
|       | *      |       |       |       |   |       |       |        |
|       | *Group |       |       |       |   |       |       |        |
|       | 4**    |       |       |       |   |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
| An    | 289    | 100.0 | 98.7  | 100   | 7 |       | 65.5  | 76.3   |
| ti-PT |        |       |       |       | 0 |       |       |        |
|       |        |       |       |       | . |       |       |        |
|       |        |       |       |       | 7 |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
| Ant   | 281    | 100   | 98.7  | 100   | 3 |       | 301.6 | 344.8  |
| i-FHA |        |       |       |       | 2 |       |       |        |
|       |        |       |       |       | 2 |       |       |        |
|       |        |       |       |       | . |       |       |        |
|       |        |       |       |       | 5 |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
| Ant   | 290    | 100   | 98.7  | 100   | 1 |       | 104.3 | 125.9  |
| i-PRN |        |       |       |       | 1 |       |       |        |
|       |        |       |       |       | 4 |       |       |        |
|       |        |       |       |       | . |       |       |        |
|       |        |       |       |       | 6 |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
|       | **     |       |       |       |   |       |       |        |
|       | Pooled |       |       |       |   |       |       |        |
|       | groups |       |       |       |   |       |       |        |
|       | 2, 3,  |       |       |       |   |       |       |        |
|       | 4**    |       |       |       |   |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
| An    | 865    | 100   | 99.6  | 100   | 7 |       | 71.1  | 77.4   |
| ti-PT |        |       |       |       | 4 |       |       |        |
|       |        |       |       |       | . |       |       |        |
|       |        |       |       |       | 2 |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
| Ant   | 802    | 100   | 99.5  | 100   | 3 |       | 301.4 | 326.8  |
| i-FHA |        |       |       |       | 1 |       |       |        |
|       |        |       |       |       | 3 |       |       |        |
|       |        |       |       |       | . |       |       |        |
|       |        |       |       |       | 9 |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+
| Ant   | 869    | 99.8  | 99.2  | 100   | 1 |       | 111.1 | 124.7  |
| i-PRN |        |       |       |       | 1 |       |       |        |
|       |        |       |       |       | 7 |       |       |        |
|       |        |       |       |       | . |       |       |        |
|       |        |       |       |       | 7 |       |       |        |
+-------+--------+-------+-------+-------+---+-------+-------+--------+

Group 1: DTPa + HepB + OPV + Hib

Group 2: DTPa-HepB-IPV lot A mixed with Hib lot A

Group 3: DTPa-HepB-IPV lot B mixed with Hib lot B

Group 4: DTPa-HepB-IPV lot C mixed with Hib lot C

N = number of subjects with results available

%=percentage of seropositive subjects

Vaccine response defined as appearance of antibodies in initially
seronegative subjects and at least

maintenance of pre-vaccination titers in initially seropositive subjects

> *Reviewer comment:* Unlike Study DTPa-HepB-IPV-044, Study
> DTPa-HepB-IPV/Hib-027 included a control group receiving separately
> administered Infanrix®. Immune responses to pertussis components
> (vaccine response and GMTs) were comparable between individual lots of
> DTPa-HepB-IPV/Hib as well pooled lots of DTPa-HepB-IPV/Hib and
> separately administered DTPa, HepB, OPV and Hib.

**Manufacturing bridge: 1^st^ to 2^nd^ lot series**

DTPa-HepB-IPV-044: Comparison of the immunogenicity of the First and
Second Lot Series vaccine (BLA Table 8.III.1-10)

  ------------- -------------------------- ---------- --------- ----------- ---------- ---------- ---------- ---------- ---------- ----------- ------- ----- ------- ----------- ------ ------- ---------- -- ----- -------- ------- --------
  **Antigen**   **Seroprotection/Vaccine                                                                                **GMT†**                                                                                                     
                response\***                                                                                                                                                                                                         

                **2^nd^ Lot Series‡**                           **1^st^ lot            **1^st^                                     **2^nd^ Lot                       **1^st^ lot                **1^st^                              
                                                                Series§**              minus\                                      Series‡**                         Series§**                  divided                              
                                                                                       2^nd^ Lot                                                                                                by\                                  
                                                                                       Series**                                                                                                 2^nd^ Lot                            
                                                                                                                                                                                                Series**                             

                **N**                      **%**      **N**                 **%**      **%**      **90% CI**                                   **N**         **%**   **N**              **%**                                **90%   
                                                                                                                                                                                                                             CI**    

                                                                                                  **LL**     **UL**                                                                                                 **LL**           **UL**

  Diphtheria    328                        99.7       106                   99.1       -0.6       -5.4       1.9 ¶                                     ---   ---     ---         ---                          ---   ---              ---

  Tetanus       328                        100        106                   100        0          -4.2       1.9 ¶                                     ---   ---     ---         ---                          ---   ---              ---

  PT            328                        99.7       104                   99.0       -0.7       -5.6       1.8 ¶                                     328   99      106         101                          1.0   0.9              1.1¶

  FHA           303                        98.3       99                    96.0       -2.4       -8.7       1.8 ¶                                     303   168     101         163                          1.0   0.9              1.1¶

  **PRN**       **328**                    **89.0**   **104**               **95.2**   **6.2**    **-0.5**   **12.3**                                  328   112     106         133                          1.2   1.0              1.4¶

  HBs           328                        99.1       106                   99.1       0          -5.1       2.8 ¶                                     328   1682    106         1455                         0.9   0.7              1.1¶

  Polio 1       326                        100        105                   100        0          -4.3       1.9 ¶                                     ---   ---     ---         ---                          ---   ---              ---

  Polio 2       326                        100        105                   100        0          -4.3       1.9 ¶                                     ---   ---     ---         ---                          ---   ---              ---

  Polio 3       325                        100        105                   100        0          -4.3       1.9 ¶                                     ---   ---     ---         ---                          ---   ---              ---
  ------------- -------------------------- ---------- --------- ----------- ---------- ---------- ---------- ---------- ---------- ----------- ------- ----- ------- ----------- ------ ------- ---------- -- ----- -------- ------- --------

\% = Percentage of subjects with SP/ VR

--- = No pre-specified limit of non-inferiority

†Units**:** •Pertussis antibodies: EL.U/ml

•HBs antibodies: mIU/ml

•Polio: None

‡Pooled data from lots Second Lot Series (Lots A, B, C) §First Lot
Series ¶Upper limit below clinical limit for non-inferiority

*Reviewer comment:* With respect to manufacturing bridging from the
1^st^ lot series to 2^nd^ lot series, SBB met their prespecified
endpoints with the exception of vaccine response rates to pertactin
**(bolded)**.

> To address the fact that the *a priori* clinical limits defining
> equivalence for manufacturing bridging were not met with respect to
> all pertussis antigens, the manufacturer hypothesized that high
> prevaccination titers (from maternal antibodies) affected the immune
> response to pertussis components. A reanalysis of the data was
> performed as follows:

**Study DTPa-HepB-IPV-044: Re-analysis of the comparison of the
immunogenicity of the First**

**and Second Lot Series of the SBB DTPa-HepB-IPV vaccine in terms of the
immune response to the pertussis antigens after adjustment for
pre-vaccination titer: vaccine response calculated after elimination of
subjects with high\* pre-vaccination titers; GMT analyzed after
adjustment for pre-vaccination titer (ANCOVA) (Table 8.III.1- 11)**

<table>
<colgroup>
<col style="width: 15%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 4%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 8%" />
<col style="width: 10%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="4"><h5 id="antigen">Antigen</h5></td>
<td colspan="7"><strong>VR†</strong></td>
<td colspan="7"><strong>GMT (EL.U/ml)</strong></td>
</tr>
<tr class="even">
<td colspan="2"><strong>2<sup>nd</sup> Lot Series‡</strong></td>
<td colspan="2"><p><strong>1<sup>st</sup> lot</strong></p>
<p><strong>Series</strong></p></td>
<td colspan="3"><p><strong>1<sup>st</sup> minus</strong></p>
<p><strong>2<sup>nd</sup>Lot Series</strong></p></td>
<td colspan="2"><p><strong>2<sup>nd</sup>Lot</strong></p>
<p><strong>Series‡</strong></p></td>
<td colspan="2"><p><strong>1<sup>st</sup> lot</strong></p>
<p><strong>Series</strong></p></td>
<td colspan="3"><p><strong>1<sup>st</sup> divided by</strong></p>
<p><strong>2<sup>nd</sup> Lot Series</strong></p></td>
</tr>
<tr class="odd">
<td rowspan="2"><strong>N</strong></td>
<td rowspan="2"><strong>%</strong></td>
<td rowspan="2"><strong>N</strong></td>
<td rowspan="2"><strong>%</strong></td>
<td rowspan="2"><strong>%</strong></td>
<td colspan="2"><strong>90% CI</strong></td>
<td rowspan="2"><strong>N</strong></td>
<td rowspan="2"></td>
<td rowspan="2"><strong>N</strong></td>
<td rowspan="2"></td>
<td rowspan="2"></td>
<td colspan="2"><strong>90% CI</strong></td>
</tr>
<tr class="even">
<td><strong>LL</strong></td>
<td><strong>UL</strong></td>
<td><strong>LL</strong></td>
<td><strong>UL</strong></td>
</tr>
<tr class="odd">
<td>PT</td>
<td>326</td>
<td>99.7</td>
<td>103</td>
<td>100</td>
<td>0.3</td>
<td>-3.9</td>
<td>2.9¶</td>
<td>328</td>
<td>99</td>
<td>104</td>
<td>102</td>
<td>1.0</td>
<td>1.0</td>
<td>1.2¶</td>
</tr>
<tr class="even">
<td>FHA</td>
<td>302</td>
<td>98.3</td>
<td>94</td>
<td>100</td>
<td>1.7</td>
<td>-3.1</td>
<td>5.2¶</td>
<td>303</td>
<td>167</td>
<td>99</td>
<td>165</td>
<td>1.0</td>
<td>0.9</td>
<td>1.1¶</td>
</tr>
<tr class="odd">
<td>PRN</td>
<td>302</td>
<td>94.7</td>
<td>98</td>
<td>99.0</td>
<td>5.3</td>
<td>0.4</td>
<td>9.8¶</td>
<td>328</td>
<td>112</td>
<td>104</td>
<td>132</td>
<td>1.2</td>
<td>1.0</td>
<td>1.3¶</td>
</tr>
</tbody>
</table>

\% = Percentage of subjects with VR

\*Anti-PT titer ³54 EL.U/ml; Anti-FHA titer ³119 EL.U/ml; Anti-PRN titer
³56 EL.U/ml

†VR definition:

•Pertussis antibodies:

-- initially seronegative subjects with post-vaccination titer ³ cut-off
(5 EL.U/ml)

-- initially seropositive subjects with post-vaccination titer ³
pre-vaccination titer

‡Pooled data from A, B, C

¶Upper limit below clinical limit for non-inferiority

> *Reviewer comment:* As was done in the evaluation of lot consistency,
> SBB performed a reanalysis of vaccine response rates adjusting for
> high prevaccination antibody titers. Under this reanalysis, the
> prespecified criteria for non-inferiority with respect to the
> pertussis antigens were met for the comparison between the first and
> second lot series.
>
> *Summary of data supporting lot-to-lot consistency and manufacturing
> bridge*: In Study DTPa-HepB-IPV-044, SBB met all prespecified
> endpoints for demonstrating lot-to-lot consistency of the 2^nd^ lot
> series, with the exception of the immune response to FHA (vaccine
> response rate) pertactin (vaccine response rate and GMT). SBB also did
> not meet their prespecified immunogenicity endpoints with respect to
> pertactin for the manufacturing bridge between the 1^st^ and 2^nd^ lot
> series. When a re-analysis was performed eliminating those subjects
> with high prevaccination titers to pertussis components, prespecified
> criteria for manufacturing bridging from the first to second lot
> series were met. However, for lot consistency, comparison between the
> three lots with respect to the vaccine response to pertactin and FHA
> exceeded the prespecified limit.
>
> Of note, Reverse Cumulative Distribution (RCD) curves (not shown) of
> the immune responses to pertussis antigens shows that virtually all
> infants (regardless of lot administered) demonstrated an immune
> response to each pertussis component. Pairwise comparison of the three
> lots demonstrates that one lot of the second lot series appeared to
> elicit lower immune response to FHA and pertactin than the other two
> lots; this lot may account at least in part for the failure to meet
> prespecified criteria for lot consistency and manufacturing bridging.
>
> To provide further support for consistency of the second lot series,
> SBB submitted data from DTPa-HepB-IPV/Hib-027 (lot consistency study
> of SBB's DTPa-HepB-IPV admixed with Hib prior to injection) utilized
> identical lots of DTPa-HepB-IPV as those used in Study
> DTPa-HepB-IPV-044. DTPa-HepB-IPV/Hib-027 met all pre-specified
> endpoints for pertussis antigens for demonstrating lot-to-lot
> consistency. In addition, DTPa-HepB-IPV/Hib included a comparison arm
> with separately administered vaccines including DTPa (Infanrix®). The
> immune response to pertussis components elicited by the three lots of
> DTPa-HepB-IPV admixed with Hib demonstrated comparable immune response
> to those of Infanrix®.
>
> The clinical relevance of the observed difference in the immune
> response to FHA and pertactin is unclear because there exists no
> generally accepted immunologic correlate(s) of protection against
> pertussis. One U.S. licensed acellular pertussis vaccine (Certiva)
> contains only pertussis toxoid. For all studies in the BLA, the
> database was searched for the occurrence of pertussis disease. Only
> one subject was diagnosed with pertussis (subject \# 4255 from
> DTPa-HepB-IPV-011) based on clinical symptomatology. This infant
> received DTPa-HepB-IPV at approximately 2, 3 and 4 months of age.
> Fifteen days after the third dose she was hospitalized for 3 days for
> apnea, cyanosis and a pertussis-like cough. No confirmatory testing
> was performed. One DTPa-HepB-IPV recipient experienced a "pertussoid
> fit of coughing" 3 days after the first dose. No confirmatory testing
> was performed. The patient recovered and went on to receive two
> subsequent doses uneventfully.

**3.2.5 Hepatitis B Vaccine Schedule Change**

The recommended schedule for administration of Engerix-B®, SBB's U.S.
licensed hepatitis B vaccine, in infants is a 0, 1 and 6 month schedule.
Under this BLA, SBB seeks an indication for DTPa-HepB-IPV administration
on a 2, 4, and 6 month schedule. Summary data on the immune response to
HBs for all studies submitted as part of the BLA are presented below.

A. Summary BLA Studies: Hepatitis B immunogenicity in infants receiving
DTPa-HepB-IPV - Effect of Variations in Schedule on Seroprotection and
GMT

+---------------+-----+-----+---------+---+---------+------+-------------+
| **Study**     | #   | **  | #       |   |         | #### | **          |
|               | Lab | N** | ## **Se |   |         | #### | \[95%CI\]** |
|               |     |     | roprote |   |         |  GMT |             |
|               |     |     | ction** |   |         |      |             |
|               |     |     |         |   |         |      |             |
|               |     |     | **%     |   |         |      |             |
|               |     |     | \[95    |   |         |      |             |
|               |     |     | %CI\]** |   |         |      |             |
+---------------+-----+-----+---------+---+---------+------+-------------+
| **2, 4, 6     |     |     |         |   |         |      |             |
| months**      |     |     |         |   |         |      |             |
+---------------+-----+-----+---------+---+---------+------+-------------+
| 002           | SBB | 19  | 100     | \ |         | 1517 | \           |
|               |     |     |         | [ |         |      | [875-2630\] |
|               |     |     |         | 7 |         |      |             |
|               |     |     |         | 9 |         |      |             |
|               |     |     |         | . |         |      |             |
|               |     |     |         | 1 |         |      |             |
|               |     |     |         | - |         |      |             |
|               |     |     |         | 1 |         |      |             |
|               |     |     |         | 0 |         |      |             |
|               |     |     |         | 0 |         |      |             |
|               |     |     |         | \ |         |      |             |
|               |     |     |         | ] |         |      |             |
+---------------+-----+-----+---------+---+---------+------+-------------+
| 004           | SBB | 46  | 100     | \ |         | 1398 | \           |
|               |     |     |         | [ |         |      | [952-2054\] |
|               |     |     |         | 9 |         |      |             |
|               |     |     |         | 0 |         |      |             |
|               |     |     |         | . |         |      |             |
|               |     |     |         | 4 |         |      |             |
|               |     |     |         | - |         |      |             |
|               |     |     |         | 1 |         |      |             |
|               |     |     |         | 0 |         |      |             |
|               |     |     |         | 0 |         |      |             |
|               |     |     |         | \ |         |      |             |
|               |     |     |         | ] |         |      |             |
+---------------+-----+-----+---------+---+---------+------+-------------+
| **015**       | MEP | 89  | 100     | \ |         | 1661 | \[          |
|               |     |     |         | [ |         |      | 1256-2198\] |
|               |     |     |         | 9 |         |      |             |
|               |     |     |         | 5 |         |      |             |
|               |     |     |         | . |         |      |             |
|               |     |     |         | 9 |         |      |             |
|               |     |     |         | - |         |      |             |
|               |     |     |         | 1 |         |      |             |
|               |     |     |         | 0 |         |      |             |
|               |     |     |         | 0 |         |      |             |
|               |     |     |         | \ |         |      |             |
|               |     |     |         | ] |         |      |             |
+---------------+-----+-----+---------+---+---------+------+-------------+
| **044 (pooled | MEP | 328 | 99.1    | \ |         | 1682 | \[          |
| 2^nd^ lot)**  |     |     |         | [ |         |      | 1428-1980\] |
|               |     |     |         | 9 |         |      |             |
|               |     |     |         | 7 |         |      |             |
|               |     |     |         | . |         |      |             |
|               |     |     |         | 4 |         |      |             |
|               |     |     |         | - |         |      |             |
|               |     |     |         | 9 |         |      |             |
|               |     |     |         | 9 |         |      |             |
|               |     |     |         | . |         |      |             |
|               |     |     |         | 8 |         |      |             |
|               |     |     |         | \ |         |      |             |
|               |     |     |         | ] |         |      |             |
+---------------+-----+-----+---------+---+---------+------+-------------+
| **044 (1^st^  | MEP | 106 | 99.1    |   | \[94.   | 1455 | \[          |
| lot)**        |     |     |         |   | 9-100\] |      | 1108-1911\] |
+---------------+-----+-----+---------+---+---------+------+-------------+
| **3, 4, 5     |     |     |         |   |         |      |             |
| months**      |     |     |         |   |         |      |             |
+---------------+-----+-----+---------+---+---------+------+-------------+
| 001           | SBB | 17  | 100     |   | \[77.   | 707  | \           |
|               |     |     |         |   | 1-100\] |      | [448-1115\] |
+---------------+-----+-----+---------+---+---------+------+-------------+
| 005           | SBB | 343 | 97.7    |   | \[95.3  | 376  | \[320-441\] |
|               |     |     |         |   | -98.9\] |      |             |
+---------------+-----+-----+---------+---+---------+------+-------------+
| 016           | MEP | 161 | 98.8    |   | \[98.8  | 484  | \[386-608\] |
|               |     |     |         |   | -99.8\] |      |             |
+---------------+-----+-----+---------+---+---------+------+-------------+
| **3, 4.5, 6   |     |     |         |   |         |      |             |
| months**      |     |     |         |   |         |      |             |
+---------------+-----+-----+---------+---+---------+------+-------------+
| 012           | SBB | 507 | 99.6    |   | \[98.   | 890  | \[798-992\] |
|               |     |     |         |   | 6-100\] |      |             |
+---------------+-----+-----+---------+---+---------+------+-------------+
| 019           | MEP | 45  | 100     |   | \[90.   | 2070 | \[          |
|               |     |     |         |   | 2-100\] |      | 1515-2829\] |
+---------------+-----+-----+---------+---+---------+------+-------------+
| **2, 3, 4     |     |     |         |   |         |      |             |
| months**      |     |     |         |   |         |      |             |
+---------------+-----+-----+---------+---+---------+------+-------------+
| 017           | MEP | 23  | 95.7    |   | \[76.0  | 472  | \[231-964\] |
|               |     |     |         |   | -99.8\] |      |             |
+---------------+-----+-----+---------+---+---------+------+-------------+
| **1.5, 2.5,   |     |     |         |   |         |      |             |
| 3.5 months**  |     |     |         |   |         |      |             |
+---------------+-----+-----+---------+---+---------+------+-------------+
| 030           | MEP | 150 | 98.7    |   | \[95.3  | 1016 | \           |
|               |     |     |         |   | -99.8\] |      | [835-1237\] |
+---------------+-----+-----+---------+---+---------+------+-------------+

> *Reviewer comment:* Clinical studies of hepatitis B vaccines have
> defined a protective antibody (anti-HBs) level as [\>]{.underline} 10
> mIU/mL. The observed anti-HBs response in infants receiving
> DTPa-HepB-IPV was significantly greater than the level considered
> protective against hepatitis B disease. In the three BLA studies
> administering DTPa-HepB-IPV on the proposed 2, 4, 6 month schedule,
> 99.1- 100% considered seroprotective, with GMTs from 1455 to 1661
> mIU/mL.
>
> Because administration of DTPa-HepB-IPV on a 2, 4, 6 month schedule
> differs from the licensed schedule of its hepatitis B vaccine
> component, Engerix-B®, data were sought demonstrating that the HBs
> immune responses for both schedules were comparable. Study
> DTPa-HepB-IPV-015 (see section 3.2.3) compared DTPa-HepB-IPV + Hib
> (group 1) with separately administered DTPa, HepB, OPV and Hib (group
> 4), but both groups received vaccinations on a 2, 4, and 6 schedule.
> Both groups achieved 100% seroprotection, but the GMTs for the group
> receiving DTPa-HepB-IPV (group 1) were 1661 mIU/mL compared with 805
> mIU/mL for the group receiving separately administered Engerix-B®
> (group 4). No data were submitted as part of the BLA directly
> comparing the anti-HBs immune response of DTPa-HepB-IPV to the immune
> response Engerix-B® administered at birth, 1 and 6 months. Supportive
> data for the change in schedule for the hepatitis B component, were
> submitted from Study DTPa-HepB-030 which evaluated SBB's DTPa-HepB
> combination (not licensed in the U.S.)

**B. DTPa-HepB-030: Supportive Study for Schedule Change for Hepatitis B
Component**

**Title:** An Open Study of the Safety and Immunogenicity of DTPa-HepB
Vaccine Administered as a Single Injection at 2, 4, and 6 Months of Age
as Compared to Engerix-B® \[Hepatitis B Vaccine (Recombinant)\]
Administered at Birth, 1, and 6 Months of Age and DTPa Vaccine
Administered at 2, 4, and 6 Months of Age.

**Location:** USA

**Investigators:** Joel Ward, MD

**Study Date (Started/Completed):** April 1996-March 1997

**Objective:**

***Primary Objective: (Immunogenicity)***

To evaluate the immune response to the hepatitis B component of the
combined DTPa-HB vaccine administered as a single injection at 2, 4, and
6 months of age as compared to the response to Engerix-B® administered
at birth, 1, and 6 months of age.

**Methodology:**

### Open, randomized, controlled trial

**Number of subjects**

Enrolled (ITT cohort): 280 (140 each group)

Completed: 210

ATP cohort for safety: 265

ATP cohort for immunogenicity: 204

**Population:** Healthy infants, between birth and 7 days of age at time
of enrollment.

**Schedule:**

Group 1 - DTPa-HepB + Hib + OPV (at 2, 4, and 6 months of age):

Group 2 - DTPa + Hib + OPV (at 2, 4, and 6 months of age) and HepB (at
birth, 1 and 6 months of age)

> DTPa-HepB-030: Immunogenicity of a three dose primary vaccination of
> the HepB antigen administered either as combined DTPa-HepB vaccine at
> 2, 4, and 6 months or as a separately-administered U.S.-licensed HepB
> vaccine at 0, 1, 6 months of age (Table 8.III.1-18)

+------+------------+----+-------+---------+------+----------------+
| ##   | *          | *  | **Ser |         | *    |                |
| **An | *Vaccine** | *N | oprot |         | *GMT |                |
| tige |            | ** | ectio |         | (m   |                |
| n**  | **(S       |    | n\*** |         | IU/m |                |
| {#an | chedule)** |    |       |         | l)** |                |
| tige |            |    |       |         |      |                |
| n-1} |            |    |       |         |      |                |
+------+------------+----+-------+---------+------+----------------+
|      |            |    | **%** | **      |      | **95%CI**      |
|      |            |    |       | 95%CI** |      |                |
+------+------------+----+-------+---------+------+----------------+
| HBs  | DTPa-HepB  | 99 | 99.0  | 9       | 1052 | 804-1377       |
|      |            |    |       | 4.5-100 |      |                |
|      | (2, 4, 6   |    |       |         |      |                |
|      | mo)        |    |       |         |      |                |
+------+------------+----+-------+---------+------+----------------+
|      | HepB       | 1  | 100   | 9       | 3717 | 2929-4718      |
|      |            | 05 |       | 6.5-100 |      |                |
|      | (0, 1, 6   |    |       |         |      |                |
|      | mo)        |    |       |         |      |                |
+------+------------+----+-------+---------+------+----------------+

\*Seroprotection definition: subjects with post-vaccination titer
[\>]{.underline} 10 mIU/ml

> *Reviewer comment:* Seroprotection for hepatitis B, defined as
> subjects with post-vaccination titers of [\>]{.underline} 10 mIU/mL,
> was the primary immunogenicity endpoint, anti-HBs GMTs were considered
> a secondary endpoint.

