# FDA Statistical Review and Evaluation

Document for the Vaccines and Related Biological Products Advisory
Committee (VRBPAC)

March 15, 2005

**ADACEL^TM^:** Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular
Pertussis Vaccine Adsorbed (Tdap)

> **Indication:** Single-dose immunization for the prevention of
> tetanus, diphtheria, and pertussis in persons aged 11 through 64 years
> of age

Henry S. Hsu, Ph.D.

FDA/CBER/OBE

This statistical briefing document covers two pivotal clinical trials
for this application. Study Td506 is a large-scale safety and
immunogenicity study to assess non-inferiority of Tdap vaccine in
healthy adults and adolescents as compared to a currently licensed Td
vaccine. Study Td505 is to assess the consistency of Tdap vaccine in
healthy adolescents using three consecutively manufactured lots.

**[I. STUDY Td506]{.underline}**

Title: "Safety and Immunogenicity of Tetanus and Diphtheria Toxoids
Adsorbed Combined with Component Pertussis (TdcP) Vaccine Compared to
Tetanus and Diphtheria Toxoids Adsorbed (Td) in Adolescents and Adults
11-64 Years of Age"

## Study Design

This was a Phase 3, randomized, controlled, modified double-blind\*,
multicenter study designed (1) to assess the safety and immunogenicity
of Tdap vaccine when given as a booster dose in subjects who had been
previously primed with the respective antigens, and (2) to compare the
safety and immunogenicity of Tdap vaccine to a licensed Td vaccine and
to historical controls. Participants ranged in age from 11 to 64 years
and at enrollment were stratified into 5 age ranges (11 to 13; 14 to 17;
18 to 28; 29 to 48; and 49 to 64 years of age).

(\*) The participant, the investigator and sponsor personnel were
blinded to which vaccine was administered.

## Primary Objectives

1\. To assess the immunogenicity of the Diphtheria and Tetanus Toxoids
of Tdap vaccine compared to a licensed Td vaccine. 2. To assess the
immunogenicity of the pertussis antigens of the Tdap vaccine compared to
the immune responses from the Sweden I Efficacy trial (DAPTACEL®) and
supportive trials conducted in Canada with Tdap vaccine.

## Primary Hypotheses

The following hypotheses were to be addressed for adolescents 11 to 17
years of age and adults 18 to 64 years of age, separately.

1a. The anti-diphtheria toxin and anti-tetanus toxin responses for
participants who receive Tdap vaccine will be non-inferior to responses
observed in participants who receive Td vaccine after a single
vaccination, assessed as the comparison of seroprotection rates at the
≥0.1 IU/mL level using the difference in rates between the groups.

1b. The anti-diphtheria toxin and anti-tetanus toxin booster responses
for participants who receive Tdap vaccine will be non-inferior to the
booster responses elicited by the licensed Td vaccine; a booster
response is defined as a four-fold response for participants with a
pre-vaccination titer equal to or below the pre-defined cut-off level
and a two-fold response for participants with pre-vaccination titers
above the cut-off levels. The cut-off levels are 2.56 IU/mL for
diphtheria and 2.7 IU/mL for tetanus.

2a. The anti-pertussis \[PT, FHA, FIM, and PRN\] responses for
participants who receive Tdap vaccine will be non-inferior to responses
observed in recipients 1 month after completing a primary series of
DAPTACEL® (Sweden I Efficacy trial) at 2, 4, and 6 months of age,
assessed as the comparison of GMCs using the ratio of GMCs of Tdap
vaccine and DAPTACEL®.

2b. The anti-pertussis \[PT, FHA, FIM, and PRN\] boosting responses for
participants who receive Tdap vaccine will be comparable to acceptable
booster responses defined from the data observed in the Aventis Pasteur
supportive trials with Tdap vaccine (81.2% for PT, 77.6% for FHA, 82.4%
for FIM, 86.4% for PRN); a booster response is defined as a four-fold
response for participants with a pre-vaccination titer equal to or below
the pre-defined cut-off levels and a two-fold response for participants
with pre-vaccination titers above the cut-off level. The cut-off levels
are: for PT 85 EU/mL, for FHA 170 EU/mL, for FIM 285 EU/mL, for PRN 115
EU/mL, respectively.

# **Determination of Sample Size**

Planned enrollment was 4400 participants, with 3000 participants in the
Tdap vaccine

group and 1400 in the Td vaccine group. A total of 2700 participants
were to be bled

for the immunogenicity assessment.