**DTPa-HepB-030: Comparison of the immunogenicity of a three-primary
vaccination of the HepB antigen administered as a combined DTPa-HepB
vaccine at 2, 4, 6 months of age and as a U.S.-licensed HepB vaccine at
0, 1, 6 months of age (Table 8.III.1-19)**

<table>
<colgroup>
<col style="width: 13%" />
<col style="width: 13%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 11%" />
<col style="width: 3%" />
<col style="width: 6%" />
<col style="width: 19%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="5"><strong>Seroprotection*</strong></td>
<td colspan="5"><strong>GMT (mIU/ml)</strong></td>
</tr>
<tr class="even">
<td><p><strong>Hep B</strong></p>
<p><strong>(2, 4, 6 mo)</strong></p></td>
<td><p><strong>DTPa-HepB</strong></p>
<p><strong>(0, 1, 6 mo)</strong></p></td>
<td colspan="3"><p><strong>HepB (0, 1, 6 mo)</strong></p>
<p><strong>minus</strong></p>
<p><strong>DTPa-HepB (2, 4, 6 mo)</strong></p></td>
<td><p><strong>HepB</strong></p>
<p><strong>(0,1,6mo)</strong></p></td>
<td><p><strong>DTPa-HepB</strong></p>
<p><strong>(2,4,6mo)</strong></p></td>
<td colspan="3"><p><strong>HepB (0, 1, 6 mo)</strong></p>
<p><strong>divided by</strong></p>
<p><strong>DTPa-HepB (2, 4, 6mo)</strong></p></td>
</tr>
<tr class="odd">
<td rowspan="2"><strong>%</strong></td>
<td rowspan="2"><strong>%</strong></td>
<td rowspan="2"><strong>%</strong></td>
<td colspan="2"><strong>90%CI</strong></td>
<td colspan="2" rowspan="2"></td>
<td rowspan="2"></td>
<td colspan="2"><strong>90%CI</strong></td>
</tr>
<tr class="even">
<td><strong>LL</strong></td>
<td><strong>UL</strong></td>
<td><strong>LL</strong></td>
<td><strong>UL</strong></td>
</tr>
<tr class="odd">
<td>99.0</td>
<td>100</td>
<td>1.0</td>
<td>-4.1</td>
<td>7.1**</td>
<td><strong>3717</strong></td>
<td><strong>1052</strong></td>
<td><strong>3.5</strong></td>
<td><strong>2.6</strong></td>
<td><strong>4.8</strong></td>
</tr>
</tbody>
</table>

\% = Percentage of subjects with a response

\*Seroprotection definition: Subjects with post-vaccination titers
[\>]{.underline} 10 mIU/ml; Clinical limit = 10% difference in
seroprotection rate

\*\*Upper limit below statistical limit for non-inferiority\` Clinical
limit = GMT ratio of 2.0

> *Reviewer comment*: The immunogenicity of DTPa-HepB combination on a
> 2, 4, 6 month schedule compared with the standard 0, 1 and 6 month
> schedule met the prespecified criteria for non-inferiority with
> respect to seroprotection (upper limit on the confidence interval of
> 7.1%), with 99.0% of subjects given the 2, 4, 6 month schedule having
> post vaccination [\>]{.underline} 10 mIU/mL, a level correlated with
> protection. The anti-HBs GMT was lower when the hepatitis B antigen
> was given on a 2, 4, 6 month schedule as part of the DTPa-HepB
> combination, compared with hepatitis B vaccine given on a 0, 1 and 6
> months schedule. However, the anti-HBs immune response of the
> DTPa-HepB combination was well above the level considered to be
> protective.

**C. Immune response to DTPa-HepB-IPV at 2, 4, 6 months of age following
a birth dose of Hepatitis B vaccine**

Two submitted studies provided data on the immune response to the
hepatitis B component following a birth dose of hepatitis B vaccine The
first study involved DTPa-HepB-IPV and the second study evaluated SBB's
DTPa-HepB-IPV/Hib vaccine (not licensed in the U.S.)

1\) Supportive study **DTPa-HepB-IPV-030,** conducted in Moldova,
evaluated the use of DTPa-HepB-IPV on a 6, 10, and 14 week schedule
following a birth dose of hepatitis B vaccine (Engerix-®). The
comparator group received a birth dose of Engerix-B® followed by a
combination vaccine containing whole cell pertussis, DTwP-IPV-Hib (not
U.S. licensed) and Engerix- B® at 6, 10 and 14 weeks of age (group 2).
Sera were obtained approximately 1 month following the third dose.
Seroprotection rates for both groups were 98.7% for group 1 and 98.0%
for the group 2, with GMTs for Group 1 1016.2 mIU/mL (90% CI =
834.6-1237.2) and GMTs for Group 2 426.6 mIU/mL (90% CI = 336.4
--540.7). This study, however, did not provide data on the proposed U.S.
schedule (2, 4 and 6 months) for DTPa-HepB-IPV.

2\) SBB has submitted supportive immunogenicity data from
**DTPa-HepB-IPV/Hib-003** evaluating the safety and immunogenicity of a
primary series of DTPa-HepB-IPV admixed with Hib, with and without a
birth dose of hepatitis B vaccine. (See Section 3.3 for study synopsis)
In this study, DTPa-HepB-IPV/Hib was administered at 2, 4 and 6 months.
The immune response data from this study are presented below.

**DTPa-HepB-IPV/Hib-003: Difference in anti-HBs immunological response
with and without birth dose of hepatitis B vaccine -- ATP cohort for
immunogenicity**

+-----------------------+-----+------------------+---------------------+
| **Group**             | #   | **Seroprotection | **GMT**             |
|                       | ### | Rate %**         |                     |
|                       | # N |                  |                     |
+-----------------------+-----+------------------+---------------------+
| Group 1               | 84  | 100%             | 1240.1              |
+-----------------------+-----+------------------+---------------------+
| Group 2               | 86  | 100%             | 2996.2              |
+-----------------------+-----+------------------+---------------------+
| Difference between    |     | **Group 1-Group  | **GMT ratio Group   |
| groups                |     | 2**              | 1/Group 2**         |
|                       |     |                  |                     |
| (90% CI)              |     |                  |                     |
+-----------------------+-----+------------------+---------------------+
|                       |     | 0% (-5.4%,       | 0.414 (0.309,       |
|                       |     | 6.9%)\*          | 0.554)\*            |
+-----------------------+-----+------------------+---------------------+

> Group 1: DTPa-HepB-IPV/Hib at 2, 4, 6 months without birth dose of
> hepatitis B vaccine (3 doses of HepB)
>
> Group 2: DTPa-HepB-IPV/Hib at 2, 4, and 6 months following a birth
> dose of hepatitis B (4 doses of HepB)
>
> \* = upper limit of the 90% CI below the non-inferiority limit; 10%
> for the difference in seroprotection rate; 2 for the GMT ratio
>
> *Reviewer comment:* Both groups of infants receiving DTPa-HepB-IPV/Hib
> at 2, 4, and 6 months of age, with or without a birth dose of
> hepatitis B vaccine, demonstrated 100% seroprotection to the hepatitis
> B component. The immune response in terms of GMTs was noticeably
> higher in the group receiving DTPa-HepB-IPV/Hib following a birth dose
> of hepatitis B vaccine (four doses of HepB).

**3.3 Safety Data**

> **3.3.1 Safety Database: DTPa-HepB-IPV for Primary Series Immunization
> (Doses 1-3)**

+------+--------+----------+--------+--------+-------+-------+-------+
| **D  | **Sc   | **\#     | **\#   | **\#   | **    | **    | **    |
| TPa- | hedule | R        | ec     | Rec    | Total | Total | Total |
| HepB | (mo)** | eceiving | eiving | eiving | \#    | \#    | \#    |
| -IPV |        | at Least | at     | at     | Do    | Do    | Do    |
| Stu  |        | One      | Least  | Least  | ses** | ses** | ses** |
| dy** |        | Dose\*   | One    | One    |       |       |       |
|      |        | (Total   | Dose** | Dose** | **(   | **(I  | **(A  |
|      |        | Co       |        |        | Total | TT)** | TP)** |
|      |        | hort)†** | **(I   | **(A   | Coho  |       |       |
|      |        |          | TT)‡** | TP)§** | rt)** |       |       |
+------+--------+----------+--------+--------+-------+-------+-------+
| 001  | 3, 4,  | 20       | 20     | 20     | 54    | 54    | 54    |
| (    | 5      |          |        |        |       |       |       |
| S)\* |        |          |        |        |       |       |       |
+------+--------+----------+--------+--------+-------+-------+-------+
| 002  | 2, 4,  | 30       | 30     | 30     | 87    | 87    | 87    |
| (S)  | 6      |          |        |        |       |       |       |
+------+--------+----------+--------+--------+-------+-------+-------+
| 004  | 2, 4,  | 50       | 50     | 50     | 149   | 149   | 149   |
| (S)  | 6      |          |        |        |       |       |       |
+------+--------+----------+--------+--------+-------+-------+-------+
| 005  | 3, 4,  | 567      | 565    | 561    | 1,694 | 1,681 | 1,669 |
| (S)  | 5      |          |        |        |       |       |       |
+------+--------+----------+--------+--------+-------+-------+-------+
| *    | **3,   | *        | **4    | **3    | **13, | **13, | **9,  |
| *011 | 4, 5** | *4,695** | ,666** | ,027** | 926** | 859** | 032** |
| (    |        |          |        |        |       |       |       |
| P)\* |        |          |        |        |       |       |       |
| \*** |        |          |        |        |       |       |       |
+------+--------+----------+--------+--------+-------+-------+-------+
| 012  | 3,     | 549      | 549    | 549    | 1,636 | 1,635 | 1,635 |
| (S)  | 4.5, 6 |          |        |        |       |       |       |
+------+--------+----------+--------+--------+-------+-------+-------+
| *    | **2,   | **200**  | *      | *      | **    | **    | **    |
| *015 | 4, 6** |          | *200** | *200** | 483** | 483** | 483** |
| (    |        |          |        |        |       |       |       |
| P)** |        |          |        |        |       |       |       |
+------+--------+----------+--------+--------+-------+-------+-------+
| 016  | 3, 4,  | 184      | 182    | 180    | 546   | 544   | 538   |
| (S)  | 5      |          |        |        |       |       |       |
+------+--------+----------+--------+--------+-------+-------+-------+
| 017  | 2, 3,  | 29       | 29     | 29     | 87    | 87    | 87    |
| (S)  | 4      |          |        |        |       |       |       |
+------+--------+----------+--------+--------+-------+-------+-------+
| 019  | 3,     | 60       | 60     | 60     | 177   | 177   | 177   |
| (S)  | 4.5, 6 |          |        |        |       |       |       |
+------+--------+----------+--------+--------+-------+-------+-------+
| 030  | 1.5.,  | 160      | 160    | 160    | 478   | 475   | 475   |
| (S)  | 2.5,   |          |        |        |       |       |       |
|      | 3.5    |          |        |        |       |       |       |
+------+--------+----------+--------+--------+-------+-------+-------+
| *    | **2,   | **484**  | *      | *      | **1   | **1,  | **1,  |
| *044 | 4, 6** |          | *482** | *476** | 422** | 418** | 402** |
| (    |        |          |        |        |       |       |       |
| P)** |        |          |        |        |       |       |       |
+------+--------+----------+--------+--------+-------+-------+-------+
| **T  |        | **5,     | **5    | **3    | **15, | **15, | **10, |
| otal |        | 379**    | ,348** | ,703** | 831** | 760** | 917** |
| (    |        |          |        |        |       |       |       |
| P)** |        |          |        |        |       |       |       |
+------+--------+----------+--------+--------+-------+-------+-------+
| **T  |        | *        | **6    | **5    | **20, | **20, | **15, |
| otal |        | *7,028** | ,993** | ,342** | 739** | 649** | 788** |
| (P+  |        |          |        |        |       |       |       |
| S)** |        |          |        |        |       |       |       |
+------+--------+----------+--------+--------+-------+-------+-------+
| **T  |        | **764**  | *      | *      | **2   | **2   | **2   |
| otal |        |          | *762** | *756** | 141** | 137** | 121** |
| on   |        |          |        |        |       |       |       |
| 2,   |        |          |        |        |       |       |       |
| 4, 6 |        |          |        |        |       |       |       |
| mo   |        |          |        |        |       |       |       |
| nths |        |          |        |        |       |       |       |
| sc   |        |          |        |        |       |       |       |
| hedu |        |          |        |        |       |       |       |
| le** |        |          |        |        |       |       |       |
+------+--------+----------+--------+--------+-------+-------+-------+

\*Supportive \*\*Pivotal

**†**[Total Cohort:]{.underline} All subjects receiving at least one
dose, regardless of whether a symptom sheet was completed

**‡**[Intent-to-Treat (ITT) Cohort:]{.underline} Subjects who received
the indicated vaccine and for whom at least one symptom sheet was
completed.

**§**[According-to-Protocol (ATP) cohort:]{.underline} Subjects who
received the indicated vaccine dose and for whom at least one symptom
sheet was completed and who were eligible for the ATP analysis.

2.  **Assessment of Safety**

```{=html}
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```
A.  **Statistical Analyses**

**Study cohorts for safety:**

[Intent-to-treat (ITT) cohort of safety]{.underline}: subjects who had
received at least one dose of study vaccine and who had safety follow-up
(at least one symptom sheet returned) after vaccination.

[According-to-Protocol (ATP) cohort of safety]{.underline}. The ATP
population was comprised of subjects who had received at least one dose
of study vaccine according to their random assignment, who had safety
follow-up after vaccination, who had not received a vaccine not
specified or forbidden in the protocol and, in the case of
double-blinded studies, for whom the randomization code was not broken.

For six of the twelve studies, the ATP safety cohort did not exclude any
subjects (i.e., the ATP cohort equaled the ITT cohort). For five of the
six remaining studies (DTPa-HepB-IPV-005**,-015**,-016,-017and**-044**),
the ATP safety cohort excluded less than 1.5% of the enrolled subjects.
For study DTPa-HepB-IPV**-011**, the ATP cohort excluded subjects who
were enrolled prior to an amendment allowing for the introduction of a
control group consisting of separately administered U.S. licensed
vaccines (approximately 35% of the enrolled subjects). 2.9% of subjects
enrolled after the amendment were excluded. Reanalysis of the ITT safety
cohort was performed only for studies which excluded \> 1.5% of the
enrolled subjects.

**Endpoints:**

1.  For [solicited symptoms]{.underline}, the following parameters were
    investigated:

-   Proportions of subjects reporting any Grade 3 solicited symptom
    during the solicited follow-up period after any vaccination (study
    DTPa-HepB-IPV-011)

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```
-   Number and proportion of subjects reporting each specified local or
    general symptom (overall and Grade 3) during the solicited follow-up
    period after any vaccination (studies DTPa-HepB-IPV-011,-015, -016,
    -030 and -044)

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```
-   Number and proportion of doses with each specified local or general
    symptom during the solicited follow-up period after any dose and
    after each dose (all studies)

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<!-- -->
```
-   Number and proportion of doses with each specified local or general
    symptom rated as Grade 3 in intensity during the solicited follow-up
    period after any dose and after each dose (all studies except
    DTPa-HepB-IPV-001)

2.  [For unsolicited symptoms]{.underline} (reported from day 0 to day
    30 after each vaccination), the following endpoints were
    investigated:

-   Number of doses followed by an AE classified by WHO Preferred Term
    (all studies contained in the BLA)

-   Number of doses followed by an AE classified by WHO Preferred Term
    with probable or suspected relationship to vaccination (all studies
    except DTPa-HepB-IPV-002 and --004)

-   Number and percentage of subjects experiencing unsolicited symptoms
    classified by WHO preferred term within 30 days after any vaccine
    dose (DTPa-HepB-IPV-011 and --044 only)

**Analyses**

[With the exception of study DTPa-HepB-IPV-011, the evaluation of safety
was limited to exploratory analyses.]{.underline}

1.  [For solicited symptoms, t]{.underline}hree statistical approaches
    were used (BLA Section 8.II.3):

-   Descriptive analyses: In studies DTPa-HepB-IPV-011, 015, -016, -030
    and -044, exact 95% CIs were provided for the rate of solicited
    symptoms within each group. In addition for studies -011, -015, and
    -044, the exact 90% CI for the difference between study groups in
    the percentage of subjects with a given symptom were provided.

-   Hypothesis testing of no treatment difference: In studies
    DTPa-HepB-IPV-015, 016, -030 and -044, the study group differences
    in the proportions of subjects with solicited symptoms were
    evaluated by examining the overlapping of 95% CI between the groups

-   Non-inferiority testing: This approach replaced the "hypothesis
    testing of no treatment difference". In Study DTPa-HepB-IPV-011, the
    90% CI for the difference in the percentage of subjects with Grade 3
    solicited symptoms over the vaccine course was obtained using the
    StatXact 3.0, exact CI for difference in proportions. Likewise, for
    each solicited symptom, 90% CIs for the difference in percentages of
    subjects with Grade 3 solicited symptoms were computed.

2.  [For unsolicited symptoms:]{.underline} Descriptive analyses were
    performed. In addition, DTPa-HepB-IPV-011 analyzed 90% CIs on the
    differences between the pooled DTPa-HepB-IPV groups and control
    group receiving U.S. licensed separately administered vaccines.

**B. Solicited Symptoms (Local and General)**

### In each study, diary cards were maintained by the parents on the day of vaccination and each of three subsequent days (for a total of 4 days). Each of the pivotal studies involved parental assessment of local and systemic symptoms via diary cards for the day of vaccination (day 0) and each of three subsequent days (days 1-3 post-vaccination). In addition, Studies 015 and 044 included telephone follow up calls between days 1 and 3 post vaccination. 

# Definitions of Solicited Adverse Events 

  ---------------------------------- ------------------------------------
  **Local Symptoms (at injection     **General (Systemic) Symptoms**
  site)**                            

  Pain on digital pressure           Fever (rectal body temperature)\*

  Redness                            Unusual crying for more than 1 hr

                                     Irritability/fussiness§

  Swelling                           Restlessness

                                     Loss of appetite

                                     Vomiting

                                     Diarrhea
  ---------------------------------- ------------------------------------

**\***All studies except for Study-001 (Supportive) had fever assessed
via rectal temperature. Study-001 assessed axillary temperature with an
adjusted scale.

§Irritability/fussiness with or without unusual crying was a solicited
symptom in studies 015, 016, 017, 019, 030, 044.

# Grading of Adverse Events:

[**Local Reactions**:]{.underline}

If **redness or swelling** were present, the largest diameter was
recorded.

Grade 1: \<5 mm

Grade 2: 5-20 mm

Grade 3: \>20 mm

**Pain**: Grade 0: absent

Grade 1: minor reaction with light touch

###  Grade 2: cried or protests to touch

Grade 3: cried when limb was moved

# 

### **[General Reactions:]{.underline}**

**Fever:**

Grade 1: 38.0-38.5C/100.4-101.3F

Grade 2: 38.6-39.5C/101.4-103.2F

Grade 3: \>39.5C/\>103.2F

**Grading of other general symptoms:** (Note: some studies differed
slightly with respect to solicited general symptoms. For example, 011
solicited the term "restlessness" and 015 solicited the term
"fussiness".)

###  Grade 1: Adverse experience (AE) easily tolerated

Grade 2: AE sufficiently discomforting to interfere with daily activity

Grade 3: AE which prevented normal everyday activities

# Irritability/Fussiness

Grade 0: child behaved as usual

Grade 1: child was slightly more irritable but had normal activity

Grade 2: prolonged crying and refused to play

Grade 3: persistent crying and refused to be comforted

**C. Unsolicited Adverse Events**

Definition of unsolicited adverse events: "any noxious, pathological, or
unintended change in anatomical, physiological, or metabolic function as
indicated by physical signs, symptoms, and/or laboratory changes which
occurred in any phase of the clinical studies whether associated with
DTPa-HepB-IPV vaccine or active comparator and whether or not considered
vaccine-related. This included an exacerbation of a

pre-existing condition or event, intercurrent illness or drug
interaction."

For the majority of studies, including DTPa-HepB-IPV-011and - 044,
unsolicited adverse events were recorded for a period of up to [30 days
following vaccination]{.underline}. For study 015, unsolicited AEs were
recorded 14 days after each vaccination. Unsolicited data were pooled
and classified according to World Health Organization (WHO) Body system
and Preferred Term.

D.  **Serious Adverse Events (SAE)**

A SAE was defined as any experience that, in the investigator's opinion,
suggested a significant hazard to the vaccinee. SAEs were recorded
during entire study period up to 30 days after 3^rd^ vaccination.
Parents/ guardians were instructed to immediately inform the
investigator of the occurrence of any severe or serious sign or symptom
at any time throughout the study period.

**3.3.3 Pivotal Safety Study: DTPa-HBV-IPV-011**

**Title:** Randomized clinical study to assess the safety and
reactogenicity of SBB's DTPa-HepB-IPV vaccine when co-administered with
Hib vaccine in two concomitant injections into opposite limbs, as a
primary vaccination course to healthy infants at the age of 3, 4, and 5
months.

**Location:** Germany (90 sites)

**Investigators:** Principal: Dr. Fred Zepp, Mainz, Germany

# Study Period (date of first to last visit): 11/16/95-12/18/97

**Objective:** The study ("pre-amendment period") was originally
designed as a comparative safety study in which all subjects were
randomized to receive SBB's DTPa-HepB-IPV concomitantly at separate
sites along with one of four Hib vaccines (manufactured by SBB, Pasteur
Merieux Connaught \[PM, now known as Aventis Pasteur\], Merck or
Lederle) in a 1:1:1:1 fashion. After enrollment of 1569 subjects, the
study was amended in order to allow for the introduction of a separate
injection control group ("post-amendment period") consisting of
Infanrix®, Act-HIB™, and ORIMUNE® (all US licensed).

**Primary:**

To assess the safety and reactogenicity of SBB's DTPa-HepB-IPV vaccine
when co-administered with either SBB's Hib vaccine or with commercially
available Hib vaccines, in comparison to co-administration of
commercially available DTPa (Infanrix®), Hib (Act-HIB™, PMC) and OPV
(ORIMUNE®) vaccines.

**Secondary:**

To investigate \"less common\" adverse events, i.e. adverse events that
occur at a rate (per subjects) of 1% or less.

**Statistical Methods:**

**Primary Endpoint:** The difference between the pooled DTPa-HepB-IPV
vaccine group and the control group in the percentage of subjects with
grade 3 solicited symptoms over the full vaccination course was computed
with its exact 90% CI (Stat Xact, difference between proportions). The
primary objective was demonstrated if the lower limit of the 90% CI was
above the --7.5% limit defining clinical non-inferiority.

**Secondary Endpoint:** To evaluate the secondary objective, the
percentage of subjects experiencing unsolicited symptoms within 30 days
after any vaccine dose, classified by WHO Preferred Terms, were
tabulated by groups with their 95% CI. Asymptotic 90% CI of the
differences in the percentages was provided to evaluate the
non-inferiority of the pooled DTPa-HBV-IPV vaccine group as compared to
the control group.

**Population:** Healthy infants, 8-16 weeks at the time of first
vaccination

**Design:** Open, randomized **Schedule:** 3, 4, 5 months

**Study Design:**

Group 1 DTPa-HepB-IPV + SBB Hib

Group 2 DTPa-HepB-IPV + PMC Hib

Group 3 DTPa-HepB-IPV +Led Hib

Group 4 DTPa-HepB-IPV + Merck Hib\*

Group 5 DTPa + PM Hib + OPV#

\*Group 4 received 2 doses of Hib at 3 and 5 months of age

#Group 5 did not receive hepatitis B vaccine during the study period.

### Total enrolled (ITT cohort): 5472

Total completed: 5318

Pooled Groups 1-4: 4696

Group 5: 776

Pre-amendment period: Enrolled: 1560; Completed 1513

Post-amendment period: Enrolled 3903; Completed 3805

ITT cohort for safety: 4666

ATP cohort for safety: Total: 3773

Pooled Groups 1-4: 3029

Group 5: 744

+----------------+----------------------+----------------+-------------+
| ###            |                      |                |             |
| ##### DTPa-Hep |                      |                |             |
| B-IPV- 011: Si |                      |                |             |
| te of Vaccine  |                      |                |             |
| Administration |                      |                |             |
+----------------+----------------------+----------------+-------------+
| **Group**      | **Right              | **Left         | **Oral      |
|                | anterolateral        | anterolateral  | admin       |
|                | thigh**              | thigh**        | istration** |
+----------------+----------------------+----------------+-------------+
| 1              | DTPa-HepB-IPV        | Hib (SBB)      |             |
+----------------+----------------------+----------------+-------------+
| 2              | DTPa-HepB-IPV        | Act-HIB™       |             |
+----------------+----------------------+----------------+-------------+
| 3              | DTPa-HepB-IPV        | HibTITER™      |             |
+----------------+----------------------+----------------+-------------+
| 4              | DTPa-HepB-IPV        | PedvaxHib™\*   |             |
+----------------+----------------------+----------------+-------------+
| 5\*\*          | DTPa (Infanrix®)     | Act-HIB™       | OPV         |
|                |                      |                | (ORIMUNE®)  |
+----------------+----------------------+----------------+-------------+

\*Only administered at 3 and 5 months of age.

\*\*Subjects in group 5 did not receive hepatitis B vaccine during the
study period. Subjects in group 5 were offered Engerix B at the end of
the study.

######## 

######## DTPa-HepB-IPV-011: Demographics

+---------------------+------------------------+---+-----------------------+
|                     | ###### Total           |   |                       |
+---------------------+------------------------+---+-----------------------+
| Categories          | **n**                  |   | **%**                 |
+---------------------+------------------------+---+-----------------------+
| Total               | **5472\***             |   |                       |
+---------------------+------------------------+---+-----------------------+
| Black               | **30**                 |   | **0.55**              |
+---------------------+------------------------+---+-----------------------+
| White               | **5260**               |   | **96.13**             |
+---------------------+------------------------+---+-----------------------+
| Asian               | **122**                |   | **2.23**              |
+---------------------+------------------------+---+-----------------------+
| Not specified       | **8**                  | * |                       |
|                     |                        | * |                       |
|                     |                        | 0 |                       |
|                     |                        | . |                       |
|                     |                        | 1 |                       |
|                     |                        | 5 |                       |
|                     |                        | * |                       |
|                     |                        | * |                       |
+---------------------+------------------------+---+-----------------------+
| Other               | **52**                 |   | **0.95**              |
+---------------------+------------------------+---+-----------------------+
| Female              | **2655**               |   | **48.52**             |
+---------------------+------------------------+---+-----------------------+
| Male                | **2816**               |   | **51.46**             |
+---------------------+------------------------+---+-----------------------+

**\***ITT cohort (total enrolled)

> *Reviewer note:* Wherever possible, data provided in this document for
> Study DTPa-HepB-IPV-011 has been provided for the ITT cohort for
> safety. In the BLA, many of the comparative tables (DTPa-HepB-IPV vs.
> separate administration control) of Study --011 were provided only for
> the ATP cohort for safety.

Primary Endpoint:

DTPa-HepB-IPV- 011: Percentage of subjects with [Grade 3 solicited
symptoms]{.underline} during the 4-day follow-up period over the full
course of vaccination (any dose): ATP analysis

<table>
<colgroup>
<col style="width: 10%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 14%" />
<col style="width: 7%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="3"><strong>Symptom</strong></td>
<td colspan="4"><p><strong>DTPa-HepB-IPV</strong></p>
<p><strong>Pooled Groups 1-4*</strong></p>
<p><strong>(N=3029)</strong></p></td>
<td colspan="4"><p><strong>Control</strong></p>
<p><strong>Group 5</strong></p>
<p><strong>(N=744)</strong></p></td>
<td colspan="3"><p><strong>Group 5 minus Pooled</strong></p>
<p><strong>Groups 1-4</strong></p></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="2"><strong>95% CI</strong></td>
<td colspan="2"></td>
<td colspan="2"><strong>95% CI</strong></td>
<td><strong>Difference</strong></td>
<td colspan="2"><strong>90% CI</strong></td>
</tr>
<tr class="odd">
<td><strong>n</strong></td>
<td><strong>%</strong></td>
<td><strong>LL</strong></td>
<td><strong>UL</strong></td>
<td><strong>n</strong></td>
<td><strong>%</strong></td>
<td><strong>LL</strong></td>
<td><strong>UL</strong></td>
<td><strong>(%)</strong></td>
<td><strong>LL</strong></td>
<td><strong>UL</strong></td>
</tr>
<tr class="even">
<td>Total</td>
<td>490</td>
<td>16.2</td>
<td>14.9</td>
<td>17.5</td>
<td>151</td>
<td>20.3</td>
<td>17.5</td>
<td>23.4</td>
<td>4.1</td>
<td>1.41.</td>
<td>7.13</td>
</tr>
<tr class="odd">
<td>Local</td>
<td>236</td>
<td>7.8</td>
<td>6.9</td>
<td>8.8</td>
<td>90</td>
<td>12.1</td>
<td>9.8</td>
<td>14.7</td>
<td>4.3</td>
<td>2.15</td>
<td>6.83</td>
</tr>
<tr class="even">
<td>General</td>
<td>318</td>
<td>10.5</td>
<td>9.4</td>
<td>11.6</td>
<td>94</td>
<td>12.6</td>
<td>10.3</td>
<td>15.2</td>
<td>2.1</td>
<td>-0.11</td>
<td>4.74</td>
</tr>
</tbody>
</table>

Group 1: DTPa-HepB-IPV + SBB Hib

Group 2: DTPa-HepB-IPV + PM Hib

Group 3: DTPa-HepB-IPV + Lederle Hib

Group 4: DTPa-HepB-IPV + Merck Hib (\*Subjects in Group 4 received only
2 doses of Hib vaccine at 3 and 5 months of age)

Group 5: SBB DTPa + PMC Hib+ Lederle OPV

N = number of subjects with at least one symptom sheet completed and/or
with an unsolicited symptom

n = number of subjects reporting the specific solicited local or general
symptom

> *Reviewer comment*: During the vaccination course, 16.2% of subjects
> in the pooled DTPa-HepB-IPV vaccine group and 20.3% in the control
> group reported any solicited symptom graded 3 in intensity. The
> percentage of subjects with grade 3 solicited symptoms over the full
> vaccination course in the pooled groups receiving DTPa-HepB-IPV
> compared with the control group did not exceed the predefined --7.5%
> limit defining clinical non-inferiority.

**Study DTaP-HepB-IPV-011 -- Incidence of any and Grade 3 solicited
local symptoms at the DTPa-based injection site, following dose 1, 2, 3
and any dose for pooled groups 1-4 and group 5 -- ITT cohort (Adapted
from SBB fax of 2/16/01)**

<table style="width:100%;">
<colgroup>
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 7%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 10%" />
<col style="width: 6%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2"><strong>Symptom</strong></td>
<td colspan="4"><p><strong>Groups 1-4 Pooled</strong></p>
<p><strong>N=4668</strong></p></td>
<td colspan="4"><h1 id="group-5">Group 5</h1>
<p><strong>N=768</strong></p></td>
<td colspan="3"><strong>Groups 1-4 pooled minus Group %</strong></td>
</tr>
<tr class="even">
<td><strong>Dose 1</strong></td>
<td></td>
<td>n</td>
<td>%</td>
<td colspan="2"><p>95%CI</p>
<p>LL UL</p></td>
<td>N</td>
<td>%</td>
<td colspan="2"><p>95% CI</p>
<p>LL UL</p></td>
<td>Diff.<br />
%</td>
<td colspan="2"><p>90% CI</p>
<p>LL UL</p></td>
</tr>
<tr class="odd">
<td><strong>Pain</strong></td>
<td><p>- any</p>
<p>- grade 3</p></td>
<td><p>653</p>
<p>32</p></td>
<td><p>14.0</p>
<p>0.7</p></td>
<td><p>13.0</p>
<p>0.5</p></td>
<td><p>15.0</p>
<p>1.0</p></td>
<td><p>109</p>
<p>10</p></td>
<td><p>14.21</p>
<p>1.3</p></td>
<td><p>11.80</p>
<p>0.6</p></td>
<td><p>16.9</p>
<p>2.4</p></td>
<td><p>-0.2</p>
<p>-0.6</p></td>
<td><p>-2.7</p>
<p>-1.6</p></td>
<td><p>2.1</p>
<p>0.1</p></td>
</tr>
<tr class="even">
<td><strong>Redness</strong></td>
<td><p>- any</p>
<p>- grade 3</p></td>
<td><p>866</p>
<p>57</p></td>
<td><p>18.6</p>
<p>1.2</p></td>
<td><p>17.5</p>
<p>0.9</p></td>
<td><p>19.7</p>
<p>1.6</p></td>
<td><p>124</p>
<p>14</p></td>
<td><p>16.1</p>
<p>1.8</p></td>
<td><p>13.6</p>
<p>1.0</p></td>
<td><p>18.9</p>
<p>3.0</p></td>
<td><p>2.4</p>
<p>-0.6</p></td>
<td><p>--0.2</p>
<p>-1.7</p></td>
<td><p>4.9</p>
<p>0.2</p></td>
</tr>
<tr class="odd">
<td><strong>Swelling</strong></td>
<td><p>- any</p>
<p>- grade 3</p></td>
<td><p>591</p>
<p>56</p></td>
<td><p>12.7</p>
<p>1.2</p></td>
<td><p>11.7</p>
<p>0.9</p></td>
<td><p>13.7</p>
<p>1.6</p></td>
<td><p>74</p>
<p>10</p></td>
<td><p>9.6</p>
<p>1.3</p></td>
<td><p>7.6</p>
<p>0.6</p></td>
<td><p>11.9</p>
<p>2.4</p></td>
<td><p>3.0</p>
<p>-0.1</p></td>
<td><p>0.8</p>
<p>-1.2</p></td>
<td><p>5.1</p>
<p>0.6</p></td>
</tr>
<tr class="even">
<td><strong>Dose 2</strong></td>
<td colspan="12"></td>
</tr>
<tr class="odd">
<td><strong>Pain</strong></td>
<td><p>- any</p>
<p>- grade 3</p></td>
<td><p>469</p>
<p>13</p></td>
<td><p>10.2</p>
<p>0.3</p></td>
<td><p>9.3</p>
<p>0.1</p></td>
<td><p>11.1</p>
<p>0.5</p></td>
<td><p>74</p>
<p>3</p></td>
<td><p>9.8</p>
<p>0.4</p></td>
<td><p>7.8</p>
<p>0.1</p></td>
<td><p>12.1</p>
<p>1.2</p></td>
<td><p>0.4</p>
<p>-0.1</p></td>
<td><p>-1.8</p>
<p>-0.9</p></td>
<td><p>2.4</p>
<p>0.3</p></td>
</tr>
<tr class="even">
<td><strong>Redness</strong></td>
<td><p>- any</p>
<p>- pain</p></td>
<td><p>1229</p>
<p>46</p></td>
<td><p>26.6</p>
<p>1.0</p></td>
<td><p>25.3</p>
<p>0.7</p></td>
<td><p>27.9</p>
<p>1.3</p></td>
<td><p>162</p>
<p>5</p></td>
<td><p>21.4</p>
<p>0.7</p></td>
<td><p>18.5</p>
<p>0.2</p></td>
<td><p>24.5</p>
<p>1.5</p></td>
<td><p>5.2</p>
<p>0.3</p></td>
<td><p>2.4</p>
<p>-0.6</p></td>
<td><p>8.0</p>
<p>1.0</p></td>
</tr>
<tr class="odd">
<td><strong>Swelling</strong></td>
<td><p>- any</p>
<p>- grade3</p></td>
<td><p>853</p>
<p>76</p></td>
<td><p>18.5</p>
<p>1.6</p></td>
<td><p>17.4</p>
<p>1.3</p></td>
<td><p>19.6</p>
<p>2.1</p></td>
<td><p>98</p>
<p>8</p></td>
<td><p>12.9</p>
<p>1.1</p></td>
<td><p>10.6</p>
<p>0.5</p></td>
<td><p>15.5</p>
<p>2.1</p></td>
<td><p>5.5</p>
<p>0.6</p></td>
<td><p>3.1</p>
<p>-0.4</p></td>
<td><p>7.9</p>
<p>1.4</p></td>
</tr>
<tr class="even">
<td><strong>Dose 3</strong></td>
<td colspan="12"></td>
</tr>
<tr class="odd">
<td><strong>Pain</strong></td>
<td><p>- any</p>
<p>- grade 3</p></td>
<td><p>452</p>
<p>12</p></td>
<td><p>9.9</p>
<p>0.3</p></td>
<td><p>9.0</p>
<p>0.1</p></td>
<td><p>10.8</p>
<p>0.5</p></td>
<td><p>61</p>
<p>1</p></td>
<td><p>8.1</p>
<p>0.1</p></td>
<td><p>6.3</p>
<p>0.0</p></td>
<td><p>10.3</p>
<p>0.7</p></td>
<td><p>1.7</p>
<p>0.1</p></td>
<td><p>-0.3</p>
<p>-0.5</p></td>
<td><p>3.7</p>
<p>0.5</p></td>
</tr>
<tr class="even">
<td><strong>Redness</strong></td>
<td><p>- any</p>
<p>- grade 3</p></td>
<td><p><strong>1171</strong></p>
<p>49</p></td>
<td><p><strong>25.6</strong></p>
<p>1.1</p></td>
<td><p><strong>24.3</strong></p>
<p>0.8</p></td>
<td><p><strong>26.9</strong></p>
<p>1.4</p></td>
<td><p><strong>156</strong></p>
<p>8</p></td>
<td><p><strong>20.8</strong></p>
<p>1.1</p></td>
<td><p><strong>17.9</strong></p>
<p>0.5</p></td>
<td><p><strong>23.9</strong></p>
<p>2.1</p></td>
<td><p><strong>4.8</strong></p>
<p>0.0</p></td>
<td><p><strong>2.0</strong></p>
<p>-1.0</p></td>
<td><p><strong>7.6</strong></p>
<p>0.8</p></td>
</tr>
<tr class="odd">
<td><strong>Swelling</strong></td>
<td><p>- any</p>
<p>- grade3</p></td>
<td><p><strong>842</strong></p>
<p>70</p></td>
<td><p><strong>18.4</strong></p>
<p>1.5</p></td>
<td><p><strong>17.3</strong></p>
<p>1.2</p></td>
<td><p><strong>19.6</strong></p>
<p>1.9</p></td>
<td><p><strong>102</strong></p>
<p>9</p></td>
<td><p><strong>13.6</strong></p>
<p>1.2</p></td>
<td><p><strong>11.2</strong></p>
<p>0.6</p></td>
<td><p><strong>16.3</strong></p>
<p>2.3</p></td>
<td><p><strong>4.8</strong></p>
<p>0.3</p></td>
<td><p><strong>2.3</strong></p>
<p>-0.7</p></td>
<td><p><strong>7.2</strong></p>
<p>1.2</p></td>
</tr>
<tr class="even">
<td><strong>Any dose</strong></td>
<td colspan="12"></td>
</tr>
<tr class="odd">
<td><strong>Pain</strong></td>
<td><p>- any</p>
<p>- grade 3</p></td>
<td><p>1075</p>
<p>55</p></td>
<td><p>23.0</p>
<p>1.2</p></td>
<td><p>21.8</p>
<p>0.9</p></td>
<td><p>24.3</p>
<p>1.5</p></td>
<td><p>171</p>
<p>12</p></td>
<td><p>22.3</p>
<p>1.6</p></td>
<td><p>19.4</p>
<p>0.8</p></td>
<td><p>25.4</p>
<p>2.7</p></td>
<td><p>0.8</p>
<p>-0.4</p></td>
<td><p>-2.1</p>
<p>-1.5</p></td>
<td><p>3.6</p>
<p>0.4</p></td>
</tr>
<tr class="even">
<td><strong>Redness</strong></td>
<td><p>- any</p>
<p>- grade 3</p></td>
<td><p><strong>1927</strong></p>
<p>137</p></td>
<td><p><strong>41.3</strong></p>
<p>2.9</p></td>
<td><p><strong>39.9</strong></p>
<p>2.5</p></td>
<td><p><strong>42.7</strong></p>
<p>3.5</p></td>
<td><p><strong>290</strong></p>
<p>24</p></td>
<td><p><strong>37.8</strong></p>
<p>3.1</p></td>
<td><p><strong>34.3</strong></p>
<p>2.0</p></td>
<td><p><strong>41.3</strong></p>
<p>4.6</p></td>
<td><p><strong>3.5</strong></p>
<p>-0.2</p></td>
<td><p><strong>0.3</strong></p>
<p>-1.6</p></td>
<td><p><strong>6.8</strong></p>
<p>0.9</p></td>
</tr>
<tr class="odd">
<td><strong>Swelling</strong></td>
<td><p>- any</p>
<p>- grade 3</p></td>
<td><p><strong>1451</strong></p>
<p>160</p></td>
<td><p><strong>31.1</strong></p>
<p>3.4</p></td>
<td><p><strong>29.8</strong></p>
<p>2.9</p></td>
<td><p><strong>32.4</strong></p>
<p>4.0</p></td>
<td><p><strong>194</strong></p>
<p>22</p></td>
<td><p><strong>25.3</strong></p>
<p>2.9</p></td>
<td><p><strong>22.2</strong></p>
<p>1.8</p></td>
<td><p><strong>28.5</strong></p>
<p>4.3</p></td>
<td><p><strong>5.8</strong></p>
<p>0.6</p></td>
<td><p><strong>2.9</strong></p>
<p>-0.8</p></td>
<td><p><strong>8.8</strong></p>
<p>1.8</p></td>
</tr>
</tbody>
</table>

Group 1- 4 pooled: DTPa-HBV-IPV vaccine concomitantly with Hib vaccine
at a separate site

Group 5: SB's DTPa + PMC's PRP-T + Lederle's OPV

N = number of symptom sheets received. For groups 1-4 pooled
N=4574-4668; for group 5 N = 750-768

n = number reporting the specific symptom

\% = percentage reporting the specific symptom

CI = Confidence Interval; LL-UL = Lower and Upper Limit

**In bold**: symptoms for which the 90% CI failed to overlap 0%
difference

> *Reviewer comment:* The above table presents solicited local reactions
> at the DTPa-HepB-IPV injection site for pooled groups 1-4 and at the
> DTPa injection site for infants in group 5 who receiving separate
> DTPa, Hib and OPV. All infants in this study received only two
> injections at each vaccination visit (DTPa-HepB-IPV + Hib in groups
> 1-4; DTPa + Hib in group 5). Local reactions were treated
> independently in SBB's analysis, with pain, redness and swelling
> assessed for each injection site separately. The analysis for the
> DTPa-based injection site is presented here because the DTPa-based
> injection site was generally more reactogenic for each dose than the
> Hib injection site for both pooled groups 1-4 and group 5. For dose 3
> and any dose, redness and swelling were between 3.3 - 5.5% greater at
> the DTPa-HepB-IPV injection site (pooled groups 1-4) than at the DTPa
> injection site (group 5), with these differences statistically
> significant. The clinical relevance of this small increase in the
> incidence of redness and swelling is questionable, particularly
> because Grade 3 redness and swelling (largest diameter \> 20 mm) were
> [not]{.underline} different between study groups.
>
> Because group 5 (separately administered vaccines) received only two
> concurrent injections at each vaccination visit (along with oral polio
> vaccine), the extent of local symptoms in the Study --011 control
> group may underestimate that of current clinical practice in the U.S.
> Under the U.S childhood immunization schedule, infants may receive as
> many as 5 separate injections.

**Study DTaP-HepB-IPV-011 -- Incidence of any and Grade 3 solicited
general symptoms, following dose 1, 2, 3 and any dose for pooled groups
1-4 and group 5 -- ITT cohort (Adapted from SBB fax of 2/16/01)**

<table style="width:100%;">
<colgroup>
<col style="width: 13%" />
<col style="width: 10%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 7%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 11%" />
<col style="width: 6%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2" rowspan="2"><strong>Symptom</strong></td>
<td colspan="4"><p><strong>Groups 1-4 Pooled</strong></p>
<p><strong>N=4668</strong></p></td>
<td colspan="4"><h1 id="group-5-1">Group 5</h1>
<h5 id="n768">N=768</h5></td>
<td colspan="3"><strong>Groups 1-4 Pooled minus Group 5</strong></td>
</tr>
<tr class="even">
<td><strong>n</strong></td>
<td><strong>%</strong></td>
<td colspan="2"><p><strong>95%CI</strong></p>
<p><strong>LL UL</strong></p></td>
<td><strong>n</strong></td>
<td><strong>%</strong></td>
<td colspan="2"><p><strong>95% CI</strong></p>
<p><strong>LL UL</strong></p></td>
<td><strong>Difference<br />
%</strong></td>
<td colspan="2"><p><strong>90% CI</strong></p>
<p><strong>LL UL</strong></p></td>
</tr>
<tr class="odd">
<td colspan="13"><strong>Dose 1</strong></td>
</tr>
<tr class="even">
<td><strong>Fever</strong></td>
<td><p><strong>T<u>&gt;</u>38C</strong></p>
<p><strong>T&gt;39.5C</strong></p></td>
<td><p><strong>1173</strong></p>
<p>14</p></td>
<td><p><strong>25.1</strong></p>
<p>0.3</p></td>
<td><p><strong>23.9</strong></p>
<p>0.2</p></td>
<td><p><strong>26.4</strong></p>
<p>0.5</p></td>
<td><p><strong>100</strong></p>
<p>2</p></td>
<td><p><strong>13.0</strong></p>
<p>0.3</p></td>
<td><p><strong>10.7</strong></p>
<p>0.0</p></td>
<td><p><strong>15.6</strong></p>
<p>0.9</p></td>
<td><p><strong>12.0</strong></p>
<p>0.0</p></td>
<td><p><strong>9.5</strong></p>
<p>-0.6</p></td>
<td><p><strong>14.4</strong></p>
<p>0.5</p></td>
</tr>
<tr class="odd">
<td>Loss of Appetite</td>
<td><p>- any</p>
<p>- grade 3</p></td>
<td><p>833</p>
<p>28</p></td>
<td><p>17.9</p>
<p>0.6</p></td>
<td><p>16.8</p>
<p>0.4</p></td>
<td><p>19.0</p>
<p>0.9</p></td>
<td><p>147</p>
<p>4</p></td>
<td><p>19.1</p>
<p>0.5</p></td>
<td><p>16.4</p>
<p>0.1</p></td>
<td><p>22.1</p>
<p>1.3</p></td>
<td><p>-1.3</p>
<p>0.1</p></td>
<td><p>-4.0</p>
<p>-0.7</p></td>
<td><p>1.2</p>
<p>0.7</p></td>
</tr>
<tr class="even">
<td><strong>Restlessness</strong></td>
<td><p>- any</p>
<p><strong>- grade 3</strong></p></td>
<td><p>1934</p>
<p><strong>142</strong></p></td>
<td><p>41.4</p>
<p><strong>3.0</strong></p></td>
<td><p>40.0</p>
<p><strong>2.6</strong></p></td>
<td><p>42.9</p>
<p><strong>3.6</strong></p></td>
<td><p>356</p>
<p><strong>44</strong></p></td>
<td><p>46.4</p>
<p><strong>5.7</strong></p></td>
<td><p>42.8</p>
<p><strong>4.2</strong></p></td>
<td><p>50.0</p>
<p><strong>7.6</strong></p></td>
<td><p>-4.9</p>
<p><strong>-2.7</strong></p></td>
<td><p>-8.1</p>
<p><strong>-4.4</strong></p></td>
<td><p>-1.7</p>
<p>-<strong>1.2</strong></p></td>
</tr>
<tr class="odd">
<td><strong>Unusual crying</strong></td>
<td><p><strong>-</strong> any</p>
<p><strong>- grade 3</strong></p></td>
<td><p>1163</p>
<p><strong>182</strong></p></td>
<td><p>24.9</p>
<p><strong>3.9</strong></p></td>
<td><p>23.7</p>
<p><strong>3.4</strong></p></td>
<td><p>26.2</p>
<p><strong>4.5</strong></p></td>
<td><p>280</p>
<p><strong>52</strong></p></td>
<td><p>36.5</p>
<p><strong>6.8</strong></p></td>
<td><p>33.0</p>
<p><strong>5.1</strong></p></td>
<td><p>40.0</p>
<p><strong>8.8</strong></p></td>
<td><p>-11.5</p>
<p><strong>-2.9</strong></p></td>
<td><p>-14.7</p>
<p><strong>-4.7</strong></p></td>
<td><p>-8.5</p>
<p>-<strong>1.3</strong></p></td>
</tr>
<tr class="even">
<td colspan="13"><strong>Dose 2</strong></td>
</tr>
<tr class="odd">
<td><strong>Fever</strong></td>
<td><p><strong>T<u>&gt;</u>38C</strong></p>
<p>T&gt;39.5C</p></td>
<td><p><strong>891</strong></p>
<p>22</p></td>
<td><p><strong>19.3</strong></p>
<p>0.5</p></td>
<td><p><strong>18.2</strong></p>
<p>0.3</p></td>
<td><p><strong>20.5</strong></p>
<p>0.7</p></td>
<td><p><strong>99</strong></p>
<p>2</p></td>
<td><p><strong>13.1</strong></p>
<p>0.3</p></td>
<td><p><strong>10.8</strong></p>
<p>0.0</p></td>
<td><p><strong>15.7</strong></p>
<p>1.0</p></td>
<td><p><strong>6.2</strong></p>
<p>0.2</p></td>
<td><p><strong>3.7</strong></p>
<p>-0.5</p></td>
<td><p><strong>8.6</strong></p>
<p>0.7</p></td>
</tr>
<tr class="even">
<td><strong>Loss of Appetite</strong></td>
<td><p><strong>- any</strong></p>
<p><strong>-</strong> grade 3</p></td>
<td><p><strong>613</strong></p>
<p>24</p></td>
<td><p><strong>13.3</strong></p>
<p>0.5</p></td>
<td><p><strong>12.3</strong></p>
<p>0.3</p></td>
<td><p><strong>14.3</strong></p>
<p>8</p></td>
<td><p><strong>123</strong></p>
<p>5</p></td>
<td><p><strong>16.2</strong></p>
<p>0.7</p></td>
<td><p><strong>13.7</strong></p>
<p>0.2</p></td>
<td><p><strong>19.1</strong></p>
<p>1.5</p></td>
<td><p><strong>-3.0</strong></p>
<p>-0.1</p></td>
<td><p><strong>-5.6</strong></p>
<p>-1.0</p></td>
<td><p><strong>-0.6</strong></p>
<p>0.4</p></td>
</tr>
<tr class="odd">
<td><strong>Restlessness</strong></td>
<td><p><strong>-</strong> any</p>
<p><strong>- grade 3</strong></p></td>
<td><p>1480</p>
<p><strong>71</strong></p></td>
<td><p>32.0</p>
<p><strong>1.5</strong></p></td>
<td><p>30.7</p>
<p><strong>1.2</strong></p></td>
<td><p>33.4</p>
<p><strong>1.9</strong></p></td>
<td><p>265</p>
<p><strong>23</strong></p></td>
<td><p>35.0</p>
<p><strong>3.0</strong></p></td>
<td><p>31.6</p>
<p><strong>1.9</strong></p></td>
<td><p>38.5</p>
<p><strong>4.5</strong></p></td>
<td><p>-3.0</p>
<p><strong>-1.5</strong></p></td>
<td><p>-6.2</p>
<p><strong>-2.9</strong></p></td>
<td><p>0.1</p>
<p><strong>-0.4</strong></p></td>
</tr>
<tr class="even">
<td><strong>Unusual crying</strong></td>
<td><p><strong>- any</strong></p>
<p>- grade 3</p></td>
<td><p><strong>764</strong></p>
<p>77</p></td>
<td><p><strong>16.5</strong></p>
<p>1.7</p></td>
<td><p><strong>15.5</strong></p>
<p>1.3</p></td>
<td><p><strong>17.6</strong></p>
<p>2.1</p></td>
<td><p><strong>149</strong></p>
<p>16</p></td>
<td><p><strong>19.7</strong></p>
<p>2.1</p></td>
<td><p><strong>16.9</strong></p>
<p>1.2</p></td>
<td><p><strong>22.7</strong></p>
<p>3.4</p></td>
<td><p>-<strong>3.1</strong></p>
<p>-0.4</p></td>
<td><p>-<strong>5.9</strong></p>
<p>-1.7</p></td>
<td><p>-<strong>0.6</strong></p>
<p>0.5</p></td>
</tr>
<tr class="odd">
<td colspan="13"><strong>Dose 3</strong></td>
</tr>
<tr class="even">
<td><strong>Fever</strong></td>
<td><p><strong>T<u>&gt;</u>38C</strong></p>
<p>T&gt;39.5C</p></td>
<td><p><strong>900</strong></p>
<p>34</p></td>
<td><p><strong>19.7</strong></p>
<p>0.7</p></td>
<td><p><strong>18.5</strong></p>
<p>0.5</p></td>
<td><p><strong>20.9</strong></p>
<p>1.0</p></td>
<td><p><strong>84</strong></p>
<p>4</p></td>
<td><p><strong>11.2</strong></p>
<p>0.5</p></td>
<td><p><strong>9.0</strong></p>
<p>0.1</p></td>
<td><p><strong>13.7</strong></p>
<p>1.4</p></td>
<td><p><strong>8.5</strong></p>
<p>0.2</p></td>
<td><p><strong>6.1</strong></p>
<p>-0.6</p></td>
<td><p><strong>10.8</strong></p>
<p>0.8</p></td>
</tr>
<tr class="odd">
<td>Loss of Appetite</td>
<td><p>- any</p>
<p>- grade 3</p></td>
<td><p>572</p>
<p>20</p></td>
<td><p>12.5</p>
<p>0.4</p></td>
<td><p>11.6</p>
<p>0.3</p></td>
<td><p>13.5</p>
<p>0.7</p></td>
<td><p>85</p>
<p>0</p></td>
<td><p>11.3</p>
<p>0.0</p></td>
<td><p>9.2</p>
<p>0.0</p></td>
<td><p>13.8</p>
<p>0.5</p></td>
<td><p>1.2</p>
<p>0.4</p></td>
<td><p>-1.1</p>
<p>-0.2</p></td>
<td><p>3.4</p>
<p>0.8</p></td>
</tr>
<tr class="even">
<td><strong>Restlessness</strong></td>
<td><p>- any</p>
<p><strong>-</strong> grade 3</p></td>
<td><p>1223</p>
<p>71</p></td>
<td><p>26.7</p>
<p>1.6</p></td>
<td><p>25.5</p>
<p>1.2</p></td>
<td><p>28.0</p>
<p>2.0</p></td>
<td><p>207</p>
<p>13</p></td>
<td><p>27.6</p>
<p>1.7</p></td>
<td><p>24.4</p>
<p>0.9</p></td>
<td><p>30.9</p>
<p>2.9</p></td>
<td><p>-0.9</p>
<p>-0.2</p></td>
<td><p>-3.9</p>
<p>-1.4</p></td>
<td><p>2.1</p>
<p>0.7</p></td>
</tr>
<tr class="odd">
<td>Unusual crying</td>
<td><p>- any</p>
<p>- grade 3</p></td>
<td><p>601</p>
<p>65</p></td>
<td><p>13.1</p>
<p>1.4</p></td>
<td><p>12.2</p>
<p>1.1</p></td>
<td><p>14.2</p>
<p>1.8</p></td>
<td><p>107</p>
<p>8</p></td>
<td><p>14.3</p>
<p>1.1</p></td>
<td><p>11.8</p>
<p>0.5</p></td>
<td><p>17.0</p>
<p>2.1</p></td>
<td><p>-1.1</p>
<p>0.4</p></td>
<td><p>-3.6</p>
<p>-0.7</p></td>
<td><p>1.1</p>
<p>1.2</p></td>
</tr>
<tr class="even">
<td colspan="13"><strong>Any dose</strong></td>
</tr>
<tr class="odd">
<td><strong>Fever</strong></td>
<td><p><strong>T<u>&gt;</u>38C</strong></p>
<p>T&gt;39.5C</p></td>
<td><p><strong>2021</strong></p>
<p>65</p></td>
<td><p><strong>43.3</strong></p>
<p>1.4</p></td>
<td><p><strong>41.9</strong></p>
<p>1.1</p></td>
<td><p><strong>44.7</strong></p>
<p>1.8</p></td>
<td><p><strong>203</strong></p>
<p>8</p></td>
<td><p><strong>26.4</strong></p>
<p>1.0</p></td>
<td><p><strong>23.3</strong></p>
<p>0.5</p></td>
<td><p><strong>29.7</strong></p>
<p>2.0</p></td>
<td><p><strong>16.7</strong></p>
<p>0.4</p></td>
<td><p><strong>13.7</strong></p>
<p>-0.6</p></td>
<td><p><strong>19.8</strong></p>
<p>1.2</p></td>
</tr>
<tr class="even">
<td>Loss of Appetite</td>
<td><p>- any</p>
<p>- grade 3</p></td>
<td><p>1447</p>
<p>64</p></td>
<td><p>31.0</p>
<p>1.4</p></td>
<td><p>29.7</p>
<p>1.1</p></td>
<td><p>32.3</p>
<p>1.7</p></td>
<td><p>257</p>
<p>8</p></td>
<td><p>33.5</p>
<p>1.0</p></td>
<td><p>30.1</p>
<p>0.5</p></td>
<td><p>36.9</p>
<p>2.0</p></td>
<td><p>-2.5</p>
<p>0.3</p></td>
<td><p>-5.6</p>
<p>-0.7</p></td>
<td><p>0.6</p>
<p>1.1</p></td>
</tr>
<tr class="odd">
<td><strong>Restlessness</strong></td>
<td><p><strong>- any</strong></p>
<p><strong>- grade 3</strong></p></td>
<td><p><strong>2728</strong></p>
<p><strong>249</strong></p></td>
<td><p><strong>58.4</strong></p>
<p><strong>5.3</strong></p></td>
<td><p><strong>57.0</strong></p>
<p><strong>4.7</strong></p></td>
<td><p><strong>59.9</strong></p>
<p><strong>6.0</strong></p></td>
<td><p><strong>475</strong></p>
<p><strong>66</strong></p></td>
<td><p><strong>61.8</strong></p>
<p><strong>8.6</strong></p></td>
<td><p><strong>58.3</strong></p>
<p><strong>6.7</strong></p></td>
<td><p><strong>65.3</strong></p>
<p><strong>10.8</strong></p></td>
<td><p><strong>-3.4</strong></p>
<p><strong>-3.3</strong></p></td>
<td><p><strong>-6.6</strong></p>
<p><strong>-5.3</strong></p></td>
<td><p><strong>-0.2</strong></p>
<p><strong>-1.5</strong></p></td>
</tr>
<tr class="even">
<td><strong>Unusual crying</strong></td>
<td><p><strong>- any</strong></p>
<p><strong>-grade 3</strong></p></td>
<td><p><strong>1771</strong></p>
<p><strong>289</strong></p></td>
<td><p><strong>37.9</strong></p>
<p><strong>6.2</strong></p></td>
<td><p><strong>36.5</strong></p>
<p><strong>5.5</strong></p></td>
<td><p><strong>39.3</strong></p>
<p><strong>6.9</strong></p></td>
<td><p><strong>374</strong></p>
<p><strong>71</strong></p></td>
<td><p><strong>48.7</strong></p>
<p><strong>9.2</strong></p></td>
<td><p><strong>45.1</strong></p>
<p><strong>7.3</strong></p></td>
<td><p><strong>52.3</strong></p>
<p><strong>11.5</strong></p></td>
<td><p><strong>-10.8</strong></p>
<p><strong>-3.1</strong></p></td>
<td><p><strong>-14.0</strong></p>
<p><strong>-5.1</strong></p></td>
<td><p><strong>-7.5</strong></p>
<p><strong>-1.2</strong></p></td>
</tr>
</tbody>
</table>