The sample size and power calculations were done for both primary and
secondary endpoints using the non-inferiority approach. The
non-inferiority margin (the relative effect deemed important to rule
out) was set to 10% for the comparison of rates and 1.5 fold for the
comparison of GMCs.

Predicted responses used in the sample size calculation were estimated
from the

observed data in previous trials with Tdap vaccine and are listed in the
following two tables.

Table 1: Predicted Booster Response Rates Levels for Diphtheria and
Tetanus

+--------------+------------+-----+------------------+---------------+
| Antigen      | Pre-V      |     | Predicted        | Power         |
|              | accination |     | Booster Response |               |
|              |            |     | Level^\*^        | (             |
|              | Titer      |     |                  | ![](media/ima |
|              | Cut-off    |     |                  | ge1.jpeg){wid |
|              | Value      |     |                  | th="0.1402777 |
|              |            |     |                  | 7777777778in" |
|              |            |     |                  | height        |
|              |            |     |                  | ="0.120138888 |
|              |            |     |                  | 88888889in"}= |
|              |            |     |                  | 0.025 )       |
+--------------+------------+-----+------------------+---------------+
| Diphtheria   | 2.56 IU/   | mL  | 92.9%            | \>99%         |
| IU/mL        |            |     |                  |               |
+--------------+------------+-----+------------------+---------------+
| Tetanus      | 2.70 IU/   | mL  | 81.6%            | 98.9%         |
| IU/mL        |            |     |                  |               |
+--------------+------------+-----+------------------+---------------+

(\*) Predicted booster response rates used for sample size calculation
were estimated from the observed data from both adolescents and adults
in TC9704(1) and TD9805(5).

As the testing of the primary hypotheses is done for adolescents and
adults separately, the power calculations for booster rates were done
using the sample size of 540 adolescents in the adolescent and adult
groups. There are 810 adults in the Tdap vaccine group and 540 adults in
Td vaccine group, so the power estimate for adults will exceed the power
estimate for adolescents.

Table 2: Predicted and Acceptable Boosting Response Rates for PT, FHA,
FIM, and PRN

  --------------- ----------------- --------------- --------------- ----------
  Antigen         Pre-Vaccination   Predicted^1^    Acceptable^2^   Power^3^
                  Titer Cut-off     Response Rates  Response Rates  α=0.025
                  Value                                             

  PT (EU/mL)      85 EU/mL          91.2%           81.2%           \> 99%

  FHA (EU/mL)     170 EU/mL         87.6%           77.6%           \> 99%

  FIM (EU/mL)     285 EU/mL         92.4%           82.4%           \> 99%

  PRN (EU/mL)     115 EU/mL         96.4%           86.4%           \> 99%
  --------------- ----------------- --------------- --------------- ----------

^1^ Predicted response rates used in the sample size calculation were
estimated using the supportive trials TC9704 and TD9805 from the
observed data in 581 participants for all antigens but PT. For PT, 570
participants were used.

^2^ Acceptable response rates are rates 10% lower than predicted ones.

^3^ As the testing of the primary hypotheses is done for adolescents and
adults separately, the power calculations were done using the sample
size of 540 adolescents. There are 810 adults in the TdcP vaccine group
and 540 adults in the Td vaccine group, so the power estimate for adults
will exceed the power estimate for adolescents.

# **Statistical Methods**

In general, the continuous variables were presented by summary
statistics (i.e., mean, standard deviation, geometric mean
concentrations (GMCs) and their confidence intervals) and the
categorical variables by frequency distributions (i.e., frequency
counts, percentages, and their confidence intervals). It was assumed
that log antibody titer for each antigen follows the normal
distribution. To establish non-inferiority according to the primary and
secondary hypotheses, statistical testing between the groups was
performed using two-sided 95% confidence intervals on the difference in
rates and two-sided 95% confidence intervals on ratios of GMCs.

To address the primary hypotheses and the secondary hypothesis,
statistical testing between groups was performed within adolescents and
adults, using the 2-sided 95% confidence interval on the difference in
rates or ratios of GMCs. To calculate the confidence interval for the
difference between two proportions, the Mantel-Haenszel method was used,
as described in 'Statistical Methods for Rates and Proportions' by
Joseph L. Fleiss, page174. This method is based on the weighted average
of differences between proportions in the two groups over the strata.
For these data, the strata were defined based on subjects' age
(adolescents and adults).