Group 1-4 pooled: DTPa-HepB-IPV vaccine concomitantly with Hib vaccine
at a separate site

Group 5: SBB's DTPa+PM Hib +OPV

N=number of symptom sheets received (for doses 1-3) or number of
subjects with at least one symptom sheet received ("any dose"), with
highest number reported

n=number reporting a specific symptom

%=percentage reporting the specific symptom

Onset of symptoms within 4 day follow up period (onset day 0-3)

**In bold**: symptoms for which the 90% CI failed to overlap the 0%
difference

> *Reviewer comment*: The incidence of fever [\>]{.underline} 38^o^ C in
> pooled groups receiving DTPa-HepB-IPV ranged from 25.1% following the
> first dose, to 19.7% following the 3^rd^ dose. The incidence of fever
> following any dose (per subject) was 43.3%.
>
> For each dose and over the full course of vaccination (any dose), the
> rate of fever (T [\>]{.underline} 38^o^ C) was [increased]{.underline}
> in subjects receiving DTPa-HepB-IPV (pooled groups 1-4) compared with
> the control group receiving separate vaccines, with these differences
> statistically significant. The difference in rate of fever
> [\>]{.underline} 38ºC between DTPa-HepB-IPV recipients and the control
> group ranged from 12.0% to 13.7% after each dose. After any dose, the
> incidence of fever in DTPa-HepB-IPV recipients was 16.7% more fever
> than the control group. Of note, the rate of Grade 3 fever was not
> different between DTPa-HepB-IPV recipients and controls.
>
> Following doses 2 and 3 and after any dose, the rates of restlessness
> and unusual crying were slightly increased in subjects receiving
> separate administration of DTPa, Hib and OPV, compared with those
> receiving DTPa-HepB-IPV and Hib, with these differences statistically
> significant.

**Antipyretic Use**

**DTPa-HepB-IPV-011 - Percentage of subjects (95%CI) receiving
antipyretics within 4 days, for each dose and over the whole vaccination
course - ITT cohorts**

+------+-------------+--------------+--------------+-----------------+
| ###  | **Dose 1**  | **Dose 2**   | **Dose 3**   | **Any**         |
| ## G |             |              |              |                 |
| roup |             |              |              |                 |
+------+-------------+--------------+--------------+-----------------+
|      | **%         | **%          | **%          | **% (95%CI)**   |
|      | (95%CI)**   | (95%CI)**    | (95%CI)**    |                 |
+------+-------------+--------------+--------------+-----------------+
| 1    | 1.1 (0.6 -  | 1.5 (0.9 -   | 1.6 (0.9 -   | 3.8 (2.8 - 5.1) |
|      | 1.9)        | 2.3)         | 2.5)         |                 |
+------+-------------+--------------+--------------+-----------------+
| 2    | 3.9 (2.8 -  | 2.0 (1.3 -   | 1.8 (1.1 -   | 6.3 (5.0 - 7.9) |
|      | 5.1)        | 3.0)         | 2.7)         |                 |
+------+-------------+--------------+--------------+-----------------+
| 3    | 1.2 (0.7 -  | 1.0 (0.5 -   | 1.6 (0.9 -   | 3.4 (2.5 - 4.6) |
|      | 2.0)        | 1.7)         | 2.5)         |                 |
+------+-------------+--------------+--------------+-----------------+
| 4    | 5.5 (4.3 -  | 1.7 (1.0 -   | 2.6 (1.7 -   | 8.1 (6.6 - 9.8) |
|      | 7.0)        | 2.6)         | 3.6)         |                 |
+------+-------------+--------------+--------------+-----------------+
| 5    | 3.6 (2.4 -  | 1.1 (0.5 -   | 0.8 (0.3 -   | 4.9 (3.5 - 6.7) |
|      | 5.2)        | 2.1)         | 1.7)         |                 |
+------+-------------+--------------+--------------+-----------------+

Group 1: DTPa-HepB-IPV + SB Hib

Group 2: DTPa-HepB-IPV + PM Hib

Group 3: DTPa-HepB-IPV + Led Hib

Group 4: DTPa-HepB-IPV + MSD Hib (Subjects in Group 4 received only 2
doses of Hib vaccine at 3 and 5 months)

Group 5: DTPa + SB Hib + OPV

*Reviewer comment:* Antipyretic use was low in this study (conducted in
Germany) compared with data presented later for Study DTPa-HepB-IPV-015
(conducted in the U.S.) According to SBB, there were no standardized
instructions on antipyretic use; however, parents were given similar
instructions across studies. Parents were instructed to administer
antipyretics if needed. The BLA database did not record whether
antipyretic medication was given prophylactically or therapeutically.
SBB noted that antipyretic use following vaccination was not a common
practice in Germany.

**Secondary Endpoint:**

**Unsolicited symptoms***:* In the ATP cohort, 1790 (59%) subjects in
the pooled DTPa-HBV-IPV vaccine group and 434 (58%) in the control
vaccine group reported an unsolicited symptom. Symptoms reported by 48
(1.6%) subjects in the pooled DTPa-HBV-IPV vaccine group and 14 (1.9%)
subjects in the control vaccine group were graded 3 in intensity
(symptom preventing normal daily activities). Rates of unsolicited
symptoms between the pooled DTPa-HBV-IPV vaccine group and the control
vaccine group not statistically different (data not shown.)

See Section 3.3.7 for summary data on unsolicited AEs, SAEs and deaths
across all studies..

4.  **Study DTPa-HB-IPV-015 (U.S. Comparative Safety and Immunogenicity
    vs. Separately Administered Vaccines)**

(See study synopsis provided in section 3.2.3)

Note: Because the ATP cohort excluded less than 1.5% of the enrolled
subjects with safety data available, the BLA did not include a
reanalysis based on the ITT cohort. Thus, the data presented below are
from the ATP cohort for safety. As was noted in section 3.2.3 , review
of these data under the BLA focused on groups 1 and 4 because group 2
evaluated a sequential IPV/OPV schedule (no longer the recommended U.S.
schedule for polio vaccines) and group 3 evaluated SBB's DTPa-HepB (not
licensed in the U.S.)

**Safety Objective (secondary objective):**

To assess the comparability in terms of safety of DTPa-HepB-IPV
co-administered with Hib and the co-administration of DTPa (Infanrix®),
hepatitis B vaccine (Engerix-B®), OPV (ORIMUNE®™), and Hib (OmniHIB™),
the co-administration of DTPa-HepB, IPV (IPOL ®), and Hib (OmniHIB™),
and two consecutive doses of SBB's DTPa-HepB-IPV co-administered with
Hib followed by co-administration of DTPa-HepB, OPV and Hib.

**Statistical methods:**

The overall percentage of subjects with at least one adverse event
(local or general, solicited and/or unsolicited), with at least one
general adverse event (solicited and/or unsolicited), and with at least
one local adverse event during the four-day follow-up period after each
vaccination was tabulated and compared between Group 1 and each of the
Groups 2, 3, and 4 using the 2-sided Fisher exact test at 5% type I
error.

Note: sample size for this study was based on the primary
(immunogenicity) endpoints.

**Schedule:** 2, 4, 6 months

Group 1: DTPa-HB-IPV + Hib at 2, 4, 6 mo

Group 2: DTPa-HB-IPV + Hib at 2, 4 mo; DTPa-HB +Hib + OPV at 6 months

Group 3: DTPa-HB + Hib + IPV at 2, 4, 6 mo

### Group 4: DTPa + HB + OPV + Hib at 2, 4, 6 mo

**Site of administration**

+--------+-----------------------+--------------------+---------------+
| ###### |                       |                    |               |
| ## Stu |                       |                    |               |
| dy DTP |                       |                    |               |
| a-HepB |                       |                    |               |
| -IPV-0 |                       |                    |               |
| 15: Si |                       |                    |               |
| te of  |                       |                    |               |
| Vaccin |                       |                    |               |
| e Admi |                       |                    |               |
| nistra |                       |                    |               |
| tion\* |                       |                    |               |
+--------+-----------------------+--------------------+---------------+
| **G    | **Right anterolateral | **Left             | **Oral        |
| roup** | thigh**               | anterolateral      | adm           |
|        |                       | thigh**            | inistration** |
+--------+-----------------------+--------------------+---------------+
| 1      | Hib (OmniHIB™)        | DTPa-HepB-IPV      |               |
+--------+-----------------------+--------------------+---------------+
| 2      | Hib (OmniHIB™)        | DTPa-HepB-IPV at   | OPV           |
|        |                       | 2, 4 mo            | (ORIMUNE®)    |
|        |                       |                    |               |
|        |                       | DTPa-HepB at 6 mo  | at 6 mo       |
+--------+-----------------------+--------------------+---------------+
| 3      | Hib (OmniHIB™): upper | DTPa-HepB          |               |
|        | thigh                 |                    |               |
|        |                       |                    |               |
|        | IPV (IPOL®): lower    |                    |               |
|        | thigh-SC              |                    |               |
+--------+-----------------------+--------------------+---------------+
| 4      | Hib (OmniHIB™): upper | ### Infanrix®      | OPV           |
|        | thigh                 |                    | (ORIMUNE®)    |
|        |                       |                    |               |
|        | HepB (Engerix®):      |                    |               |
|        | lower thigh           |                    |               |
+--------+-----------------------+--------------------+---------------+

\*Schedule: 2, 4, 6 months unless otherwise noted

**DTPa-HepB-IPV-015: Demographics\***

+---------------------------+-----------------------+------------------+
| **Categories**            | ###### **Total**      |                  |
+---------------------------+-----------------------+------------------+
|                           | **n**                 | **%**            |
+---------------------------+-----------------------+------------------+
| Total                     | **332**               |                  |
+---------------------------+-----------------------+------------------+
| Black                     | **37**                | **11.14**        |
+---------------------------+-----------------------+------------------+
| ### White                 | **161**               | **48.49**        |
+---------------------------+-----------------------+------------------+
| Asian                     | **4**                 | **1.2**          |
+---------------------------+-----------------------+------------------+
| Filipino                  | **7**                 | **2.11**         |
+---------------------------+-----------------------+------------------+
| Hispanic                  | **113**               | **34.04**        |
+---------------------------+-----------------------+------------------+
| Indian                    | **1**                 | **0.30**         |
+---------------------------+-----------------------+------------------+
| Middle Eastern            | **7**                 | **2.11**         |
+---------------------------+-----------------------+------------------+
| Samoan                    | **1**                 | **0.30**         |
+---------------------------+-----------------------+------------------+
| Vietnamese                | **1**                 | **0.30**         |
+---------------------------+-----------------------+------------------+
| Female                    | **156**               | **46.99**        |
+---------------------------+-----------------------+------------------+
| Male                      | **176**               | **53.01**        |
+---------------------------+-----------------------+------------------+

\*ATP cohort for immunogenicity

DTPa-HepB-IPV-015: Incidence of [solicited local symptoms]{.underline}
following any dose during the 4-day follow-up period per subject: ATP
analysis

<table>
<colgroup>
<col style="width: 12%" />
<col style="width: 15%" />
<col style="width: 4%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 6%" />
<col style="width: 4%" />
<col style="width: 7%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="3"><strong>Symptom</strong></td>
<td rowspan="3"><strong>Injection site</strong></td>
<td colspan="4"><p><strong>Group 1</strong></p>
<p><strong>(N=100)</strong></p></td>
<td colspan="4"><p><strong>Group 4</strong></p>
<p><strong>(N=98)</strong></p></td>
<td colspan="3"><strong>Group 1 minus Group 4</strong></td>
</tr>
<tr class="even">
<td><strong>n</strong></td>
<td><strong>%</strong></td>
<td colspan="2"><strong>95%CI</strong></td>
<td><strong>n</strong></td>
<td><strong>%</strong></td>
<td colspan="2"><strong>95%CI</strong></td>
<td><strong>Difference</strong></td>
<td colspan="2"><strong>90%CI</strong></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td><strong>LL</strong></td>
<td><strong>UL</strong></td>
<td></td>
<td></td>
<td><strong>LL</strong></td>
<td><strong>UL</strong></td>
<td><strong>(%)</strong></td>
<td><strong>LL</strong></td>
<td><strong>UL</strong></td>
</tr>
<tr class="even">
<td rowspan="4">Pain</td>
<td>Overall</td>
<td>57</td>
<td>57.0</td>
<td>46.7</td>
<td>66.9</td>
<td>51</td>
<td>52.0</td>
<td>41.7</td>
<td>62.2</td>
<td>5.0</td>
<td>-7.1</td>
<td>17.7</td>
</tr>
<tr class="odd">
<td>DTPa-based</td>
<td>55</td>
<td>55.0</td>
<td>44.7</td>
<td>65.0</td>
<td>48</td>
<td>49.0</td>
<td>38.7</td>
<td>59.3</td>
<td>6.0</td>
<td>-6.1</td>
<td>18.9</td>
</tr>
<tr class="even">
<td>HepB</td>
<td>-</td>
<td>-</td>
<td>-</td>
<td>-</td>
<td>42</td>
<td>42.9</td>
<td>32.9</td>
<td>53.3</td>
<td>-</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Hib</td>
<td>40</td>
<td>40.0</td>
<td>30.3</td>
<td>50.3</td>
<td>45</td>
<td>45.9</td>
<td>35.8</td>
<td>56.3</td>
<td>-</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td rowspan="4">Redness</td>
<td>Overall</td>
<td>40</td>
<td>40.0</td>
<td>30.3</td>
<td>50.3</td>
<td>31</td>
<td>31.6</td>
<td>22.6</td>
<td>41.8</td>
<td>8.4</td>
<td>-3.1</td>
<td>21.2</td>
</tr>
<tr class="odd">
<td>DTPa-based</td>
<td>35</td>
<td>35.0</td>
<td>25.7</td>
<td>45.2</td>
<td>28</td>
<td>28.6</td>
<td>19.9</td>
<td>38.6</td>
<td>6.4</td>
<td>-4.9</td>
<td>19.2</td>
</tr>
<tr class="even">
<td>HepB</td>
<td>-</td>
<td>-</td>
<td>-</td>
<td>-</td>
<td>17</td>
<td>17.3</td>
<td>10.4</td>
<td>26.3</td>
<td>-</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Hib</td>
<td>24</td>
<td>24.0</td>
<td>16.0</td>
<td>33.6</td>
<td>19</td>
<td>19.4</td>
<td>12.1</td>
<td>28.6</td>
<td>-</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td rowspan="4">Swelling</td>
<td>Overall</td>
<td>36</td>
<td>36.0</td>
<td>26.6</td>
<td>46.2</td>
<td>27</td>
<td>27.6</td>
<td>19.0</td>
<td>37.5</td>
<td>8.4</td>
<td>-2.9</td>
<td>21.2</td>
</tr>
<tr class="odd">
<td>DTPa-based</td>
<td>31</td>
<td>31.0</td>
<td>22.1</td>
<td>41.0</td>
<td>20</td>
<td>20.4</td>
<td>12.9</td>
<td>29.7</td>
<td>10.6</td>
<td>-0.4</td>
<td>22.9</td>
</tr>
<tr class="even">
<td>HepB</td>
<td>-</td>
<td>-</td>
<td>-</td>
<td>-</td>
<td>8</td>
<td>8.2</td>
<td>3.6</td>
<td>15.5</td>
<td>-</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Hib</td>
<td>13</td>
<td>13.0</td>
<td>7.1</td>
<td>21.2</td>
<td>14</td>
<td>14.3</td>
<td>8.0</td>
<td>22.8</td>
<td>-</td>
<td></td>
<td></td>
</tr>
</tbody>
</table>

Group 1 = DTPa-HepB-IPV + Hib

Group 4 = DTPa + HepB + Hib + OPV

N = number of subjects with at least one symptom sheet completed

n = number of subjects reporting the specific solicited local symptom

\% = percentage of subjects (n/Nx100) reporting the specific solicited
local symptom

Overall = local symptom reported for any vaccination site (For local
symptoms following multiple injections, a symptom was counted once even
if reported at multiple sites.)

> *Reviewer comment:* This analysis compares local reactogenicity in
> infants receiving DTPa-HepB-IPV and Hib (group 1) and separately
> administered DTPa, HepB, Hib and OPV (group 5). When comparing the
> local reactions occurring at the DTPa-HepB-IPV site with the DTPa
> site, the incidence of redness was 6.4% greater at the DPTa-HepB-IPV
> site and the incidence of swelling was 10.6% higher. These
> differences, however, were not statistically significant. Of note, the
> sample size of the study was base on immunogenicity endpoints and may
> have been too small to detect a difference in local symptoms.
>
> As was noted previously in Study-011, it is possible that Study-015
> underestimated the incidence of local reactions in the separate
> vaccine control arm. Group 4 (control group of separately administered
> vaccines) received OPV rather than IPV which is now the recommended
> polio regimen. Moreover, in the analysis of overall local symptoms, a
> symptom was counted only once even if it was reported at multiple
> sites. Thus, this analysis could not assess any additive local
> reactogenicity for multiple injection sites.

DTPa-HepB-IPV-015: Incidence of [Grade 3 solicited local
symptoms]{.underline} following any dose during the 4-day follow-up
period per subject: ATP analysis

  -------------- --------------- --------- ------- -------- -------- --------- ------- -------- --------
  **Symptom**    **Vaccine**     **Group 1                           **Group 4                  
                                 (N =                                (N =                       
                                 100)**                              98)**                      

                                 **n**     **%**   **LL**   **UL**   **n**     **%**   **LL**   **UL**

  **Pain**       Overall         3         3.0     0.6      8.5      5         5.1     1.7      11.5

                 DTPa            \-        \-      \-       \-       5         5.1     1.7      11.5

                 DTPa-HepB-IPV   2         2.0     0.2      7.0      \-        \-      \-       \-

                 HepB            \-        \-      \-       \-       4         4.1     1.1      10.1

                 Hib             1         1.0     0.0      5.4      5         5.1     1.7      11.5

  **Redness**    Overall         3         3.0     0.6      8.5      1         1.0     0.0      5.6

                 DTPa            \-        \-      \-       \-       0         0.0     0.0      3.7

                 DTPa-HepB-IPV   3         3.0     0.6      8.5      \-        \-      \-       \-

                 HepB            \-        \-      \-       \-       0         0.0     0.0      3.7

                 Hib             0         0.0     0.0      3.6      1         1.0     0.0      5.6

  **Swelling**   Overall         6         6.0     2.2      12.6     3         3.1     0.6      8.7

                 DTPa            \-        \-      \-       \-       1         1.0     0.0      5.6

                 DTPa-HepB-IPV   6         6.0     2.2      12.6     \-        \-      \-       \-

                 HepB            \-        \-      \-       \-       0         0.0     0.0      3.7

                 Hib             1         1.0     0.0      5.4      2         2.0     0.2      7.2
  -------------- --------------- --------- ------- -------- -------- --------- ------- -------- --------

Group 1 = DTPa-HepB-IPV + Hib

Group 4 = DTPa + HepB + Hib + OPV

N = number of subjects with at least one symptom sheet completed n =
number of subjects reporting the specific solicited local symptom

\% = percentage of subjects (n/Nx100) reporting the specific solicited
local symptom

Overall = local symptom reported for any vaccination site (For local
symptoms following multiple injections,

a symptom was counted once even if reported at multiple sites.)

DTPa-HepB-IPV-015: Incidence of [all solicited general
symptoms]{.underline} during the 4-day follow-up period per subject (any
dose): ATP cohort

<table>
<colgroup>
<col style="width: 12%" />
<col style="width: 9%" />
<col style="width: 4%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 0%" />
<col style="width: 6%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 12%" />
<col style="width: 7%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2"><h5 id="symptom">Symptom</h5></td>
<td rowspan="2"><strong>Onset</strong></td>
<td colspan="4"><p><strong>Group 1</strong></p>
<p><strong>N=100</strong></p></td>
<td colspan="6"><p><strong>Group 4</strong></p>
<p><strong>N=98</strong></p></td>
<td colspan="5"><strong>Group 1 minus Group 4</strong></td>
</tr>
<tr class="even">
<td><strong>n</strong></td>
<td><strong>%</strong></td>
<td colspan="2"><p><strong>90% CI</strong></p>
<p><strong>LL UL</strong></p></td>
<td><strong>n</strong></td>
<td colspan="2"><strong>%</strong></td>
<td colspan="3"><p><strong>90% CI</strong></p>
<p><strong>LL UL</strong></p></td>
<td><p><strong>Difference</strong></p>
<p><strong>%</strong></p></td>
<td colspan="4"><p><strong>90% CI</strong></p>
<p><strong>LL UL</strong></p></td>
</tr>
<tr class="odd">
<td rowspan="2">Diarrhea</td>
<td>Onset 2 days</td>
<td>25</td>
<td>25.0</td>
<td>16.9</td>
<td>34.7</td>
<td colspan="2">25</td>
<td colspan="2">25.5</td>
<td>17.2</td>
<td>35.3</td>
<td>-0.5</td>
<td colspan="2">-12.4</td>
<td colspan="2">11.0</td>
</tr>
<tr class="even">
<td>Total</td>
<td>26</td>
<td>26.0</td>
<td>17.7</td>
<td>35.7</td>
<td colspan="2">28</td>
<td colspan="2">28.6</td>
<td>19.9</td>
<td>38.6</td>
<td>-2.6</td>
<td colspan="2">-14.6</td>
<td colspan="2">9.1</td>
</tr>
<tr class="odd">
<td rowspan="2">Fussiness</td>
<td>Onset 2 days</td>
<td>80</td>
<td>80.0</td>
<td>70.8</td>
<td>87.3</td>
<td colspan="2">81</td>
<td colspan="2">82.7</td>
<td>73.7</td>
<td>89.6</td>
<td>-2.7</td>
<td colspan="2">-14.5</td>
<td colspan="2">7.7</td>
</tr>
<tr class="even">
<td>Total</td>
<td>82</td>
<td>82.0</td>
<td>73.1</td>
<td>89.0</td>
<td colspan="2">84</td>
<td colspan="2">85.7</td>
<td>77.2</td>
<td>92.0</td>
<td>-3.7</td>
<td colspan="2">-15.2</td>
<td colspan="2">6.2</td>
</tr>
<tr class="odd">
<td rowspan="2">Loss of appetite</td>
<td>Onset 2 days</td>
<td>36</td>
<td>36.0</td>
<td>26.6</td>
<td>46.2</td>
<td colspan="2">37</td>
<td colspan="2">37.8</td>
<td>28.2</td>
<td>48.1</td>
<td>-1.8</td>
<td colspan="2">-14.1</td>
<td colspan="2">10.2</td>
</tr>
<tr class="even">
<td>Total</td>
<td>38</td>
<td>38.0</td>
<td>28.5</td>
<td>48.3</td>
<td colspan="2">38</td>
<td colspan="2">38.8</td>
<td>29.1</td>
<td>49.2</td>
<td>-0.8</td>
<td colspan="2">-13.2</td>
<td colspan="2">11.2</td>
</tr>
<tr class="odd">
<td rowspan="2">Restlessness</td>
<td>Onset 2 days</td>
<td>37</td>
<td>37.0</td>
<td>27.6</td>
<td>47.2</td>
<td colspan="2">39</td>
<td colspan="2">39.8</td>
<td>30.0</td>
<td>50.2</td>
<td>-2.8</td>
<td colspan="2">-15.2</td>
<td colspan="2">9.2</td>
</tr>
<tr class="even">
<td>Total</td>
<td>42</td>
<td>42.0</td>
<td>32.2</td>
<td>52.3</td>
<td colspan="2">42</td>
<td colspan="2">42.9</td>
<td>32.9</td>
<td>53.3</td>
<td>-0.9</td>
<td colspan="2">-13.5</td>
<td colspan="2">11.2</td>
</tr>
<tr class="odd">
<td rowspan="2"><p>Sleeping more than</p>
<p>usual</p></td>
<td>Onset 2 days</td>
<td>63</td>
<td>63.0</td>
<td>52.8</td>
<td>72.4</td>
<td colspan="2">57</td>
<td colspan="2">58.2</td>
<td>47.8</td>
<td>68.1</td>
<td>4.8</td>
<td colspan="2">-7.2</td>
<td colspan="2">17.3</td>
</tr>
<tr class="even">
<td>Total</td>
<td>64</td>
<td>64.0</td>
<td>53.8</td>
<td>73.4</td>
<td colspan="2">59</td>
<td colspan="2">60.2</td>
<td>49.8</td>
<td>70.0</td>
<td>3.8</td>
<td colspan="2">-8.2</td>
<td colspan="2">16.2</td>
</tr>
<tr class="odd">
<td rowspan="2">Fever (T <u>&gt;</u> 38°C)</td>
<td><strong>Onset 2 days</strong></td>
<td><strong>39</strong></td>
<td><strong>39.0</strong></td>
<td><strong>29.4</strong></td>
<td><strong>49.3</strong></td>
<td colspan="2"><strong>27</strong></td>
<td colspan="2"><strong>27.6</strong></td>
<td><strong>19.0</strong></td>
<td><strong>37.5</strong></td>
<td><strong>11.4</strong></td>
<td colspan="2"><strong>0.1</strong></td>
<td colspan="2"><strong>24.1</strong></td>
</tr>
<tr class="even">
<td>Total</td>
<td>41</td>
<td>41.0</td>
<td>31.3</td>
<td>51.3</td>
<td colspan="2">29</td>
<td colspan="2">29.6</td>
<td>20.8</td>
<td>39.7</td>
<td>11.4</td>
<td colspan="2">0.0</td>
<td colspan="2">24.1</td>
</tr>
<tr class="odd">
<td rowspan="2">Grade 3 (T &gt; 39.5°C)</td>
<td>Onset 2 days</td>
<td>3</td>
<td>3.0</td>
<td>0.6</td>
<td>8.5</td>
<td colspan="2">2</td>
<td colspan="2">2.0</td>
<td>0.2</td>
<td>7.2</td>
<td>1.0</td>
<td colspan="2">-5.3</td>
<td colspan="2">8.8</td>
</tr>
<tr class="even">
<td>Total</td>
<td>3</td>
<td>3.0</td>
<td>0.6</td>
<td>8.5</td>
<td colspan="2">2</td>
<td colspan="2">2.0</td>
<td>0.2</td>
<td>7.2</td>
<td>1.0</td>
<td colspan="2">-5.3</td>
<td colspan="2">8.8</td>
</tr>
<tr class="odd">
<td rowspan="2">Unusual Crying</td>
<td>Onset 2 days</td>
<td>4</td>
<td>4.0</td>
<td>1.1</td>
<td>9.9</td>
<td colspan="2">5</td>
<td colspan="2">5.1</td>
<td>1.7</td>
<td>11.5</td>
<td>-1.1</td>
<td colspan="2">-9.3</td>
<td colspan="2">6.7</td>
</tr>
<tr class="even">
<td>Total</td>
<td>6</td>
<td>6.0</td>
<td>2.2</td>
<td>12.6</td>
<td colspan="2">6</td>
<td colspan="2">6.1</td>
<td>2.3</td>
<td>12.9</td>
<td>-0.1</td>
<td>-8.8</td>
<td colspan="2"></td>
<td>8.2</td>
</tr>
<tr class="odd">
<td rowspan="2">Vomiting</td>
<td>Onset 2 days</td>
<td>12</td>
<td>12.0</td>
<td>6.4</td>
<td>20.0</td>
<td colspan="2">15</td>
<td colspan="2">15.3</td>
<td>8.8</td>
<td>24.0</td>
<td>-3.3</td>
<td>-13.8</td>
<td colspan="2"></td>
<td>6.8</td>
</tr>
<tr class="even">
<td>Total</td>
<td>13</td>
<td>13.0</td>
<td>7.1</td>
<td>21.2</td>
<td colspan="2">16</td>
<td colspan="2">16.3</td>
<td>9.6</td>
<td>25.2</td>
<td>-3.3</td>
<td>-14.0</td>
<td colspan="2"></td>
<td>7.0</td>
</tr>
</tbody>
</table>

Group 1 = DTPa-HepB-IPV + Hib

Group 4 = DTPa + HepB + Hib + OPV

N = number of subjects with at least one symptom sheet completed

n = number of subjects reporting the specific solicited general symptom

\% = percentage of subjects (n/Nx100) reporting the specific solicited
general symptom

Onset 2 days = onset of symptoms within 2 days after vaccination

Total = onset of symptoms within the four day follow up period (Day 0-3)

> *Reviewer comment*: As in Study -011, an increased rate of fever (T
> [\>]{.underline} 38ºC) was observed in subjects receiving
> DTPa-HepB-IPV compared with separate immunization controls (point
> estimate of 11.4% with 90% CI 0.1 - 24.1). This difference was
> statistically significant for onset within two days of vaccination.
> The difference in rates of Grade 3 fever (T \> 39.5ºC) in group 1
> minus group 4 was not statistically significant.

# Antipyretic Use

**DTPa-HepB-IPV-015 - Percentage of subjects (95%CI) receiving
antipyretics within 4 days, for each dose and over the whole vaccination
course - ATP cohort**

  ----------- ---------------- -------------- -------------- -----------------
  **Group**   **Dose 1**       **Dose 2**     **Dose 3**     **Any**

              **% (95%CI)**    **% (95%CI)**  **% (95%CI)**  **% (95%CI)**

  1           79.0 (69.7 -     67.7 (57.4 -   62.1 (51.6 -   91.0 (83.6 -
              86.5)            76.9)          71.9)          95.8)

  4           82.7 (73.7 -     70.1 (59.4 -   59.5 (48.3 -   90.8 (83.3 -
              89.6)            79.5)          70.1)          95.7)
  ----------- ---------------- -------------- -------------- -----------------

Group 1: 3 doses DTPa-HepB-IPV + PMC's Hib

Group 4: DTPa + HepB + PMC's Hib + OPV

\% = percentage of subjects who received at least one dose of
antipyretics among subjects included

in the analysis of solicited fever (95% confidence interval)

> *Reviewer comment:* While a statistical analysis was not performed,
> the differences in antipyretic use between groups 1 and 4 do not
> appear to be clinically important. As previously noted, antipyretic
> use in this U.S. study was significantly higher than in Study --011
> conducted in Germany. The rates of fever, however, appear similar both
> studies. The difference observed in use of antipyretics may reflect
> different clinical practices in the U.S. and Germany.

**Serious Adverse Events: Total of 9 reports in 8 subjects**

**Group 1**: 3 subjects

-   Subject 27: Respiratory Syncytial Virus; hospitalized 20 days after
    3^rd^ dose

-   Subject 298: Seizure disorder, 1st seizure 2 weeks after 1^st^ dose

-   Subject 319: Urticarial rash 2 days after 3^rd^ vaccination

    **Group 2:** 3 subjects

```{=html}
<!-- -->
```
-   Subject 209: Hospitalized 14 days after 3^rd^ dose for possible
    apnea

-   Subject 215: 2 weeks after 1^st^ dose had onset of weak cry.
    Diagnosed with neuroblastoma, died 14 months later.

-   Subject 276: 5 days after 1^st^ dose, hospitalized to rule out
    sepsis. Diagnosed with viral syndrome.

**Group 3**: 1 subject (subject 59): Pneumonia 48 days after 2^nd^ dose.

**Group 4**: 1 subject (2 reports): Subject 322: Hospitalized for
bronchiolitis/right otitis media 27 days after 2^nd^ dose, hospitalized
for bronchiolitis 9 days after 3^rd^ dose.

**3.3.5 Study DTPa-HB-IPV-044: (Lot-to-lot consistency and manufacturing
bridge from 1^st^ to 2^nd^ lot series)**

**See synopsis provided in Clinical Review Section 3.2.4**

Group 1: DTPa-HepB-IPV, Lot A 2nd lot series + Hib (OmniHIB™)

Group 2: DTPa-HepB-IPV, Lot B 2nd lot series + Hib (OmniHIB™)

Group 3: DTPa-HepB-IPV, Lot C 2nd lot series + Hib (OmniHIB™)

Group 4: DTPa-HepB-IPV, 1st lot series + Hib (OmniHIB™)

**Safety Objectives (Secondary):**

-   To evaluate the lot-to-lot consistency in terms of reactogenicity
    for three production lots of DTPa-HepB-

IPV vaccine manufactured according to the new manufacturing process
(second lot series).

-   To evaluate whether DTPa-HepB-IPV vaccine manufactured according to
    the new manufacturing

process (second lot series) results in increased reactogenicity as
compared to DTPa-HepB-IPV vaccine manufactured according to the initial
manufacturing process (first lot series).

**Statistical methods (Reactogenicity):**

All reactogenicity analyses were exploratory. The difference between the
first series (Group 4) and the second series (pooled Groups 1, 2, and 3)
in the percentage of subjects experiencing any graded \"3\" solicited
symptom, the percentage of subjects experiencing each solicited symptom,
whatever the intensity rating and with intensity rated \"3\", whatever
the dose and the site of vaccination, were calculated with their exact
90% CIs.

For the lot-to-lot consistency of the second series lots, the pairwise
differences between Group 1 and Group 2, Group 1 and Group 3, and Group
2 and Group 3 in the percentage of subjects experiencing any grade \"3\"
solicited symptoms during the four-day follow-up period after any of the
three doses were evaluated using exact 90% CIs.

Note: Sample size was based on the primary (immunogenicity) endpoints

# Demographics\*

<table style="width:100%;">
<colgroup>
<col style="width: 22%" />
<col style="width: 13%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 4%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 10%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="3"><strong>Characteristics</strong></td>
<td rowspan="3"><strong>Categories</strong></td>
<td colspan="2"><strong>Group 1</strong></td>
<td colspan="2"><p id="group-2" class="heading">Group 2</p></td>
<td colspan="2"><strong>Group 3</strong></td>
<td colspan="2"><strong>Group 4</strong></td>
<td colspan="2"><strong>Total</strong></td>
</tr>
<tr class="even">
<td rowspan="2"><p><strong>n</strong></p>
<p><strong>107</strong></p></td>
<td rowspan="2"><strong>%</strong></td>
<td rowspan="2"><p><strong>n</strong></p>
<p><strong>112</strong></p></td>
<td rowspan="2"><strong>%</strong></td>
<td rowspan="2"><p><strong>n</strong></p>
<p><strong>109</strong></p></td>
<td rowspan="2"><strong>%</strong></td>
<td rowspan="2"><p><strong>n</strong></p>
<p><strong>106</strong></p></td>
<td rowspan="2"><strong>%</strong></td>
<td rowspan="2"><p><strong>n</strong></p>
<p><strong>434</strong></p></td>
<td rowspan="2"><strong>%</strong></td>
</tr>
<tr class="odd">
</tr>
<tr class="even">
<td>Race</td>
<td>White</td>
<td>92</td>
<td>86.0</td>
<td>101</td>
<td>90.2</td>
<td>93</td>
<td>85.3</td>
<td>94</td>
<td>88.7</td>
<td>380</td>
<td>87.6</td>
</tr>
<tr class="odd">
<td></td>
<td>Black</td>
<td>4</td>
<td>3.7</td>
<td>3</td>
<td>2.7</td>
<td>2</td>
<td>1.8</td>
<td>1</td>
<td>0.9</td>
<td>10</td>
<td>2.3</td>
</tr>
<tr class="even">
<td></td>
<td>Asian</td>
<td>1</td>
<td>0.9</td>
<td>0</td>
<td></td>
<td>2</td>
<td>1.8</td>
<td>0</td>
<td></td>
<td>3</td>
<td>0.7</td>
</tr>
<tr class="odd">
<td></td>
<td>Other</td>
<td>10</td>
<td>9.4</td>
<td>8</td>
<td>7.1</td>
<td>12</td>
<td>11.0</td>
<td>11</td>
<td>10.4</td>
<td>41</td>
<td>9.5</td>
</tr>
<tr class="even">
<td>Gender</td>
<td>Female</td>
<td>40</td>
<td>37.4</td>
<td>52</td>
<td>46.4</td>
<td>56</td>
<td>51.4</td>
<td>54</td>
<td>50.9</td>
<td>202</td>
<td>46.5</td>
</tr>
<tr class="odd">
<td></td>
<td>Male</td>
<td>67</td>
<td>62.6</td>
<td>60</td>
<td>53.6</td>
<td>53</td>
<td>48.6</td>
<td>52</td>
<td>49.1</td>
<td>232</td>
<td>53.5</td>
</tr>
</tbody>
</table>

\*ATP cohort for immunogenicity

DTPa-HepB-IPV-044: Assessment of Groups 1, 2, and 3 pooled (Second Lot
series) and Group 4 (First Lot series) in terms of reactogenicity during
the 4-day follow-up period \* - ATP cohort (BLA 8.III, Table 4E)

+-----------------------+---+--------+---+--------+--------+-----------+
| **Solicited symptom** | * |        | * |        | **     |           |
|                       | * |        | * |        | Differ |           |
|                       | P |        | G |        | ence** |           |
|                       | o |        | r |        |        |           |
|                       | o |        | o |        | *      |           |
|                       | l |        | u |        | *Group |           |
|                       | e |        | p |        | 4      |           |
|                       | d |        | 4 |        | minus  |           |
|                       | G |        | * |        | pooled |           |
|                       | r |        | * |        | Groups |           |
|                       | o |        |   |        | 1, 2,  |           |
|                       | u |        |   |        | and    |           |
|                       | p |        |   |        | 3**    |           |
|                       | s |        |   |        |        |           |
|                       | * |        |   |        |        |           |
|                       | * |        |   |        |        |           |
|                       |   |        |   |        |        |           |
|                       | * |        |   |        |        |           |
|                       | * |        |   |        |        |           |
|                       | 1 |        |   |        |        |           |
|                       | , |        |   |        |        |           |
|                       | 2 |        |   |        |        |           |
|                       | , |        |   |        |        |           |
|                       | 3 |        |   |        |        |           |
|                       | * |        |   |        |        |           |
|                       | * |        |   |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
|                       | # | **Rate | * | **Rate |        |           |
|                       | # | (%)**  | * | (%)**  |        |           |
|                       | # |        | N |        |        |           |
|                       | # |        | * |        |        |           |
|                       | # |        | * |        |        |           |
|                       |   |        |   |        |        |           |
|                       | N |        |   |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
|                       |   |        |   |        | *      | **90%     |
|                       |   |        |   |        | *Diff. | CI**      |
|                       |   |        |   |        | (%)**  |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Any grade \"3\"       | 3 | 18.2   | 1 | 15.1   | -3.0   | \[-10.2 ; |
| solicited symptom     | 5 |        | 1 |        |        | 4.6\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| **Local (at injection |   |        |   |        |        |           |
| site)**               |   |        |   |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Pain                  | 3 | 49.7   | 1 | 49.6   | -0.1   | \[-9.3 ;  |
|                       | 5 |        | 1 |        |        | 8.7\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Pain graded \"3\"^\*^ | 3 | 3.4    | 1 | 0.8    | -2.5   | \[-6.0 ;  |
|                       | 5 |        | 1 |        |        | 1.9\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Redness               | 3 | 57.5   | 1 | 54.6   | -2.9   | \[-12.0 ; |
|                       | 5 |        | 1 |        |        | 5.9\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Redness \> 20 mm      | 3 | 4.5    | 1 | 2.5    | -1.9   | \[-6.1 ;  |
|                       | 5 |        | 1 |        |        | 3.1\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Swelling              | 3 | 39.1   | 1 | 37.8   | -1.3   | \[-10.3 ; |
|                       | 5 |        | 1 |        |        | 7.4\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Swelling \> 20 mm     | 3 | 3.6    | 1 | 5.0    | 1.4    | \[-2.9 ;  |
|                       | 5 |        | 1 |        |        | 7.9\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| **General**           |   |        |   |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Fever†                | 3 | 54.7   | 1 | 47.9   | -6.8   | \[-15.9 ; |
| [\>]{.underline} 38C  | 5 |        | 1 |        |        | 2.0\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Fever† \> 39.5C       | 3 | 0.8    | 1 | 0.8    | 0.0    | \[-2.6 ;  |
|                       | 5 |        | 1 |        |        | 4.9\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Diarrhea              | 3 | 32.1   | 1 | 33.6   | 1.5    | \[-7.0 ;  |
|                       | 5 |        | 1 |        |        | 10.9\]    |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Diarrhea graded       | 3 | 0.6    | 1 | 0.0    | -0.6   | \[-2.9 ;  |
| \"3\"^\*\*\*^         | 5 |        | 1 |        |        | 3.1\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Loss of appetite      | 3 | 43.6   | 1 | 37.8   | -5.8   | \[-14.8 ; |
|                       | 5 |        | 1 |        |        | 2.9\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Loss of appetite      | 3 | 0.6    | 1 | 0.8    | 0.3    | \[-2.2 ;  |
| graded \"3\"^\*\*\*^  | 5 |        | 1 |        |        | 5.2\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Fussiness             | 3 | 87.7   | 1 | 89.1   | 1.4    | \[-5.6 ;  |
|                       | 5 |        | 1 |        |        | 8.2\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Fussiness graded      | 3 | 8.4    | 1 | 4.2    | -4.2   | \[-9.2 ;  |
| \"3\"^\*\*^           | 5 |        | 1 |        |        | 1.6\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Restlessness          | 3 | 57.0   | 1 | 57.1   | 0.2    | \[-8.6 ;  |
|                       | 5 |        | 1 |        |        | 9.8\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Restlessness graded   | 3 | 2.8    | 1 | 2.5    | -0.3   | \[-4.1 ;  |
| \"3\"^\*\*\*^         | 5 |        | 1 |        |        | 4.7\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Sleeping more than    | 3 | 64.5   | 1 | 58.0   | -6.5   | \[-15.5 ; |
| usual                 | 5 |        | 1 |        |        | 2.3\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Sleeping more than    | 3 | 2.5    | N | 2.5    | 0.0    | \[-3.6 ;  |
| usual graded          | 5 |        | P |        |        | 5.7\]     |
| \"3\"^\*\*\*^         | 8 |        |   |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Vomiting              | 3 | 27.1   | 1 | 22.7   | -4.4   | \[-12.5 ; |
|                       | 5 |        | 1 |        |        | 3.8\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+
| Vomiting graded       | 3 | 1.1    | 1 | 0.0    | -1.1   | \[-3.7 ;  |
| \"3\"^\*\*\*^         | 5 |        | 1 |        |        | 2.6\]     |
|                       | 8 |        | 9 |        |        |           |
+-----------------------+---+--------+---+--------+--------+-----------+

Group 1: DTPa-HBV-IPV, second series Lot A + Hib

Group 2: DTPa-HBV-IPV, second series Lot B + Hib

Group 3: DTPa-HBV-IPV, second series Lot C + Hib

Group 4: DTPa-HBV-IPV, first series + Hib

\* grade \"3\" pain at injection site = cried when the limb was moved/
spontaneously painful

(prevented normal everyday activity)

\*\* = Grade \"3\" irritability/fussiness was described as: Crying\*\*
or irritability that could not be

comforted.

\*\* Parents were instructed to contact the investigator if the child
cried continuously for more than 3

hours.

\*\*\* grade \"3\" = adverse experience preventing normal daily
activities (such an adverse experience

would, for example, prevent attendance at school/ kindergarten/ a
day-care center and would cause

the parents/guardians to seek medical advice)

†rectal temperature

N = number of subjects with at least one documented dose

NP=Not provided

> *Reviewer comment:* In this comparison of the first to second lot
> series, the incidence of fever was 6.8% higher in pooled groups
> receiving the second lots series compared with the group receiving the
> first lot series, although this difference was not statistically
> significant.

#  

**3.3.6 Safety of a Primary Series of DTPa-HepB-IPV Following a Birth
Dose of Hepatitis B Vaccine**

In the studies filed with the BLA, there were no comparative trials
examining the use of DTPa-HepB-IPV with and without a birth dose of
hepatitis B. The BLA included the supportive study **DTPa-HepB-IPV-030**
from Moldova in which [all]{.underline} infants received a birth dose of
hepatitis B vaccine. Assessment of safety data from this study was
further hampered by the inclusion of a combination vaccine containing
whole cell pertussis as the comparator to DTPa-HepB-IPV (see Section
3.5.1: Clinical Trial Summary Table for outline of this study).

As an amendment to the BLA, SBB submitted the complete study report of
study DTPa-HepB-IPV/Hib-003 to provide supportive data (BLA amendment
11/3/00). This study compared a primary series at 2, 4, 6 months of age
of SBB's DTPa-HepB-IPV/Hib product (DTPa-HepB-IPV mixed extemporaneously
with SBB's Hib \[PRP-T\] prior to injection) following a birth dose of
hepatitis B vaccine, with a primary series of DTPa-HepB-IPV/Hib given
without a birth dose. Monitoring for adverse events was performed as in
previously described studies of DTPa-HepB-IPV.

**DTPa-HepB-IPV/Hib-003: Supportive study**

**Title:** A phase III open randomized multicenter controlled study of
the safety and immunogenicity of three doses of SBB's DTPa-HBV-IPV/Hib
vaccine administered at 2, 4 and 6 months of age following a birth dose
of Engerix-B ® compared to three doses of SBB's DTPa-HBV-IPV/Hib vaccine
administered at 2, 4 and 6 months of age without a birth dose of
hepatitis B vaccine.

**Location:** USA

**Schedule:** 2, 4, 6 months

**Study Design:** open, randomized, multicenter

**Group 1:** DTPa-HepB-IPV/Hib without birth dose of hepatitis B

**Group 2:** DTPa-HepB-IPV/Hib with birth dose of hepatitis B

Number of subjects enrolled (ITT cohort): 550 (275 each group)

ATP cohort for safety: 525

Group 1: 259

Group 2: 266

ATP cohort for immunogenicity: 170

Group 1: 84

Group 2: 86

Note: Because the ATP cohort excluded less than 1.5% of the enrolled
subjects with safety data available, the BLA did not include a
reanalysis based on the ITT cohort. Thus, the data presented below are
from the ATP cohort for safety.