The weighted average is calculated as

![](media/image2.png){width="2.0520833333333335in"
height="0.5833333333333334in"}

where n~i1~, p~i1~ are the sample size and proportion of the first group
and n~i2~, p~i2~ are the sample size and proportion of the second group
in strata i.

The standard error for the CIs is derived as follows:

![](media/image3.png){width="2.8645833333333335in"
height="1.0416666666666667in"}

# Safety

For 'Any' and 'Moderate and Severe' Erythema, Swelling, Pain, and Fever
rates during Days 0-14, the non-inferiority of Tdap vaccine to Td
vaccine will be concluded if the upper limit of the two-sided 95% CI for
the difference in event rates is \<10%.

# Immunogenicity

Per the primary hypotheses 1a and 1b, for diphtheria and tetanus, the
non-inferiority of Tdap vaccine to Td vaccine will be concluded if the
lower limits of the 2-sided 95% CIs of the difference in
post-vaccination seroprotection rates (at the level of ≥ 0.1 IU/mL) and
booster rates between the two groups are above --10% (i.e., negative
10%).

Per primary hypothesis 2a, for each pertussis antigen, the
non-inferiority of Tdap vaccine to DAPTACEL® (Sweden I Efficacy trial)
will be concluded if the lower limit of the 2-sided 95% CI of the
post-vaccination GMCs ratio between the two vaccines is above 0.67.

Per primary hypothesis 2b, for each pertussis antigen, the booster
response for Tdap vaccine will be comparable to the booster response
observed in the supportive trials if the lower limit of the two-sided
95% CI for the booster rate in Tdap vaccine is above the acceptable
booster rate defined from the data observed in the supportive trials.
The acceptable booster response rates are: 81.2% for PT, 77.6% for FHA,
82.4% for FIM,

and 86.4% for PRN.

# **Results and Conclusions**

A total of 4501 participants were enrolled, of which 4480 were
randomized and 4461 were vaccinated, as shown in Table 3. For 30 of
these vaccinated participants, it could not be determined with certainty
which vaccine they received; of the remaining 4431 participants, 3017
received Tdap vaccine and 1414 received Td vaccine. A subset of study
participants (2720 participants) were bled for immunogenicity
assessment, of which 18 had unknown vaccine administration, one
participant did not receive the vaccine, and 92 participants from Site
119 were not included in the Intent-to-Treat immunogenicity analysis. A
total of 84.4% (2296/2720) of the bled participants were in compliance
with the protocol for immunogenicity assessment: 84.4% (1270/1504) of
Tdap vaccine recipients, 85.6% (1026/1198) of Td vaccine recipients.
Both study groups were comparable in participant disposition and
demographic characteristics.

Table 3: Participant Disposition

+------+------------------------+------+-----+----+-----+-----+-----+
|      |                        | Tdap |     | Td |     | All |     |
+------+------------------------+------+-----+----+-----+-----+-----+
| Age  | Study Termination      | n    | \%  | n  | \%  | n   | \%  |
|      | Information            |      |     |    |     |     |     |
+------+------------------------+------+-----+----+-----+-----+-----+
| 1    | Enrolled and           | 1225 | 10  | 8  | 10  | 20  | 10  |
| 1-17 | Randomized             | 1208 | 0.0 | 18 | 0.0 | 531 | 0.0 |
|      |                        | 1194 | 9   | 8  | 9   | 20  | 9   |
|      | Completed Visit 2      |      | 8.6 | 12 | 9.3 | 291 | 8.8 |
|      |                        | 31   | 9   | 8  | 9   | 20  | 9   |
|      | Completed entire study |      | 7.5 | 02 | 8.0 | 051 | 7.7 |
|      |                        |      | 2.5 | 16 | 2.0 | 48  | 2.3 |
|      | Terminated the Study   |      |     |    |     |     |     |
|      | (early)                |      |     |    |     |     |     |
+------+------------------------+------+-----+----+-----+-----+-----+
| 1    | Enrolled and           | 1807 | 10  | 6  | 10  | 24  | 10  |
| 8-64 | Randomized             | 1780 | 0.0 | 00 | 0.0 | 272 | 0.0 |
|      |                        | 1720 | 9   | 5  | 9   | 23  | 9   |
|      | Completed Visit 2      |      | 8.5 | 94 | 9.0 | 942 | 8.6 |
|      |                        | 87   | 9   | 5  | 9   | 23  | 9   |
|      | Completed entire study |      | 5.2 | 75 | 5.8 | 152 | 5.4 |
|      |                        |      | 4.8 | 25 | 4.2 | 112 | 4.6 |
|      | Terminated the Study   |      |     |    |     |     |     |
|      | (early)                |      |     |    |     |     |     |
+------+------------------------+------+-----+----+-----+-----+-----+
| T    | Enrolled and           | 3032 | 10  | 14 | 10  | 44  | 10  |
| otal | Randomized             | 2988 | 0.0 | 18 | 0.0 | 803 | 0.0 |
| 1    |                        | 2914 | 9   | 14 | 9   | 44  | 9   |
| 1-64 | Completed Visit 2      | 118  | 8.5 | 06 | 9.2 | 233 | 8.7 |
|      |                        |      | 9   | 13 | 9   | 43  | 9   |
|      | Completed entire study |      | 6.1 | 77 | 7.1 | 203 | 6.4 |
|      |                        |      | 3.9 | 41 | 2.9 | 160 | 3.6 |
|      | Terminated the Study   |      |     |    |     |     |     |
|      | (early)                |      |     |    |     |     |     |
+------+------------------------+------+-----+----+-----+-----+-----+