######## Study DTP-HepB-IPV/Hib-003: \"Grade 3\" solicited symptoms during the 8-day follow-up period after any of the 3 DTPa-HepB-IPV/Hib doses

+-----------------------+-----+----+------+----+----+---+------------+
| #####                 | *   |    | **G  |    | ** |   |            |
|  Symptom {#symptom-1} | *Gr |    | roup |    | Di |   |            |
|                       | oup |    | 2**  |    | ff |   |            |
|                       | 1** |    |      |    | er |   |            |
|                       |     |    |      |    | en |   |            |
|                       |     |    |      |    | ce |   |            |
|                       |     |    |      |    | ** |   |            |
|                       |     |    |      |    |    |   |            |
|                       |     |    |      |    | ** |   |            |
|                       |     |    |      |    | (G |   |            |
|                       |     |    |      |    | ro |   |            |
|                       |     |    |      |    | up |   |            |
|                       |     |    |      |    | 2  |   |            |
|                       |     |    |      |    | m  |   |            |
|                       |     |    |      |    | in |   |            |
|                       |     |    |      |    | us |   |            |
|                       |     |    |      |    | G  |   |            |
|                       |     |    |      |    | ro |   |            |
|                       |     |    |      |    | up |   |            |
|                       |     |    |      |    | 1) |   |            |
|                       |     |    |      |    | ** |   |            |
+-----------------------+-----+----+------+----+----+---+------------+
|                       |     |    |      |    | *  | * |            |
|                       |     |    |      |    | *D | * |            |
|                       |     |    |      |    | if | 9 |            |
|                       |     |    |      |    | f. | 0 |            |
|                       |     |    |      |    | ** | % |            |
|                       |     |    |      |    |    | C |            |
|                       |     |    |      |    |    | I |            |
|                       |     |    |      |    |    | * |            |
|                       |     |    |      |    |    | * |            |
+-----------------------+-----+----+------+----+----+---+------------+
|                       | **  | *  | *    | *  | *  | * | **UL**     |
|                       | N** | *% | *N** | *% | *( | * |            |
|                       |     | ** |      | ** | %) | L |            |
|                       |     |    |      |    | ** | L |            |
|                       |     |    |      |    |    | * |            |
|                       |     |    |      |    |    | * |            |
+-----------------------+-----+----+------+----+----+---+------------+
| Any \"grade 3\"       | 259 | 23 | 265  | 22 | -0 | - | 6.1\*      |
| solicited symptoms‡   |     | .2 |      | .6 | .5 | 7 |            |
|                       |     |    |      |    |    | . |            |
|                       |     |    |      |    |    | 4 |            |
+-----------------------+-----+----+------+----+----+---+------------+
| \"Grade 3\" pain at   | 259 | 3  | 265  | 4  | 0  | - | 5.0        |
| injection site        |     | .9 |      | .5 | .7 | 3 |            |
|                       |     |    |      |    |    | . |            |
|                       |     |    |      |    |    | 1 |            |
+-----------------------+-----+----+------+----+----+---+------------+
| Redness \>20 mm at    | 259 | 5  | 265  | 3  | -2 | - | 1.5        |
| injection site        |     | .4 |      | .0 | .4 | 6 |            |
|                       |     |    |      |    |    | . |            |
|                       |     |    |      |    |    | 6 |            |
+-----------------------+-----+----+------+----+----+---+------------+
| Swelling \>20 mm at   | 259 | 7  | 265  | 3  | -3 | - | 0.3        |
| injection site        |     | .7 |      | .8 | .9 | 8 |            |
|                       |     |    |      |    |    | . |            |
|                       |     |    |      |    |    | 6 |            |
+-----------------------+-----+----+------+----+----+---+------------+
| \"Grade 3\" fever     | 259 | 0  | 265  | 2  | 2  | - | 5.7        |
| (\>39.5°C)            |     | .4 |      | .6 | .3 | 0 |            |
|                       |     |    |      |    |    | . |            |
|                       |     |    |      |    |    | 3 |            |
+-----------------------+-----+----+------+----+----+---+------------+
| \"Grade 3\"           | 259 | 4  | 265  | 4  | -0 | - | 6.1        |
| drowsiness            |     | .6 |      | .2 | .5 | 7 |            |
|                       |     |    |      |    |    | . |            |
|                       |     |    |      |    |    | 4 |            |
+-----------------------+-----+----+------+----+----+---+------------+
| \"Grade 3\"           | 259 | 9  | 265  | 13 | 3  | - | 9.7        |
| i                     |     | .7 |      | .6 | .9 | 1 |            |
| rritability/fussiness |     |    |      |    |    | . |            |
|                       |     |    |      |    |    | 3 |            |
+-----------------------+-----+----+------+----+----+---+------------+
| \"Grade 3\" loss of   | 259 | 2  | 265  | 0  | -1 | - | 0.8        |
| appetite              |     | .3 |      | .4 | .9 | 5 |            |
|                       |     |    |      |    |    | . |            |
|                       |     |    |      |    |    | 1 |            |
+-----------------------+-----+----+------+----+----+---+------------+

Group 1: without birth dose hepatitis B vaccine

Group 2: with birth dose of hepatitis B vaccine

N = number of subjects with at least one symptom sheet completed

\% = percentage of subjects reporting the specific symptom during the
8-day follow-up period after any

vaccination

‡ = primary endpoint

\* = upper 90% CI limit below the 7.5% clinical limit for
non-inferiority (defined only for the primary

endpoint)

> *Reviewer comment:* With respect to the primary endpoint of any grade
> 3 solicited symptoms, DTPa-HepB-IPV/Hib administered following a birth
> dose of hepatitis B was shown to be within the prespecified limits of
> non-inferiority when compared with DTPa-HepB-IPV/Hib administered
> without a birth dose of hepatitis B. With respect to specific grade 3
> solicited symptoms, fever (\>39.5C) was increased in the group
> receiving the birth dose, but this difference was not statistically
> significant.

**3.3.7 Summary Safety Data**

**A. Bridging Between 3, 4, 5 month schedule and 2, 4, 6 month
schedule**

SBB submitted data to support comparability of safety data obtained on a
3, 4, 5 month schedule in Germany (DTPa-HepB-IPV-011) with that obtained
on a 2, 4, 6 month schedule (DTPa-HepB-IPV-015 and --044). This
comparison was sought to determine whether the safety profile of
DTPa-HepB-IPV was similar for infants administered under the 3, 4, 5
month regimen in which the first dose was administered approximately one
month later and the schedule was more compressed when compared to the 2,
4, 6 month schedule. Of note, study designs and subject monitoring were
similar across the studies (see Section 3.3.2-3.5.5). To examine this
issue, SBB provided a comparison of the age distribution for each dose
and examined the incidence of solicited symptoms under the two
schedules.

The following figure compares the age distribution of the subjects for
each dose between the Studies --011 and --015. The age of enrollment for
Study --011 was 8-16 weeks; for studies --015 and --044 the allowable
age of enrollment was 6-12 weeks.

**Comparison of the age distribution (relative number of subjects per
age in days) at each dose for the groups who received three consecutive
doses of DTPa- HepB- IPV vaccine in study 011 (Germany- schedule 3, 4,
5) and in study 015 (US- schedule 2, 4, 6) (BLA, Figure 8.II. 9- 1)**

> ![](media/image1.png){width="6.2in" height="3.113888888888889in"}
>
> Reviewer comment: Study DTPa-HepB-IPV-011 utilized a 3, 4, 5 month
> schedule while Study --015 used a 2, 4 , 6 month schedule. The age at
> the time of vaccination overlapped between the two studies, with the
> timing of the second dose most similar.

**The percentage of subjects with solicited local symptoms (any grade
and by dose) and over the full vaccination course - ATP safety cohort
(BLA Table 8. II. 9- 6)**

+-----+-------+------+-------+------+-------+------+-------+--------+
| **L | *     |      |       |      | *     |      |       |        |
| oca | *DTPa |      |       |      | *DTPa |      |       |        |
| l** | -HepB |      |       |      | -HepB |      |       |        |
|     | -IPV- |      |       |      | -IPV- |      |       |        |
| *   | 011** |      |       |      | 015** |      |       |        |
| *So |       |      |       |      |       |      |       |        |
| lic |       |      |       |      |       |      |       |        |
| ite |       |      |       |      |       |      |       |        |
| d** |       |      |       |      |       |      |       |        |
|     |       |      |       |      |       |      |       |        |
| **S |       |      |       |      |       |      |       |        |
| ymp |       |      |       |      |       |      |       |        |
| tom |       |      |       |      |       |      |       |        |
| s** |       |      |       |      |       |      |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
|     | **G   |      | *     |      | **    |      | *     |        |
|     | roups |      | *Cont |      | Group |      | *Cont |        |
|     | 1-4** |      | rol** |      | 1**   |      | rol** |        |
|     |       |      |       |      |       |      |       |        |
|     | *     |      | *     |      | *     |      | *     |        |
|     | *DTPa |      | *DTPa |      | *DTPa |      | *DTPa |        |
|     | -HepB |      | +Hib+ |      | -HepB |      | +HepB |        |
|     | -IPV+ |      | OPV** |      | -IPV+ |      | +Hib+ |        |
|     | Hib** |      |       |      | Hib** |      | OPV** |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
|     | **    | **G  | **    | **G  | **    | **G  | **    | *      |
|     | Any** | rade | Any** | rade | Any** | rade | Any** | *Grade |
|     |       | 3**  |       | 3**  |       | 3**  |       | 3**    |
+-----+-------+------+-------+------+-------+------+-------+--------+
|     | **%   | **%  | **%   | **%  | **%   | **%  | **%   | **%    |
|     | (LL-  | (    | (LL-  | (    | (LL.- | (    | (LL-  | (LL    |
|     | UL)** | LL-U | UL)** | LL-U | UL)** | LL-U | UL)** | -UL)** |
|     |       | L)** |       | L)** |       | L)** |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
| **D |       |      |       |      |       |      |       |        |
| ose |       |      |       |      |       |      |       |        |
| 1** |       |      |       |      |       |      |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
| P   | 16.7( | 1.4  | 20.7( | 3.0  | 38.0  | 3.0  | 38.8  | 4.1    |
| ain | 15.3- | (    | 17.8- | (    | (     | (    | 29.1- | (1.1   |
|     | 18.1) | 1.0- | 23.8) | 1.9- | 28.5- | 0.6- | 49.2) | -10.1) |
|     |       | 1.8) |       | 4.4) | 48.3) | 8.5) |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
| R   | 23.8( | 2.3  | 24.7( | 6.2  | 18.0  | 2.0  | 17.3  | 0.0    |
| edn | 22.3- | (    | 21.7- | (    | (     | (    | 10.4- | (0.    |
| ess | 25.4) | 1.8- | 28.0) | 4.6- | 11.0- | 0.2- | 26.3) | 0-3.7) |
|     |       | 2.9) |       | 8.2) | 26.9) | 7.0) |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
| Sw  | 17.2  | 1.8  | 16.5( | 3.0  | 12.0  | 2.0  | 11.2  | 2.0    |
| ell | (     | (    | 13.9- | (    | (6.4- | (    | (5.7- | (0.    |
| ing | 15.9- | 1.4- | 19.4) | 1.9- | 20.0) | 0.2- | 19.2) | 2-7.2) |
|     | 18.6) | 2.4) |       | 4.4) |       | 7.0) |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
| **D |       |      |       |      |       |      |       |        |
| ose |       |      |       |      |       |      |       |        |
| 2** |       |      |       |      |       |      |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
| P   | 11.3  | 0.4  | 11.5  | 0.5  | 28.1  | 0.0  | 20.7( | 0.0    |
| ain | (     | (    | (9.3- | (    | (     | (    | 12.7- | (0.    |
|     | 10.2- | 0.2- | 14.0) | 0.1- | 19.4- | 0.0- | 30.7) | 0-4.2) |
|     | 12.5) | 0.7) |       | 1.4) | 38.2) | 3.8) |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
| R   | 29.0  | 1.2  | 26.2( | 1.4  | 18.8  | 1.0  | 12.6  | 0.0    |
| edn | (     | (    | 23.0- | (    | (     | (    | (6.5- | (0.    |
| ess | 27.4- | 0.9- | 29.5) | 0.7- | 11.5- | 0.0- | 21.5) | 0-4.2) |
|     | 30.6) | 1.7) |       | 2.5) | 28.0) | 5.7) |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
| Sw  | 21.0  | 2.0  | 15.3( | 1.8  | 17.7  | 2.1  | 14.9  | 2.1    |
| ell | (     | (    | 12.8- | (    | (     | (    | (8.2- | (0.    |
| ing | 19.5- | 1.5- | 18.1) | 0.9- | 10.7- | 0.3- | 24.2) | 0-6.2) |
|     | 22.5) | 2.5) |       | 3.0) | 26.8) | 7.3) |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
| **D |       |      |       |      |       |      |       |        |
| ose |       |      |       |      |       |      |       |        |
| 3** |       |      |       |      |       |      |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
| P   | 11.4  | 0.4  | 9.7   | 0.4  | 22.1  | 0.0  | 22.6( | 1.2    |
| ain | (     | (    | (7.7- | (    | (     | (    | 14.2- | (0.    |
|     | 10.3- | 0.2- | 12.1) | 0.1- | 14.2- | 0.0- | 33.0) | 0-6.5) |
|     | 12.6) | 0.7) |       | 1.2) | 31.8) | 3.8) |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
| R   | 29.1  | 1.4  | 25.3( | 1.6  | 23.2  | 0.0  | 14.3  | 1.2    |
| edn | (     | (    | 22.2- | (    | (     | (    | (7.6- | (0.    |
| ess | 27.5- | 1.0- | 28.6) | 0.9- | 15.1- | 0.0- | 23.6) | 0-6.5) |
|     | 30.8) | 1.9) |       | 2.8) | 32.9) | 3.8) |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
| Sw  | 21.1  | 1.7  | 17.2( | 1.6  | 17.9  | 2.1  | 11.9  | 1.2    |
| ell | (     | (    | 14.6- | (    | (     | (    | (5.9- | (0.    |
| ing | 19.6- | 1.3- | 20.2) | 0.9- | 10.8- | 0.3- | 20.8) | 0-6.5) |
|     | 22.6) | 2.3) |       | 2.8) | 27.1) | 7.4) |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
| **  |       |      |       |      |       |      |       |        |
| Ove |       |      |       |      |       |      |       |        |
| ral |       |      |       |      |       |      |       |        |
| l** |       |      |       |      |       |      |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
| P   | 26.5  | 2.0  | 28.4( | 3.6  | 57.0  | 3.0  | 52.0( | 5.1    |
| ain | (     | (    | 25.1- | (    | (     | (    | 41.7- | (1.7   |
|     | 25.0- | 1.5- | 31.7) | 2.4- | 46.7- | 0.6- | 62.2) | -11.5) |
|     | 28.2) | 2.5) |       | 5.2) | 66.9) | 8.5) |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
| R   | 46.3  | 4.2  | 45.6( | 8.3  | 40.0  | 3.0  | 31.6( | 1.0    |
| edn | (     | (    | 41.9- | (6   | (     | (    | 22.6- | (0.    |
| ess | 44.5- | 3.5- | 49.2) | .4-1 | 30.3- | 0.6- | 41.8) | 0-5.6) |
|     | 48.0) | 5.0) |       | 0.6) | 50.3) | 8.5) |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+
| Sw  | 35.9  | 4.1  | 33.2( | 5.0  | 36.0  | 6.0  | 27.6( | 3.1    |
| ell | (     | (    | 29.8- | (    | (     | (2   | 19.0- | (0.    |
| ing | 34.2- | 3.4- | 36.7) | 3.5- | 26.6- | .2-1 | 37.5) | 6-8.7) |
|     | 37.7) | 4.9) |       | 6.8) | 46.2) | 2.6) |       |        |
+-----+-------+------+-------+------+-------+------+-------+--------+

**Comparison of subjects with [solicited general symptoms]{.underline}
in study DTPa-HepB-IPV-011 (3, 4, 5 month schedule) and
DTPa-HepB-IPV-015 (2, 4, 6 month schedule (ATP cohort for safety)
(Adapted from Table 8. II. 9- 7)**

+----------+-----------+---------------+---------------+--------------+
| **G      | **D       |               | **DTPa-H      |              |
| eneral** | TPa-HepB- |               | epB-IPV-015** |              |
|          | IPV-011** |               |               |              |
| **Sol    |           |               |               |              |
| icited** |           |               |               |              |
|          |           |               |               |              |
| **Sy     |           |               |               |              |
| mptoms** |           |               |               |              |
+----------+-----------+---------------+---------------+--------------+
|          | **Groups  | **Group       | **Group 1**   | **Group 4-   |
|          | 1-4**     | 5-Control**   |               | Control**    |
|          |           |               | **DTPa-H      |              |
|          | **D       | **D           | epB-IPV+Hib** | **DTPa+He    |
|          | TPa-HepB- | TPa+Hib+OPV** |               | pB+Hib+OPV** |
|          | IPV+Hib** |               |               |              |
+----------+-----------+---------------+---------------+--------------+
|          | **%       | **% (LL-UL)** | **% (LL-UL)** | **%          |
|          | (LL-UL)** |               |               | (LL-UL)**    |
+----------+-----------+---------------+---------------+--------------+
| **Dose   |           |               |               |              |
| 1**      |           |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Loss of  | 17.8      | 19.5          | 25.0          | 23.5         |
| appetite | (1        | (16.7-22.5)   | (16.9-34.7)   | (15.5-33.1)  |
|          | 6.4-19.2) |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Rest     | 42.8      | 46.4          | 62.0          | 63.3         |
| lessness | (4        | (42.7-50.0)   | (51.7-71.5)   | (52.9-72.8)  |
|          | 1.0-44.6) |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Fever    | 22.6      | 13.4          | 23.0          | 15.3         |
| (T       | (2        | (11.1-16.1)   | (15.2-32.5)   | (8.8-24.0)   |
| [\>]{.un | 1.1-24.2) |               |               |              |
| derline} |           |               |               |              |
| 38C)     |           |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Unusual  | 25.6      | 36.6          | 2.0 (0.2-7.0) | 3.1          |
| crying   | (2        | (33.1-40.1)   |               | (0.6-8.7)    |
|          | 4.0-27.2) |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Vomiting | 9.7       | 12.0          | 9.0           | 10.2         |
|          | (         | (9.7-14.5)    | (4.2-16.4)    | (5.0-18.0)   |
|          | 8.6-10.8) |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| **Dose   |           |               |               |              |
| 2**      |           |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Loss of  | 14.0      | 16.3          | 16.7          | 13.8         |
| appetite | (1        | (13.7-19.1)   | (9.8-25.6)    | (7.3-22.9)   |
|          | 2.7-15.2) |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Rest     | 33.2      | 34.7          | 55.2          | 48.3         |
| lessness | (3        | (31.3-38.2)   | (44.7-65.4)   | (37.4-59.2)  |
|          | 1.5-34.9) |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Fever    | 18.2      | 13.3          | 17.7          | 13.8         |
| (T       | (1        | (10.9-15.9)   | (10.7-26.8)   | (7.3-22.9)   |
| [\>]{.un | 6.8-19.6) |               |               |              |
| derline} |           |               |               |              |
| 38C)     |           |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Unusual  | 17.5      | 19.9          | 3.1 (0.6-8.9) | 1.1          |
| crying   | (1        | (17.1-23.0)   |               | (0.0-6.2)    |
|          | 6.2-18.9) |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Vomiting | 7.5       | 8.4           | 4.2           | 8.0          |
|          | (6.5-8.5) | (6.5-10.6)    | (1.1-10.3)    | (3.3-15.9)   |
+----------+-----------+---------------+---------------+--------------+
| **Dose   |           |               |               |              |
| 3**      |           |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Loss of  | 12.5      | 11.2          | 12.6          | 16.7         |
| appetite | (1        | (9.0-13.7)    | (6.7-21.0)    | (9.4-26.4)   |
|          | 1.3-13.8) |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Rest     | 27.0      | 27.5          | 47.4          | 48.8         |
| lessness | (2        | (24.3-30.9)   | (37.0-57.9)   | (37.7-60.0)  |
|          | 5.4-28.6) |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Fever (T | 19.1      | 11.2          | 16.8          | 13.1         |
| [\>]{.un | (1        | (9.0-13.7)    | (9.9-25.9)    | (6.7-22.2)   |
| derline} | 7.7-20.5) |               |               |              |
| 38C)     |           |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Unusual  | 13.4      | 14.2          | 1.1 (0.0-5.7) | 2.4          |
| crying   | (         | (11.8-17.0)   |               | (0.3-8.3)    |
|          | 1.2-14.7) |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Vomiting | 5.6       | 5.2 (3.7-7.1) | 2.1 (0.3-7.4) | 4.8          |
|          | (4.8-6.5) |               |               | (1.3-11.7)   |
+----------+-----------+---------------+---------------+--------------+
| **O      |           |               |               |              |
| verall** |           |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Loss of  | 31.6      | 33.9          | 38.0          | 38.8         |
| appetite | (2        | (30.5-37.4)   | (28.5-48.3)   | (29.1-49.2)  |
|          | 9.9-33.3) |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Rest     | 59.6      | 61.8          | 82.0          | 85.          |
| lessness | (5        | (58.2-65.3)   | (73.1-89.0)   | 7(77.2-92.0) |
|          | 7.8-61.3) |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Fever    | 40.6      | 27.0          | 41.0          | 29.          |
| (T       | (3        | (23.9-30.4)   | (31.3-51.3)   | 6(20.8-39.7) |
| [\>]{.un | 8.9-42.4) |               |               |              |
| derline} |           |               |               |              |
| 38C)     |           |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Unusual  | 39.2      | 48.9          | 6.0           | 6.1          |
| crying   | (3        | (45.3-52.6)   | (2.2-12.6)    | (2.3-12.9)   |
|          | 7.5-41.0) |               |               |              |
+----------+-----------+---------------+---------------+--------------+
| Vomiting | 17.2      | 19.6          | 13.0          | 16.3         |
|          | (1        | (16.8-22.7)   | (7.1-21.2)    | (9.6-25.2)   |
|          | 5.8-18.6) |               |               |              |
+----------+-----------+---------------+---------------+--------------+

**Comparison of subjects with solicited [grade 3 general
symptoms]{.underline} in study DTPa-HepB-IPV-011 (3, 4, 5 month
schedule) and DTPa-HepB-IPV-015 (2, 4, 6 month schedule) (ATP cohort for
safety) (Adapted from Table 8. II. 9- 7)**

+----------+------------+---------------+---------------+-------------+
| **G      | *          |               | **DTPa-H      |             |
| eneral** | *DTPa-HepB |               | epB-IPV-015** |             |
|          | -IPV-011** |               |               |             |
| **Sol    |            |               |               |             |
| icited** |            |               |               |             |
|          |            |               |               |             |
| **Sy     |            |               |               |             |
| mptoms** |            |               |               |             |
+----------+------------+---------------+---------------+-------------+
|          | **Groups   | **Group       | **Group 1**   | **Group 4-  |
|          | 1-4**      | 5-Control**   |               | Control**   |
|          |            |               | **DTPa-H      |             |
|          | *          | **D           | epB-IPV+Hib** | **DTPa+Hep  |
|          | *DTPa-HepB | TPa+Hib+OPV** |               | B+Hib+OPV** |
|          | -IPV+Hib** |               |               |             |
+----------+------------+---------------+---------------+-------------+
|          | **Grade    | **Grade 3**   | **Grade 3**   | **Grade 3** |
|          | 3**        |               |               |             |
|          |            | **% (LL-UL)** | **% (LL-UL)** | **%         |
|          | **%        |               |               | (LL-UL)**   |
|          | (LL-UL)**  |               |               |             |
+----------+------------+---------------+---------------+-------------+
| **Dose   |            |               |               |             |
| 1**      |            |               |               |             |
+----------+------------+---------------+---------------+-------------+
| Loss of  | 0.6        | 0.5 (0.1-1.4) | 0.0 (0.0-3.6) | 1.0         |
| appetite | (0.4-1.0)  |               |               | (0.0-5.6)   |
+----------+------------+---------------+---------------+-------------+
| Rest     | 2.6        | 5.6 (4.1-7.6) | 2.0 (0.2-7.0) | 4.          |
| lessness | (2.1-3.3)  |               |               | 1(1.1-10.1) |
+----------+------------+---------------+---------------+-------------+
| Fever    | 0.3        | 0.1 (0.0-0.7) | 1.0 (0.0-5.4) | 0.0         |
|          | (0.1-0.5)  |               |               | (0.0-3.7)   |
+----------+------------+---------------+---------------+-------------+
| Unusual  | 3.8        | 6.5 (4.8-8.5) | 0.0 (0.0-3.6) | 0.0         |
| crying   | (3.1-4.5)  |               |               | (0.0-3.7)   |
+----------+------------+---------------+---------------+-------------+
| Vomiting | 0.2        | 0.0 (0.0-0.5) | 0.0 (0.0-3.6) | 1.1         |
|          | (0.1-0.5)  |               |               | (0.0-5.6)   |
+----------+------------+---------------+---------------+-------------+
| **Dose   |            |               |               |             |
| 2**      |            |               |               |             |
+----------+------------+---------------+---------------+-------------+
| Loss of  | 0.6        | 0.7 (0.2-1.6) | 1.0 (0.0-5.7) | 1.1         |
| appetite | (0.4-1.0)  |               |               | (0.0-6.2)   |
+----------+------------+---------------+---------------+-------------+
| Rest     | 1.5        | 3.0 (1.9-4.5) | 3.1 (0.6-8.9) | 4.          |
| lessness | (1.1-2.0)  |               |               | 6(1.3-11.4) |
+----------+------------+---------------+---------------+-------------+
| Fever    | 0.5        | 0.1 (0.0-0.8) | 1.0 (0.0-5.7) | 2.3         |
|          | (0.3-0.8)  |               |               | (0.3-8.1)   |
+----------+------------+---------------+---------------+-------------+
| Unusual  | 1.7        | 2.0 (1.1-3.3) | 0.0 (0.0-3.8) | 0.0         |
| crying   | (1.3-2.3)  |               |               | (0.0-4.2)   |
+----------+------------+---------------+---------------+-------------+
| Vomiting | 0.4        | 0.5 (0.1-1.4) | 1.0 (0.0-5.7) | 1.1         |
|          | (0.2-0.7)  |               |               | (0.0-6.2)   |
+----------+------------+---------------+---------------+-------------+
| **Dose   |            |               |               |             |
| 3**      |            |               |               |             |
+----------+------------+---------------+---------------+-------------+
| Loss of  | 0.5        | 0.0 (0.0-0.5) | 0.0 (0.0-3.8) | 0.0         |
| appetite | (0.3-0.8)  |               |               | (0.0-4.3)   |
+----------+------------+---------------+---------------+-------------+
| Rest     | 1.5        | 1.8 (1.0-3.0) | 3.2 (0.7-9.0) | 4.          |
| lessness | (1.1-2.0)  |               |               | 8(1.3-11.7) |
+----------+------------+---------------+---------------+-------------+
| Fever    | 0.8        | 0.5 (0.1-1.4) | 1.1 (0.0-5.7) | 0.0         |
|          | (0.5-1.2)  |               |               | (0.0-4.3)   |
+----------+------------+---------------+---------------+-------------+
| Unusual  | 1.5        | 1.1 (0.5-2.1) | 0.0 (0.0-3.8) | 0.0         |
| crying   | (1.1-2.0)  |               |               | (0.0-4.3)   |
+----------+------------+---------------+---------------+-------------+
| Vomiting | 0.5        | 0.1 (0.0-0.8) | 0.0 (0.0-3.8) | 0           |
|          | (0.3-0.9)  |               |               | .0(0.0-4.3) |
+----------+------------+---------------+---------------+-------------+
| **O      |            |               |               |             |
| verall** |            |               |               |             |
+----------+------------+---------------+---------------+-------------+
| Loss of  | 1.5        | 1.1 (0.5-2.1) | 1.0 (0.0-5.4) | 2           |
| appetite | (1.1-2.0)  |               |               | .0(0.2-7.2) |
+----------+------------+---------------+---------------+-------------+
| Rest     | 5.1        | 8.6(6.7-10.9) | 7.0           | 11.         |
| lessness | (4.3-5.9)  |               | (2.9-13.9)    | 2(5.7-19.2) |
+----------+------------+---------------+---------------+-------------+
| Fever    | 1.4        | 0.8 (0.3-1.7) | 3.0 (0.6-8.5) | 2           |
|          | (1.0-1.9)  |               |               | .0(0.2-7.2) |
+----------+------------+---------------+---------------+-------------+
| Unusual  | 6.0        | 8.9(6.9-11.1) | 0.0 (0.0-3.6) | 0(0.0-3.7)  |
| crying   | (5.2-6.9)  |               |               |             |
+----------+------------+---------------+---------------+-------------+
| Vomiting | 1.1        | 0.7 (0.2-1.6) | 1.0 (0.0-5.4) | 2           |
|          | (0.7-1.5)  |               |               | .0(0.2-7.2) |
+----------+------------+---------------+---------------+-------------+

Note - The analyses presented in the preceding 3 tables examined the ATP
cohorts for safety, therefore figures may be different from that
presented in section 3.3.3 for Study -011.)

> *Reviewer comment:* The previous three tables compared the observed
> rates of local and general symptoms between infants in study
> DTPa-HepB-IPV-011 (3, 4, 5 month schedule in Germany) and
> DTPa-HepB-IPV-015 (2, 4, 6 month schedule in the U.S.)
>
> Similar trends were seen in each group, with overall fever
> [\>]{.underline} 38C occurring in DTPa-HepB-IPV recipients in
> approximately 40% of subjects in both studies.
>
> Some differences were observed in the incidence of local and general
> solicited symptoms when comparing the vaccine schedules. For local
> symptoms, the incidence of "any pain" was higher in the U.S.
> population. For general symptoms, the incidence of "unusual crying"
> was higher in the German population, while the incidence of
> restlessness\" was higher in the US population. When comparing Grade 3
> symptoms, the rates of both local and general symptoms appeared
> similar in the two studies.
>
> Given the overlap in age of vaccination for each dose and the overall
> similarities in local symptom rates, it appears reasonable to consider
> the 3, 4, 5 months schedule comparable to the 2, 4, 6 months schedule
> with respect to the safety profile for solicited adverse events.

B.  **Table: Incidence of Unsolicited Adverse Events -- Subjects
    Receiving DTPa-HepB-IPV Compared with Separately Administered U.S.
    Licensed Vaccines (Data to be available at VRPBAC)**

C.  **Narrative summary of subjects across all studies reported to have
    experienced Serious Adverse Events "SAEs" considered to be related
    to vaccination (Directly from BLA 8.II.5.2.1)**

[DTPa-HepB-IPV-011:]{.underline} Subject no. 5390, a 2½ month-old male
with a past medical history of vomiting, received the first dose of
DTPa-HepB-IPV and PM Hib vaccines simultaneously at separate sites.
Approximately 30 minutes after vaccination, the child began to cry and
was noted to have pain, redness, and swelling at the Hib vaccine
injection site. The crying continued for several hours and eventually
resolved later that day following administration of medication. Two more
episodes of crying lasting approximately two hours each were noted,

one on the day of vaccination and the other on the following day. The
investigator stated that the event was a significant side effect, which
was *related* to study vaccination. The child received his second and
third doses of DTPa-HepB-IPV and PM Hib vaccines uneventfully.

[DTPa-HepB-IPV-011]{.underline}: Subject no. 6811, a 2 month-old male,
received his first dose of DTPa-HepB-IPV and Merck Hib vaccines
simultaneously at separate sites. Approximately five hours later, the
child developed restlessness, fever, and severe pain on pressure at the
Hib injection site associated with redness of the

whole outer thigh. He recovered completely the next day. The
investigator stated that these events were *related* to the study
vaccination and that the local events were *related* to the Hib
vaccination. The child completed the vaccination course.

[DTPa-HepB-IPV-011]{.underline}: Subject no. 7321, a 3 month-old male,
developed a high fever (39.0°C/102.2°F) beginning two days after the
second dose of DTPa-HepB-IPV and Merck Hib vaccines simultaneously at
separate sites. He continued to have a fever for the next two days which
increased to 41.0°C/105.8°F associated with restlessness and sleeping
more than usual. The investigator stated that the event was *definitely
related* to the study vaccination. The child recovered; however, the
vaccination course was discontinued.

**SAEs considered to be possibly related to vaccination:**

[DTPa-HepB-IPV-011]{.underline}: Subject no. 133, a 6 month-old male,
received the second dose of DTPa-HepB-IPV vaccine and Lederle Hib
vaccine simultaneously at separate sites. In the evening, the child
experienced a change in behavior associated with a fever (rectal
temperature up to 40.0°C/104.0°F. Three days

later, he was given an antipyretic and approximately one hour later, he
vomited and became hypotonic. He was hospitalized and treated with
diazepam: On admission, he was agitated and febrile (39.7°C/103.5°F).Lab
tests and EEG were within normal limits. He was treated with intravenous
fluids, the fever resolved, and no convulsions were observed. After two
days, the child recovered and was discharged. Of note, the child
reportedly had rhinitis and purulent conjunctivitis for several days
prior to vaccination. The investigator stated that the events were
*possibly relate*d to study vaccination but they could also be
associated with a suspected influenza infection. The vaccination course
was discontinued for this child since he was withdrawn from the study by
his parents. . *\[Reviewer comment:* It is not clear from the available
information whether seizures were diagnosed in this infant.\]

[DTPa-HepB-IPV-011]{.underline}: Subject no. 4926, a 5½ month-old
female, developed fever and tachycardia one day after administration of
the third dose of DTPa-HepB-IPV vaccine and PM Hib vaccine
simultaneously at separate sites. The child was hospitalized and on
admission was found to have regular cardiac rhythm, fever and rhinitis
without evidence of cardiac failure, cyanosis, pathologic cardiac
murmur, or exanthema. She continued to have a fever (rectal temperature
of 39.9°C/103.8°F) with elevated heart rate (145-200/min) for the next
two days and was treated with intravenous fluid and antipyretics. Four
days post-vaccination she was discharged with a diagnosis of possible
viral infection with tachycardia secondary to fever; however, the
investigator could not rule out a *possible associatio*n with study
vaccination*.*

**D. Hospitalizations (All BLA Studies)**

A total of 173 subjects were hospitalized across all clinical studies
included in the BLA.

**Number of subjects reporting SAEs resulting in hospitalization by
vaccine administered (Adapted from BLA amendment 3/3/00, Table 63-1)**

+-----------------+-----------+---------------+-----------------------+
| **Dose number** | **Any     | **DT          | **Comparator          |
|                 | Vaccine** | Pa-HepB-IPV** | Vaccine**             |
|                 |           |               |                       |
|                 |           | **N=7028      | **N=1764 (rate)**     |
|                 |           | (rate)**      |                       |
+-----------------+-----------+---------------+-----------------------+
| **1**           | 68        | 61 (0.87%)    | 7 (0.40%)             |
+-----------------+-----------+---------------+-----------------------+
| **2**           | 46        | 34 (0.48%)    | 12 (0.68%)            |
+-----------------+-----------+---------------+-----------------------+
| **3**           | 53        | 42 (0.60%)    | 11 (0.62%)            |
+-----------------+-----------+---------------+-----------------------+
| **More than one | 7         | 6 (0.085%)    | 1 (0.057%)            |
| dose\***        |           |               |                       |
+-----------------+-----------+---------------+-----------------------+
| **TOTAL**       | 173       | 142 (2.0%)    | 31 (1.8%)             |
+-----------------+-----------+---------------+-----------------------+

\*7 subjects were hospitalized following more than one dose during the
study period.

The overall rates of hospitalization were similar for DTPa-HepB-IPV
vaccine and comparator vaccine recipients (2.0% and 1.8%, respectively).
For the DTPa-HepB-IPV vaccine group, more reports were received after
the first dose than after subsequent doses.

**G. Deaths (All BLA Studies[)]{.underline}**

**6 deaths reported during course of 12 BLA trials (BLA 8.II.7)**

**[DTPa-HepB-IPV:]{.underline}**

5 deaths; N=7028

Cause of death: 2 SIDS, 1 convulsive disorder, 1 congenital
immunodeficiency with sepsis, 1 neuroblastoma)

**[Control regimens:]{.underline}**

1 death; N=1,764

Cause of death: 1 SIDS

**Narrative summary of deaths in all BLA studies:**

**[Study 011:]{.underline}** 4 total: 3 (DTPa-HepB-IPV); 1 (Control)

**DTPa-HepB-IPV:** Subject 1030: Seizures associated with T 38.3^o^C 4
days after 1^st^ vaccination. Subsequent afebrile seizures. Evaluation
including CSF, stool, serology, head sonogram and MRI normal. Found dead
in crib 4 weeks later, clinically felt to be related to seizure
disorder. Parents refused autopsy.

**DTPa-HepB-IPV:** Subject 1377: Past medical history significant for
preterm birth (BW 1490 g), apnea on aminophylline, cerebral bleeding,
transitional hypoparathyroidism. 23 days after 3^rd^ vaccination, child
had febrile convulsion. Hospitalized, died a few days later. Autopsy dx
of "congenital deficiency immunopathy."

**DTPa-HepB-IPV:** Subject 6860: 18 days after 2^nd^ vaccination died of
SIDS. No further details. No autopsy.

**Control (DTaP+HepB+OPV)**: Subject 6208: Previously healthy, 21 days
after 2^nd^ vaccination he was found dead. Clinical dx SIDS. Parents
refused autopsy.

**[Study 002:]{.underline}**

**DTPa-HepB-IPV**: SIDS death in 10 week old infant 4 days after 1st
vaccination. Autopsy consistent with SIDS. No fever or local reactions;
cried \> 1 hr after vaccination**.**

**[Study 015:]{.underline}**

**DTPa-HepB-IPV:** 2 month old infant, 2 weeks after first vaccination
had onset of progressively weak cry, decreased po intake, decreased
motor activity. 1 1/2 months after vaccination had quadriparesis. MRI
and CT revealed neuroblastoma. The infant died 1 year later.

**3.4 Safety and Immunogenicity of DTPa-HepB-IPV with Concurrent
Immunizations**

**3.4.1 DTPa-HepB-IPV administered concurrently with *Haemophilus
influenzae* type** **(Hib) vaccine**

Concurrent Hib vaccine was administered in BLA studies
DTPa-HepB-IPV-002, -004, -011, -012, -015, -016,- 017, -030, and --044.
Each study included evaluation of both safety and immunogenicity, with
exception of DTPa-HepB-IPV-011 which included only safety endpoints.
Comparative data on the immune responses to Hib vaccine when
DTPa-HepB-IPV was concurrently administered with Hib compared with
immunization with separate injections of DTPa, hepatitis B, IPV, and Hib
vaccine were obtained in DTPa-HepB-IPv-012 and DTPa-HepB-IPV-015 (see
table below).

## Comparative safety data on DTPa-HepB-IPV given concomitantly with Hib vaccines from different manufacturers were obtained in studies DTPa-HepB-IPV-011 (U.S.) and DTPa-HepB-IPV-012 (Lithuania). 

A.  **DTPa-HepB-IPV administered concurrently with Hib vaccine:
    Immunogenicity data**

**Summary across all BLA studies: Immune response to PRP one month after
primary vaccination with Hib vaccine and SBB DTPa- HepB- IPV vaccine
administered separately (BLA Table 8. III. 1- 23)**

  --------------------- ----------- --------- ------- -------------- ---------------- ---------- ---------------- -----------------
  **Study**             **Hib       **Lab**   **N**   **Anti-PRP**                                                
                        vaccine**                                                                                 

                                                      **0.15                        **1.0                     **GMT (mcg/ml)**
                                                      mcg/ml**                        mcg/ml**                    

                                                      **%**          **\[95% CI\]**   **%**      **\[95% CI\]**   **\[95% CI\]**

  **2-4-6 months**                                                                                                

  DTPa-HepB-IPV-002     Lederle Hib SBB       25      91.3           NC               NC         NC               1.9 \[NC\]

  DTPa-HepB-IPV-004     PM Hib      SBB       46      97.8           \[87.0--99.9\]   89.1       \[75.6--95.9\]   6.3 \[4.0--9.8\]

  DTPa-HepB-IPV-015     PM Hib      MEP       90      98.9           \[94.0--100\]    94.4       \[87.5--98.2\]   6.2 \[4.9 --
                                                                                                                  7.8\]

  DTPa-HepB-IPV-044\*   PM Hib      MEP       328     100            \[98.9--100\]    90.9       \[87.2--93.7\]   5.5 \[4.8--6.2\]

  DTPa-HepB-IPV-044†    PM Hib      MEP       106     100            \[96.6--100\]    91.5       \[84.5--96.0\]   6.8 \[5.4--8.6\]

  **3-4-5 months**                                                                                                

  DTPa-HepB-IPV-005     SBB Hib     SBB       343     98.8           \[96.8--99.6\]   92.7       \[89.3--95.1\]   5.5 \[4.8--6.3\]

  DTPa-HepB-IPV-016     SBB Hib     MEP       161     98.1           \[94.7--99.6\]   88.2       \[82.2--92.7\]   5.6 \[4.5--7.0\]

  **3-4.5-6 months**                                                                                              

  DTPa-HepB-IPV-012     SBB Hib     SBB       202     100            \[97.7--100\]    96.0       \[92.1--98.1\]   7.2 \[6.2--8.3\]

                        PM Hib      SBB       101     99.0           \[93.8--99.9\]   94.1       \[87.0--97.6\]   6.7\[5.4--8.2\]

                        Lederle Hib SBB       100     100            \[95.4--100\]    88.0       \[79.6--93.4\]   5.8 \[4.4--7.5\]

                        Merck Hib‡  SBB       105     100            \[95.6--100\]    90.5       \[82.8--95.1\]   5.0 \[4.0--6.1\]

  **2-3-4 months**                                                                                                

  DTPa-HepB-IPV-017     SBB Hib     MEP       23      100            \[82.2--100\]    73.9       \[51.3--88.9\]   3.2 \[1.6--6.3\]

  **1.5-2.5-3.5                                                                                                   
  months**                                                                                                        

  DTPa-HepB-IPV-030§    SBB Hib     MEP       150     96.0           \[91.5--98.5\]   65.3       \[57.1--72.9\]   1.9 \[1.5--2.4\]
  --------------------- ----------- --------- ------- -------------- ---------------- ---------- ---------------- -----------------

N=Number of subjects %= percentage of subjects the specified titer

\*One of three second lot series administered concomitantly

†One First Lot Series lot (lot 21710A2) administered concomitantly

‡Subjects received only 2 doses of Merck Hib vaccine at 3 and 6 months

§HepB vaccine at birth

N. B.: Data not always directly comparable due to differences in
methodology

DTPa-HepB-IPV-012 & DTPa-HepB-IPV-015: Immunogenicity of Hib vaccine
administered concurrently (at separate sites) with DTPa-HepB-IPV
compared with separate administration of DTPa, hepatitis B, IPV, and Hib
vaccines

+---------------+------+---+---+--------+----+---------+----+--------+
| **Stu         | *    | * | * |        | *  |         | *  |        |
| dy/Location** | *Gro | * | * |        | *% |         | *G |        |
|               | up** | N | % |        | ≥1 |         | MT |        |
| *             |      | * | ≥ |        | .0 |         | (m |        |
| *(schedule)** |      | * | 0 |        | mc |         | cg |        |
|               |      |   | . |        | g/ |         | /m |        |
|               |      |   | 1 |        | ml |         | l) |        |
|               |      |   | 5 |        | ** |         | ** |        |
|               |      |   | m |        |    |         |    |        |
|               |      |   | c |        |    |         |    |        |
|               |      |   | g |        |    |         |    |        |
|               |      |   | / |        |    |         |    |        |
|               |      |   | m |        |    |         |    |        |
|               |      |   | l |        |    |         |    |        |
|               |      |   | * |        |    |         |    |        |
|               |      |   | * |        |    |         |    |        |
+---------------+------+---+---+--------+----+---------+----+--------+
|               |      |   |   | **\[95 |    | **\[95  |    | **\[95 |
|               |      |   |   | %      |    | %       |    | %      |
|               |      |   |   | CI\]** |    | CI\]**  |    | CI\]** |
+---------------+------+---+---+--------+----+---------+----+--------+
| DTPa-         | G    | 2 | 1 | \      | 96 | \[92.1- | 7  | \[6.2- |
| HepB-IPV-012/ | roup | 0 | 0 | [97.7- | .0 | -98.1\] | .2 | -8.3\] |
| Lithuania     | 1    | 2 | 0 | -100\] |    |         |    |        |
|               |      |   |   |        |    |         |    |        |
| (3, 4.5, 6 m) |      |   |   |        |    |         |    |        |
+---------------+------+---+---+--------+----+---------+----+--------+
|               | G    | 1 | 9 | \[     | 94 | \[87.0- | 6  | \[5.4- |
|               | roup | 0 | 9 | 93.8-- | .1 | -97.6\] | .7 | -8.2\] |
|               | 2    | 1 | . | 99.9\] |    |         |    |        |
|               |      |   | 0 |        |    |         |    |        |
+---------------+------+---+---+--------+----+---------+----+--------+
|               | G    | 1 | 1 | \      | 88 | \[79.6- | 5  | \[4.4- |
|               | roup | 0 | 0 | [95.4- | .0 | -93.4\] | .8 | -7.5\] |
|               | 3    | 0 | 0 | -100\] |    |         |    |        |
+---------------+------+---+---+--------+----+---------+----+--------+
|               | G    | 1 | 1 | \      | 90 | \[82.8- | 5  | \[4.0- |
|               | roup | 0 | 0 | [95.6- | .5 | -95.1\] | .0 | -6.1\] |
|               | 4    | 5 | 0 | -100\] |    |         |    |        |
+---------------+------+---+---+--------+----+---------+----+--------+
| DTPa-         | G    | 9 | 9 | \      | 94 | \[87.5- | 6  | \[4.9- |
| HepB-IPV-015/ | roup | 0 | 8 | [94.0- | .4 | -98.2\] | .2 | -7.8\] |
| U.S.          | 1    |   | . | -100\] |    |         |    |        |
|               |      |   | 9 |        |    |         |    |        |
| (2, 4, 6m)    |      |   |   |        |    |         |    |        |
+---------------+------+---+---+--------+----+---------+----+--------+
|               | G    | 7 | 1 | \      | 94 | \[87.4- | 7  | \      |
|               | roup | 8 | 0 | [95.4- | .9 | -98.6\] | .8 | [6.1-- |
|               | 4    |   | 0 | -100\] |    |         |    | 10.1\] |
+---------------+------+---+---+--------+----+---------+----+--------+

DTPa-HepB-IPV-012:

Group 1 - SBB DTPa-HepB-IPV + SBB Hib

Group 2 - SBB DTPa-HepB-IPV + PM Hib

Group 3 - SBB DTPa-HepB-IPV + Lederle Hib

Group 4 - Dose 1 & 3: SBB DTPa-HepB-IPV + Merck Hib; Dose 2: SBB
DTPa-HepB-IPV

DTPa-HepB-IPV-015:

Group 1 -- SBB DTPa-HepB-IPV + PM Hib

Group 4 -- SBB DTPa + SBB HepB + Lederle OPV + PM Hib

N = Number of subjects

\% = Percentage of subjects

> [*Reviewer Comment:*]{.underline} No significant differences were
> observed in immune responses to Hib vaccine when DTPa-HepB-IPV was
> concurrently administered with Hib compared with immunization with
> separate injections.

**B. DTPa-HepB-IPV administered concurrently with Hib vaccine: Safety
data**

In all three pivotal studies, infants in each group received concurrent
Hib vaccine. See sections 3.3.3-3.3.5 for safety data.

**3.4.2 DTPa-HepB-IPV administered concurrently with pneumococcal
conjugate vaccine (Prevnar)**

No data have been submitted to the FDA to date evaluating DTPa-HepB-IPV
with concurrent Prevnar, Wyeth-Lederle's 7-valent pneumococcal conjugate
vaccine. This product was not licensed until February 2000, after
submission of the DTPa-HepB-IPV BLA in July 1999.

Although no data are available evaluating concurrent DTPa-HepB-IPV and
Prevnar, data submitted to the FDA under PLA 99-0279 (Pneumococcal
7-valent Conjugate Vaccine \[Diphtheria~197~ CRM\] Protein \[Prevnar™\])
have suggested that concurrent administration of Prevnar with DTPa or
DTPa combination vaccines may affect both immunogenicity and
reactogenicity. (See Appendix 1).

**3.5 4^th^ Dose DTPa (Infanrix®) following a primary series of
DTPa-HepB-IPV**

While not formally considered a part of this BLA, SBB submitted summary
safety and immunogenicity data on 4^th^ (toddler) dose of Infanrix® or
Infanrix®-based combinations following a primary series with
DTPa-HepB-IPV. Only one of these studies (DTPa-HepB-IPV-015B) compared
the safety and immunogenicity of a booster dose of separately
administered Infanrix® and Hib vaccine in children who received a
primary series of DTPa-HepB-IPV versus separate injections of DTPa +
hepatitis B + OPV. Those data are found in Appendix 2.

4.  **Summary of Available Data Under Consideration for BLA**

+---------------------+---------------+-------------+-----------------+
| ### **Objective**   | # Data        | **Study     |                 |
|                     |               | No.**       |                 |
+---------------------+---------------+-------------+-----------------+
|                     |               | **Pivotal** | **Supportive**  |
+---------------------+---------------+-------------+-----------------+
| ## Primar           | Safety/I      | DTPa-H      | DTP             |
| y series in infants | mmunogenicity | epB-IPV-011 | a-HepB-IPV-001, |
|                     |               | (Safety     | -002, -004,     |
|                     |               | Only),      | -005, -012,     |
|                     |               |             | -016, -017,     |
|                     |               | -015, -044  | -019, -030      |
+---------------------+---------------+-------------+-----------------+
| Lot consistency     | Safety/I      | DTPa-H      | DT              |
|                     | mmunogenicity | epB-IPV-044 | Pa-HepB-IPV-005 |
|                     |               |             |                 |
|                     |               |             | DTPa-H          |
|                     |               |             | epB-IPB/Hib-027 |
+---------------------+---------------+-------------+-----------------+
| Clinical bridge for | Safety/I      | DTPa-H      | \--             |
| manufacturing       | mmunogenicity | epB-IPV-044 |                 |
| change (1st to 2nd  |               |             |                 |
| lot series)         |               |             |                 |
+---------------------+---------------+-------------+-----------------+
| ## Concurrent v     | Safety/I      | DTPa-H      | DTP             |
| accination with Hib | mmunogenicity | epB-IPV-015 | a-HepB-IPV-012, |
|                     |               |             | -002, -004,     |
|                     |               |             | -011, -016,     |
|                     |               |             | -017, -030      |
+---------------------+---------------+-------------+-----------------+
| Hepatitis B         | Safety/I      | \--         | DTPa-HepB-030   |
| schedule change     | mmunogenicity |             |                 |
+---------------------+---------------+-------------+-----------------+
| DTPa-HepB-IPV at 2, | ## Safety/I   | \--         | DTPa-H          |
| 4, 6 months         | mmunogenicity |             | epB-IPV/Hib-003 |
| following a birth   |               |             |                 |
| dose of hepatitis B |               |             | DT              |
|                     |               |             | Pa-HepB-IPV-030 |
+---------------------+---------------+-------------+-----------------+
| 4^th^ dose DTPa     | Safety/I      | \--         | DTPa-H          |
| (Infanrix®) booster | mmunogenicity |             | epB-IPV-015B, - |
| following primary   |               |             | 028,            |
| series with         |               |             | -061(booster to |
| DTPa-HepB-IPV at 2, |               |             | --044)          |
| 4, 6 months of age  |               |             |                 |
+---------------------+---------------+-------------+-----------------+

**Data Not Submitted in BLA:** Concurrent vaccination with Prevnar
(7vPnC); use in infants born to hepatitis B surface antigen positive
mothers; concurrent administration with MMR and varicella vaccines;
fifth dose (4-6 yrs) Infanrix® DTPa following primary series of
DTPa-HepB-IPV; and safety and immunogenicity in former preterm infants.

**Appendix 1: Concurrent Immunization of Prevnar and DTPa or
DTPa-combination**

Although no data are available evaluating concurrent DTPa-HepB-IPV and
Prevnar (Wyeth-Lederle's 7-valent pneumococcal conjugate vaccine), data
submitted to the FDA under PLA 99-0279 (Pneumococcal 7-valent Conjugate
Vaccine \[Diphtheria~197~ CRM\] Protein \[Prevnar™\]) have suggested
that concurrent administration of Prevnar with either of two DTPa
vaccines may affect both immunogenicity and reactogenicity endpoints.