# Comparison of Seroprotection Rates

As per the primary hypothesis 1a that Tdap vaccine is non-inferior to Td
vaccine with respect to seroprotection rates, both **diphtheria and
tetanus** meet the --10% criterion for the lower limits of the 95% CIs
for the differences in 1-month post-vaccination seroprotection rates
between the Tdap vaccine group and Td vaccine group for both age groups,
as shown in Table 4. The lower limit of the 95% confidence interval for
the difference between Tdap and Td vaccines was -0.53% and -3.55% in
adolescents and adults, respectively, and for the entire 11 to 64
year-old population was -1.92% for **diphtheria**. The lower limit of
the 95% confidence interval for the difference between Tdap and Td
vaccines was 0.00% and -0.19% in adolescents and adults, respectively,
and for the entire 11 to 64 year-old population was -0.10% for
**tetanus**.

Table 4: Seroprotection Rates Between Tdap and Td Groups (PPI
Population\*)

+-------------+--------------+--------+--------+-------+-------+------+
| Antigen     | Age in Years | 1      |        |       |       |      |
|             |              | Month  |        |       |       |      |
|             |              | Post   |        |       |       |      |
|             |              | -vacci |        |       |       |      |
|             |              | nation |        |       |       |      |
+-------------+--------------+--------+--------+-------+-------+------+
|             |              | Tdap   | Td     | Diff  | LCL   | UCL  |
|             |              | Rate % |        | %     |       |      |
|             |              |        | Rate % |       |       |      |
+-------------+--------------+--------+--------+-------+-------+------+
| Diphtheria  | 11-17        | 99.8   | 99.8   | 0.00  | -0.53 | 0.54 |
|             |              | 94.1   | 95.1   |       |       |      |
|             | 18-64        |        |        | -1.01 | -3.55 | 1.53 |
|             |              | 96.7   | 97.3   |       |       |      |
|             | 11-64        |        |        | -0.54 | -1.92 | 0.85 |
+-------------+--------------+--------+--------+-------+-------+------+
| Tetanus     | 11-17        | 100.0  | 100.0  | 0.00  | 0.00  | 0.00 |
|             |              | 100.0  |        |       |       |      |
|             | 18-64        |        | 99.8   | 0.20  | -0.19 | 0.58 |
|             |              | 100.0  |        |       |       |      |
|             | 11-64        |        | 99.9   | 0.11  | -0.10 | 0.31 |
+-------------+--------------+--------+--------+-------+-------+------+

\* Per-Protocol Immunogenicity Population is defined as all participants
who were

randomized, received assigned vaccine, and were bled to have the data
according to the protocol.

# 

# Comparison of Booster Response Rates

As per the primary hypothesis 1b that Tdap vaccine is non-inferior to
the Td vaccine with respect to the 4-fold rise booster rates, both
diphtheria and tetanus meet the --10% criterion. That is, the lower
limits of the 95% CIs for the differences in 1-month post-vaccination
booster rates between Tdap and Td vaccine groups are above -10% for both
adolescents and adults, and for the entire study population, as shown in
Table 5 below.

Table 5: Booster Response Rates Between Tdap and Td Groups (PPI
Population\*)

+------------+-------+---------+---------+------------+-------+------+
| Antigen    | Years | Tdap    | Td      | Difference | LCL   | UCL  |
|            |       |         |         | %          |       |      |
|            |       | Rate %  | Rate %  |            |       |      |
+------------+-------+---------+---------+------------+-------+------+
| Diphtheria | 11-17 | 95.1    | 95.0    | 0.11       | -2.53 | 2.76 |
+------------+-------+---------+---------+------------+-------+------+
|            | 18-64 | 87.4    | 83.4    | 4.02       | -0.01 | 8.04 |
+------------+-------+---------+---------+------------+-------+------+
|            | 11-64 | 91.0    | 88.8    | 2.20       | -0.28 | 4.69 |
+------------+-------+---------+---------+------------+-------+------+
| Tetanus    | 11-17 | 91.7    | 91.3    | 0.37       | -3.02 | 3.76 |
+------------+-------+---------+---------+------------+-------+------+
|            | 18-64 | 63.1    | 66.8    | -3.72      | -9.09 | 1.64 |
+------------+-------+---------+---------+------------+-------+------+
|            | 11-64 | 76.3    | 78.1    | -1.83      | -5.11 | 1.45 |
+------------+-------+---------+---------+------------+-------+------+

\* Per-Protocol Immunogenicity Population is defined as all participants
who were

> randomized, received assigned vaccine, and were bled to have the data
> according to the protocol.

# 

# Comparison of Geometric Mean Concentrations

Statistical comparisons of diphtheria and tetanus GMCs using the 95%
confidence interval for the GMC ratio between Tdap vaccine and Td
vaccine showed non-inferiority of Tdap vaccine to Td vaccine. Table 6
below shows that the lower limits (LCL) of the 95% CIs of GMC ratios
1-month post-vaccination are above 0.67, both for adolescents and
adults, as well as for the entire study population.

Table 6: Geometric Mean Concentrations Between Tdap and Td (PPI
Population\*)

+-------------+--------+---------+---------+---------+-------+------+
| Antigen     | Years  | Tdap    | Td      | GMC     | LCL   | UCL  |
|             |        |         |         | Ratio   |       |      |
|             |        | GMC     | GMC2    |         |       |      |
+-------------+--------+---------+---------+---------+-------+------+
| Diphtheria  | 11-17  | 8.462   | 7.096   | 1.19    | **1   | 1.39 |
|             |        |         |         |         | .03** |      |
+-------------+--------+---------+---------+---------+-------+------+
|             | 18-64  | 2.487   | 2.368   | 1.05    | **0   | 1.29 |
|             |        |         |         |         | .86** |      |
+-------------+--------+---------+---------+---------+-------+------+
|             | 11-64  | 4.137   | 4.119   | 1.12    | **0   | 1.27 |
|             |        |         |         |         | .98** |      |
+-------------+--------+---------+---------+---------+-------+------+
| Tetanus     | 11-17  | 12.869  | 14.346  | 0.90    | **0   | 0.96 |
|             |        |         |         |         | .84** |      |
+-------------+--------+---------+---------+---------+-------+------+
|             | 18-64  | 7.651   | 8.179   | 0.94    | **0   | 1.01 |
|             |        |         |         |         | .86** |      |
+-------------+--------+---------+---------+---------+-------+------+
|             | 11-64  | 9.495   | 10.853  | 0.92    | **0   | 0.97 |
|             |        |         |         |         | .87** |      |
+-------------+--------+---------+---------+---------+-------+------+

\* Per-Protocol Immunogenicity Population is defined as all participants
who were

randomized, received assigned vaccine, and were bled to have the data
according to the protocol.

# 

# Comparison of TdcP Vaccine to Sweden I Pertussis Results 

As per the primary hypothesis 2a that the pertussis immune responses to
Tdap vaccine are non-inferior to those responses observed in the subset
of DAPTACEL® recipients from the Sweden I Efficacy trial who were tested
in the ADACEL™ Serology Bridging study, the results are shown in the
following Tables 7 and 8 for adolescents and adults, respectively. GMCs
for the Tdap vaccine are consistently higher than the Sweden I Efficacy
trial levels for all pertussis antigens, both for adults and
adolescents. That is, the lower limits of the 95% CIs for the ratio of
GMCs for all pertussis antigens are above 0.67.