Specifically, data from prelicensure studies of Prevnar demonstrated
decreased immune response to certain pertussis components and increased
fever (\>38.0C) when Prevnar was given concurrently with Wyeth-Lederle's
DTPa vaccine (Acel-Imune) (see Appendix 6, Prevnar package insert Tables
5, 6, 10, and 11). In addition, Study 118-503, conducted in Germany on a
3, 4, 5 month schedule under a post-licensure commitment between the FDA
and Wyeth-Lederle, evaluated the immunogenicity and reactogenicity of
SBB's DTPa-IPV/Hib administered concurrently with Prevnar. SBB's
DTPa-IPV/Hib vaccine consists of the same DTPa (Infanrix®) and IPV
components as in SBB's DTPa-HepB-IPV, and contains SBB's PRP-T vaccine.
As was found with concurrent administration of Prevnar with Acel-Immune,
this study demonstrated decreased immune response to certain pertussis
components and increased fever (\>38.0C) when Prevnar was administered
concurrently with DTPa-IPV/Hib (see study synopsis below).

**Wyeth-Lederle Post-marketing Study**

> **Title:** Multicenter, randomized study evaluating the safety,
> immunogenicity and reactogenicity of Wyeth-Lederle's 7-valent
> Pneumococcal Conjugate Vaccine (7VPnC) concurrently administered to
> SBB's DTPa-IPV/Hib vaccine compared to administration of DTPa-IPV/Hib
> only, for the infant immunization series at 3, 4, and 5 month of age
>
> **Location:** Germany
>
> **Products:** Wyeth-Lederle's Prevnar and SBB's DTPa-IPV/Hib
>
> (Concurrent hepatitis B was permitted with the study vaccines,
> Subjects who received hepatitis B (N=83) were evenly divided between
> the Prevnar group and the control group.)
>
> **Sponsor:** Lederle-Arzneimittel GmbH (on behalf of Wyeth-Lederle
> Vaccines)
>
> **Study Site:** Twelve study centers in Germany
>
> **Status:** Study described as ongoing at the time of the report.
>
> Total planned: 200
>
> Total enrolled: 231
>
> Analyzed for Safety: 231
>
> Analyzed for Immunogenicity (ITT): 223
>
> Analyzed for Immunogenicity (ATP): 158

**Objective:** To show that Prevnar administered with DTPa-IPV/Hib does
not diminish the immunogenicity to antigens in DTPa-IPV/Hib

**Schedule:** 3, 4, and 5 months of age

**Study Design:**

Randomized (1:1), multicenter, open-label study.

231 healthy 3 mo old infants (57 days to 112 days of age) enrolled.

Blood samples obtained pre dose 1, and one month post dose 3

**Statistical Analyses:**

GMCs by ANCOVA, using pre-dose 1 GMCs as covariate.

Proportion responders by Fisher's exact.

**Wyeth-Lederle Post-Marketing Study: Comparison of
seroconversion/vaccine response rates to antigens in SBB's DTPa-IPV/Hib
in infants with and without concurrent 7VPnC -- Post dose 3, ATP
cohort**

+-------------+-----------+------------+---------+--------------------+
| **Antigen** | **%       |            |         | **Difference in    |
|             | Achieving |            |         | Proportion**       |
|             | Antibody  |            |         |                    |
|             | Level**   |            |         |                    |
+-------------+-----------+------------+---------+--------------------+
|             | **7VPnC** | *          | **P-Val | **7VPnC Group --   |
|             |           | *Control** | ue^‡^** | Control**          |
|             | **        |            |         |                    |
|             | Group\*** | **         |         | **(95% CI)**       |
|             |           | Group^†^** |         |                    |
|             | **N=83**  |            |         |                    |
|             |           | ##### N=75 |         |                    |
+-------------+-----------+------------+---------+--------------------+
| **PRP**     |           |            |         |                    |
+-------------+-----------+------------+---------+--------------------+
| **0.15      | 98.7      | 95.5       | 0.4975  | 3.2 (-6.2 - 17.9)  |
| g/mL**      |           |            |         |                    |
+-------------+-----------+------------+---------+--------------------+
| **1.0       | 65.8      | 67.2       | 0.4937  | -1.4 (-19.1 -      |
| g/mL**      |           |            |         | 15.0)              |
+-------------+-----------+------------+---------+--------------------+
| **D         |           |            |         |                    |
| iphtheria** |           |            |         |                    |
+-------------+-----------+------------+---------+--------------------+
| **0.01 IU   | 100       | 100        | 0.5973  | 0.0 (-7.3 -- 10.9) |
| /mL**       |           |            |         |                    |
+-------------+-----------+------------+---------+--------------------+
| **0. 1 IU   | 98.7      | 97.0       |         | 1.7 (-7.3 -- 16.5) |
| /mL**       |           |            |         |                    |
+-------------+-----------+------------+---------+--------------------+
| **Tetanus** |           |            |         |                    |
+-------------+-----------+------------+---------+--------------------+
| **0.01 IU   | 100       | 100        |         | 0.0 (-7.5 -- 10.9) |
| /mL**       |           |            |         |                    |
+-------------+-----------+------------+---------+--------------------+
| **0. 1 IU   | 100       | 100        |         | 0.0 (-7.5 -- 10.9) |
| /mL**       |           |            |         |                    |
+-------------+-----------+------------+---------+--------------------+
| **PT**      |           |            |         |                    |
+-------------+-----------+------------+---------+--------------------+
| **2 fold    | 94.0      | 96.0       | 0.7223  | -2.0 (-16.7 --     |
| rise**      |           |            |         | 8.5)               |
+-------------+-----------+------------+---------+--------------------+
| **4 fold    | 84.3      | 92.0       | 0.1516  | -7.7 (-23.5 --     |
| rise**      |           |            |         | 5.2)               |
+-------------+-----------+------------+---------+--------------------+
| **          |           |            |         |                    |
| Pertactin** |           |            |         |                    |
+-------------+-----------+------------+---------+--------------------+
| **2 fold    | 85.7      | 98.5       | 0.0090  | -12.8 (-28.5 --    |
| rise**      |           |            |         | -1.1)              |
+-------------+-----------+------------+---------+--------------------+
| **4 fold    | 80.0      | 95.5       | 0.0084  | -15.5 (-32.0 -     |
| rise**      |           |            |         | -2.0)              |
+-------------+-----------+------------+---------+--------------------+
| **FHA**     |           |            |         |                    |
+-------------+-----------+------------+---------+--------------------+
| **2 fold    | 79.5      | 89.3       | 0.1260  | -9.8 (-26.0 --     |
| rise**      |           |            |         | 3.9)               |
+-------------+-----------+------------+---------+--------------------+
| **4 fold    | 68.7      | 77.3       | 0.2831  | -8.7 (-25.3 --     |
| rise**      |           |            |         | 6.7)               |
+-------------+-----------+------------+---------+--------------------+
| **Polio     |           |            |         |                    |
| 1:10**      |           |            |         |                    |
+-------------+-----------+------------+---------+--------------------+
| **Type 1**  | 100       | 96.9       | 0.2228  | 3.1 (-5.7 -- 17.4) |
+-------------+-----------+------------+---------+--------------------+
| **Type 2**  | 100       | 100        | 0.3769  | 0.0 (-7.9 -- 11.2) |
+-------------+-----------+------------+---------+--------------------+
| **Type 3**  | 100       | 100        | 0.3769  | 0.0 (-7.9 -- 11.2) |
+-------------+-----------+------------+---------+--------------------+

\*DTPa-IPV/Hib + 7VPnC at 3, 4, 5 months of age

†DTPa-IPV/Hib (no concurrent 7vPnC) at 3, 4, 5 months of age

‡P-value by Fisher's Exact Test

**Wyeth-Lederle Post-Marketing Study: Comparison of DTPa-IPV/Hib
Antibody GMC's in infants with and without concurrent 7VPnC -- Post dose
3, ATP cohort**

+-----------+-----------+------------+--------+----------------------+
| **        | **GMC\*   |            |        | **Ratio of GMC of    |
| Antigen** | Post Dose |            |        | 7VPnC Group to       |
|           | 3         |            |        | Control**            |
|           | A         |            |        |                      |
|           | ntibody** |            |        | **(95% CI)**         |
+-----------+-----------+------------+--------+----------------------+
|           | **7VPnC** | *          | **     |                      |
|           |           | *Control** | P-Valu |                      |
|           | **Gr      |            | e^‡^** |                      |
|           | oup\*\*** | **         |        |                      |
|           |           | Group^†^** |        |                      |
+-----------+-----------+------------+--------+----------------------+
|           | **N=83**  | **N=75**   |        |                      |
+-----------+-----------+------------+--------+----------------------+
| **PRP**   | 1.68      | 1.94       | 0.5007 | 0.863 (0.560 --      |
|           |           |            |        | 1.329)               |
+-----------+-----------+------------+--------+----------------------+
| ##### Di  | 1.15      | 0.61       | \<     | 1.959 (1.528 --      |
| phtheria  |           |            | 0.0001 | 2.511)               |
+-----------+-----------+------------+--------+----------------------+
| **        | 3.79      | 4.44       | 0.2865 | 0.876 (0.686 --      |
| Tetanus** |           |            |        | 1.119)               |
+-----------+-----------+------------+--------+----------------------+
| **PT**    | 37.8      | 44.3       | 0.3691 | 0.901 (0.716 --      |
|           |           |            |        | 1.133)               |
+-----------+-----------+------------+--------+----------------------+
| **Pe      | **138.5** | **236.3**  | **0.   | **0.653 (0.483 --    |
| rtactin** |           |            | 0057** | 0.881)**             |
+-----------+-----------+------------+--------+----------------------+
| **FHA**   | 60.6      | 67.5       | 0\.    | 0.995 (0.780 --      |
|           |           |            | 9664   | 1.269)               |
+-----------+-----------+------------+--------+----------------------+
| **Polio   | 241       | 289        | 0.2306 | 0.763 (0.489 --      |
| type 1**  |           |            |        | 1.190)               |
+-----------+-----------+------------+--------+----------------------+
| **Polio   | 234       | 282        | 0.4381 | 0.847 (0.554 --      |
| type 2**  |           |            |        | 1.294)               |
+-----------+-----------+------------+--------+----------------------+
| **Polio   | 558       | 682        | 0.3370 | 0.878 (0.671 --      |
| type 3**  |           |            |        | 1.148)               |
+-----------+-----------+------------+--------+----------------------+

> \*GMCs expressed as mcg/mL for Hib (PRP), IU/mL for diphtheria and
> tetanus, EU/mL for pertussis antigens, and as neutralizing antibody
> per mL for polio antigens.
>
> \*\*DTPa-IPV/Hib + 7VPnC at 3, 4, 5 months
>
> †DTPa-IPV/Hib (no concurrent 7vPnC) at 3, 4, 5 months
>
> ‡P-value assesses the difference between treatment groups post-dose 3
> using ANCOVA

**Wyeth-Lederle Post-Marketing Study 118-503: Fever and antipyretic use
within 3 days of SBB's**

# DTPa-IPV/Hib with and without concurrent 7VPnC\*\*

<table>
<colgroup>
<col style="width: 10%" />
<col style="width: 4%" />
<col style="width: 0%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 7%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="3"><p><strong>Systemic Reaction</strong></p>
<p><strong>N=</strong></p></td>
<td colspan="6"><strong>Dose 1 (3 month)</strong></td>
<td colspan="5"><strong>Dose 2 (4 month)</strong></td>
<td colspan="5"><strong>Dose 3 (5 month)</strong></td>
</tr>
<tr class="even">
<td colspan="3"><strong>7VPnC</strong></td>
<td colspan="2"><strong>Control Group</strong></td>
<td rowspan="2"><p><strong>P-</strong></p>
<p><strong>value*</strong></p></td>
<td colspan="2"><strong>7VPnC</strong></td>
<td colspan="2"><strong>Control Group</strong></td>
<td rowspan="2"><p><strong>P-</strong></p>
<p><strong>value*</strong></p></td>
<td colspan="2"><strong>7VPnC</strong></td>
<td colspan="2"><strong>Control Group</strong></td>
<td rowspan="2"><strong>P-value*</strong></td>
</tr>
<tr class="odd">
<td colspan="2"><strong>116</strong></td>
<td><strong>%</strong></td>
<td><strong>110</strong></td>
<td><strong>%</strong></td>
<td><strong>112</strong></td>
<td><strong>%</strong></td>
<td><strong>107</strong></td>
<td><strong>%</strong></td>
<td><strong>110</strong></td>
<td><strong>%</strong></td>
<td><strong>107</strong></td>
<td><strong>%</strong></td>
</tr>
<tr class="even">
<td colspan="17">Fever</td>
</tr>
<tr class="odd">
<td>&gt; 38C</td>
<td>49</td>
<td colspan="2">44.5</td>
<td>32</td>
<td>29.9</td>
<td>0.035</td>
<td>35</td>
<td>33.0</td>
<td>29</td>
<td>28.2</td>
<td>0.447</td>
<td>31</td>
<td>29.0</td>
<td>24</td>
<td>23.1</td>
<td>0.350</td>
</tr>
<tr class="even">
<td>&gt; 39.1C</td>
<td>4</td>
<td colspan="2">3.8</td>
<td>5</td>
<td>4.8</td>
<td>0.747</td>
<td>3</td>
<td>2.9</td>
<td>2</td>
<td>1.0</td>
<td>0.683</td>
<td>5</td>
<td>4.7</td>
<td>1</td>
<td>1.0</td>
<td>0.212</td>
</tr>
<tr class="odd">
<td>Antipyretic use</td>
<td><strong>18</strong></td>
<td colspan="2"><strong>15.9</strong></td>
<td><strong>4</strong></td>
<td><strong>3.7</strong></td>
<td><strong>0.003</strong></td>
<td>11</td>
<td>9.8</td>
<td>5</td>
<td>4.7</td>
<td>0.195</td>
<td>8</td>
<td>7.3</td>
<td>4</td>
<td>3.8</td>
<td>0.374</td>
</tr>
</tbody>
</table>

\*P-value assesses the difference between treatment groups and is
calculated using Fisher's exact test.

\*\*Analysis included all subjects who received at least one dose.

*Reviewer comment*: Data from a Wyeth-Lederle-sponsored German study of
Prevnar given concurrently with SBB's DTPa-IPV/Hib (containing the same
DTPa and IPV as DTPa-HepB-IPV) suggest that concurrent administration of
these vaccines may interfere with the immune response to acellular
pertactin. This study also demonstrated a trend towards increased fever
([\>]{.underline} 38C) as well as a statistically significant increase
in antipyretic use in those infants receiving DTPa-IPV/Hib concurrently
with Prevnar. It is important to note that this study was not designed
as a non-inferiority trial and had a small sample size. These data are
shown to illustrate that data from studies of concurrent immunization of
Prevnar with two DTPa products have shown diminution of the immune
response to pertactin. The sample sizes are too small to draw definitive
conclusions but these studies suggest the possibility of immune
interference with respect to pertactin when Prevnar is administered
concomitantly with these DTPa vaccines.

**Appendix 2: 4^th^ Dose DTPa (Infanrix®) following a Primary Series of
DTPa-HepB-IPV**

While not formally considered a part of this BLA, SBB submitted summary
safety and immunogenicity data on 4^th^ (toddler) dose of Infanrix® or
Infanrix®-based combinations following a primary series with
DTPa-HepB-IPV. Only one of these studies (DTPa-HepB-IPV-015B) compared
the safety and immunogenicity of a booster dose of Infanrix® and Hib
vaccine in children receiving a primary series of DTPa-HepB-IPV versus
separate injections of DTPa + Hep B + OPV.

+-----------------+--------+-----------------+-------------------------+
| **Study**       | **Cou  | ##### Infanrix® |                         |
|                 | ntry** |  following prim |                         |
|                 |        | ary series with |                         |
|                 |        |  DTPa-HepB-IPV  |                         |
+-----------------+--------+-----------------+-------------------------+
|                 |        | ##### N for sa  | **N for immunogenicity  |
|                 |        | fety evaluation | evaluation**            |
+-----------------+--------+-----------------+-------------------------+
| DTPa-           | USA    | 125             | 116                     |
| HepB-IPV/015B\* |        |                 |                         |
+-----------------+--------+-----------------+-------------------------+
| DT              | G      | 166             | 0                       |
| Pa-HepB-IPV-028 | ermany |                 |                         |
+-----------------+--------+-----------------+-------------------------+
| DTPa-H          | USA    | 94              | 90                      |
| epB-IPV-061\*\* |        |                 |                         |
+-----------------+--------+-----------------+-------------------------+
| **Total**       |        | **385**         | **206**                 |
+-----------------+--------+-----------------+-------------------------+

\*DTPa-HepB-IPV-015B was the booster phase of Study DTPa-HepB-IPV-015.

\*\*\*DTPa-HepB-IPV-016 was the booster phase of Study
DTPa-HepB-IPV-044.

**Study Synopsis: DTPa-HepB-IPV-015B**

**Title:** An open study of the safety and immunogenicity of
DTPa-HepB-IPV vaccine administered as a three dose primary series or in
a sequential IPV/OPV schedule at 2, 4, and 6 months of age

**Principle investigator:** Dr. Joel Ward

**Study period:** 9/97 to 3/98

**Objectives**: To evaluate the safety and immunogenicity of Infanrix®
(DTPa vaccine) administered simultaneously at separate sites with
OmniHIB (Hib vaccine) as a booster in subjects 12 to 18 months of age
who were primed with the following vaccines:

Group 1: DTPa-HepB-IPV + Hib at 2, 4, and 6 months

Group 2: DTPa-HepB-IPV + Hib administered at 2, and 4 months of age and
DTPa-HepB + OPV + Hib administered at 6 months of age

Group 3: DTPa-HepB + IPOL® (IPV) + Hib administered at 2, 4, and 6
months of age

Group 4: DTPa (Infanrix®) + hepatitis B (Engerix-B) + OPV + Hib at 2, 4,
6 months of age

**Study Design:** open, single center, phase III. Blood samples were
taken prior to and one month after booster dose

**Number of subjects in booster study:**

Enrolled: 232

Completed: 227

ATP cohort for immunogenicity: 210

ITT/ATP cohort for safety: 232

**DTPa-HepB-IPV-015B: Seroprotection/ vaccine response and GMTs
following booster dose of Infanrix® an Hib vaccine**

+---------------+------+------+----+-----+----+-----+-------+------+
| *             | **G  |      | ## |     | #  |     | **    |      |
| *Antibodies** | roup |      | ## |     | ## |     | Group |      |
|               | 1**  |      | #  |     | ## |     | 4**   |      |
|               |      |      | Gr |     |  G |     |       |      |
|               | **N= |      | ou |     | ro |     | **N   |      |
|               | 62** |      | p  |     | up |     | =48** |      |
|               |      |      | 2  |     |  3 |     |       |      |
|               |      |      | {# |     |    |     |       |      |
|               |      |      | gr |     | ** |     |       |      |
|               |      |      | ou |     | N= |     |       |      |
|               |      |      | p- |     | 46 |     |       |      |
|               |      |      | 2- |     | ** |     |       |      |
|               |      |      | 1} |     |    |     |       |      |
|               |      |      |    |     |    |     |       |      |
|               |      |      | ## |     |    |     |       |      |
|               |      |      | ## |     |    |     |       |      |
|               |      |      | #  |     |    |     |       |      |
|               |      |      | N= |     |    |     |       |      |
|               |      |      | 54 |     |    |     |       |      |
+---------------+------+------+----+-----+----+-----+-------+------+
|               | *    | **G  | *  | *   | *  | *   | **%** | **G  |
|               | *%** | MT** | *% | *GM | *% | *GM |       | MT** |
|               |      |      | ** | T** | ** | T** |       |      |
+---------------+------+------+----+-----+----+-----+-------+------+
| *             | 100  | 2    | 1  | 2.  | 1  | 2.  | 100   | 1    |
| *Diphtheria** |      | .429 | 00 | 090 | 00 | 004 |       | .853 |
+---------------+------+------+----+-----+----+-----+-------+------+
| **Tetanus**   | 100  | 7    | 1  | 6.  | 1  | 6.  | 100   | 6    |
|               |      | .436 | 00 | 879 | 00 | 142 |       | .240 |
+---------------+------+------+----+-----+----+-----+-------+------+
| **PT**        | 100  | 1    | 1  | 14  | 1  | 10  | 100   | 1    |
|               |      | 48.5 | 00 | 6.8 | 00 | 0.0 |       | 10.0 |
+---------------+------+------+----+-----+----+-----+-------+------+
| **FHA**       | 98.0 | 2    | 1  | 28  | 96 | 27  | 100   | 3    |
|               |      | 51.0 | 00 | 9.5 | .8 | 9.5 |       | 67.6 |
+---------------+------+------+----+-----+----+-----+-------+------+
| **PRN**       | 98.4 | 3    | 1  | 32  | 95 | 30  | 93.5  | 3    |
|               |      | 51.7 | 00 | 8.8 | .3 | 2.6 |       | 55.0 |
+---------------+------+------+----+-----+----+-----+-------+------+
| **PRP         | 100  | 23   | 1  | 25. | 1  | 26. | 100   | 26   |
| ([\>          |      | .826 | 00 | 508 | 00 | 937 |       | .494 |
| ]{.underline} |      |      |    |     |    |     |       |      |
| 1.0mcg/mL[)]{ |      |      |    |     |    |     |       |      |
| .underline}** |      |      |    |     |    |     |       |      |
+---------------+------+------+----+-----+----+-----+-------+------+

Primary vaccination :

Group 1: DTPa-HepB-IPV + Hib at 2, 4, and 6 months

Group 2: DTPa-HepB-IPV + Hib at 2, and 4 months and DTPa-HepB + OPV +
Hib at 6 months

Group 3: DTPa-HepB + \*IPV + Hib administered at 2, 4, and 6 months of
age

Group 4: DTPa + hepatitis B + OPV + Hib at 2, 4, 6 months of age

Booster: All groups received DTPa + Hib

Seroprotection/vaccine response and GMT units as described in previous
studies

**DTPa-HepB-IPV-015B: Incidence of local and general symptoms following
booster dose of Infanrix® and Hib vaccine**

<table>
<colgroup>
<col style="width: 11%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2"><strong>Symptom</strong></td>
<td colspan="3"><strong>Group 1</strong></td>
<td colspan="3"><h5 id="group-2-2">Group 2</h5></td>
<td colspan="3"><strong>Group 3</strong></td>
<td colspan="3"><strong>Group 4</strong></td>
</tr>
<tr class="even">
<td><strong>%</strong></td>
<td colspan="2"><strong>95%CI</strong></td>
<td><strong>%</strong></td>
<td colspan="2"><strong>95%CI</strong></td>
<td><strong>%</strong></td>
<td colspan="2"><strong>95%CI</strong></td>
<td><strong>%</strong></td>
<td colspan="2"><strong>95%CI</strong></td>
</tr>
<tr class="odd">
<td><strong>Redness</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong>Any</strong></td>
<td>28.4</td>
<td>18.0</td>
<td>40.7</td>
<td>35.1</td>
<td>22.9</td>
<td>48.9</td>
<td>24.0</td>
<td>13.1</td>
<td>38.2</td>
<td>30.9</td>
<td>19.1</td>
<td>44.8</td>
</tr>
<tr class="odd">
<td><strong>Grade 3</strong></td>
<td>1.5</td>
<td>0.0</td>
<td>8.0</td>
<td>3.5</td>
<td>0.4</td>
<td>12.1</td>
<td>8.0</td>
<td>2.2</td>
<td>19.2</td>
<td>3.6</td>
<td>0.4</td>
<td>12.5</td>
</tr>
<tr class="even">
<td><strong>Pain</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>Any</strong></td>
<td>22.4</td>
<td>13.1</td>
<td>34.2</td>
<td>31.6</td>
<td>19.9</td>
<td>45.2</td>
<td>32.0</td>
<td>19.5</td>
<td>46.7</td>
<td>34.5</td>
<td>22.2</td>
<td>48.6</td>
</tr>
<tr class="even">
<td><strong>Grade 3</strong></td>
<td>3.0</td>
<td>0.4</td>
<td>10.4</td>
<td>0.0</td>
<td>0.0</td>
<td>6.3</td>
<td>0.0</td>
<td>0.0</td>
<td>7.1</td>
<td>1.8</td>
<td>0.0</td>
<td>9.7</td>
</tr>
<tr class="odd">
<td><strong>Swelling</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong>Any</strong></td>
<td>13.4</td>
<td>6.3</td>
<td>24.0</td>
<td>15.8</td>
<td>7.5</td>
<td>27.9</td>
<td>18.0</td>
<td>8.6</td>
<td>31.4</td>
<td>23.6</td>
<td>13.2</td>
<td>37.0</td>
</tr>
<tr class="odd">
<td><strong>Grade 3</strong></td>
<td>0.0</td>
<td>0.0</td>
<td>5.4</td>
<td>1.8</td>
<td>0.0</td>
<td>9.4</td>
<td>2.0</td>
<td>0.1</td>
<td>10.6</td>
<td>3.6</td>
<td>0.4</td>
<td>12.5</td>
</tr>
<tr class="even">
<td><strong>Fever</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><strong><u>&gt;</u>38C</strong></td>
<td>11.9</td>
<td>5.3</td>
<td>22.2</td>
<td>22.8</td>
<td>12.7</td>
<td>35.8</td>
<td>20.0</td>
<td>10.0</td>
<td>33.7</td>
<td>18.2</td>
<td>9.1</td>
<td>30.9</td>
</tr>
<tr class="even">
<td><strong><u>&gt;</u>39.5C</strong></td>
<td>1.5</td>
<td>0.0</td>
<td>8.0</td>
<td>3.5</td>
<td>0.4</td>
<td>12.1</td>
<td>2.0</td>
<td>0.1</td>
<td>10.6</td>
<td>0.0</td>
<td>0.0</td>
<td>6.5</td>
</tr>
</tbody>
</table>

Primary vaccination :

Group 1: DTPa-HepB-IPV + Hib at 2, 4, and 6 months

Group 2: DTPa-HepB-IPV + Hib at 2, and 4 months and DTPa-HepB + OPV +
Hib at 6 months

Group 3: DTPa-HepB + IPV + Hib administered at 2, 4, and 6 months of age

Group 4: DTPa + hepatitis B + OPV + Hib at 2, 4, 6 months of age

Booster: All groups received DTPa + Hib

> *Reviewer comment*: In this small study, the safety and immunogenicity
> of Infanrix® (DTPa) toddler booster following a primary series of
> DTPa-HepB-IPV was comparable to the safety and immunogenicity
> following a primary series of separately administered DTPa, hepatitis
> B and oral polio vaccine.

[^1]: ^^ SmithKline Beecham Biologicals has recently merged with Glaxo.
    The manufacturer will be referred to as SBB in this document because
    the change in name is not yet official for U.S. regulatory purposes.