Table 7: Comparisons of Pertussis Antigens Between Tdap in Td506
(Adolescents, 11- 17 Years, PPI Population\*) and DAPTACEL in the Sweden
I Efficacy Trial

+---------+------+-----+-------+-------+-------+--------+-----------+
| A       | Time | T   |       | DAP   |       | Tdap   |           |
| ntigens |      | dap |       | TACEL |       | vs.    |           |
|         |      |     |       | S     |       | DA     |           |
|         |      | Td  |       | weden |       | PTACEL |           |
|         |      | 506 |       | I     |       |        |           |
|         |      | Tr  |       | Eff   |       |        |           |
|         |      | ial |       | icacy |       |        |           |
|         |      |     |       | Trial |       |        |           |
+---------+------+-----+-------+-------+-------+--------+-----------+
|         |      | n   | GMC   | n     | GMC   | GMC    | 95% CI    |
|         |      |     |       |       |       | Ratio  |           |
+---------+------+-----+-------+-------+-------+--------+-----------+
| PT      | Pre  | 527 | 14.46 | 80    | 5.24  | 2.76   | (2.06,    |
|         | Post | 524 | 3     |       |       | 3.57   | 3.70)     |
| (EU/mL) |      |     | 09.26 | 80    | 86.55 |        | (2.83,    |
|         |      |     |       |       |       |        | 4.52)     |
+---------+------+-----+-------+-------+-------+--------+-----------+
| FHA     | Pre  | 527 | 19.49 | 80    | 5.21  | 3.74   | (2.81,    |
|         | Post | 526 | 2     |       |       | 5.38   | 4.99)     |
| (EU/mL) |      |     | 14.83 | 80    | 39.95 |        | (4.46,    |
|         |      |     |       |       |       |        | 6.49)     |
+---------+------+-----+-------+-------+-------+--------+-----------+
| FIM     | Pre  | 527 | 25.80 | 80    | 13.26 | 1.94   | (1.52,    |
|         | Post | 526 | 17    |       | 3     | 5.25   | 2.50)     |
| (EU/mL) |      |     | 92.40 | 80    | 41.10 |        | (3.90,    |
|         |      |     |       |       |       |        | 7.09)     |
+---------+------+-----+-------+-------+-------+--------+-----------+
| PRN     | Pre  | 526 | 10.01 | 80    | 2.15  | 4.67   | (3.46,    |
|         | Post | 526 | 3     |       | 1     | 3.19   | 6.30)     |
| (EU/mL) |      |     | 44.52 | 80    | 08.12 |        | (2.48,    |
|         |      |     |       |       |       |        | 4.10)     |
+---------+------+-----+-------+-------+-------+--------+-----------+

> \* Per-Protocol Immunogenicity Population is defined as all
> participants who were randomized, received assigned vaccine, and were
> bled to have the data according to the protocol.

Table 8: Comparison of Pertussis Antigens Between Tdap in Td506 (Adults
18-64 Years, PPI Population\*) and DAPTACEL in the Sweden I Efficacy
Trial

+----------+------+------+-------+-------+-------+-------+-----------+
| Antigens | Time | Tdap |       | DAP   |       | Tdap  |           |
|          |      |      |       | TACEL |       | vs.   |           |
|          |      | T    |       | S     |       | DAP   |           |
|          |      | d506 |       | weden |       | TACEL |           |
|          |      | T    |       | I     |       |       |           |
|          |      | rial |       | Eff   |       |       |           |
|          |      |      |       | icacy |       |       |           |
|          |      |      |       | Trial |       |       |           |
+----------+------+------+-------+-------+-------+-------+-----------+
|          |      | n    | GMC   | n     | GMC   | GMC   | 95% CI    |
|          |      |      |       |       |       | Ratio |           |
+----------+------+------+-------+-------+-------+-------+-----------+
| PT       | Pre  | 741  | 12.54 | 80    | 5.24  | 2.39  | (1.80,    |
|          | Post | 741  | 1     |       |       |       | 3.18)     |
| (EU/mL)  |      |      | 78.84 | 80    | 86.55 | 2.07  | (1.58,    |
|          |      |      |       |       |       |       | 2.70)     |
+----------+------+------+-------+-------+-------+-------+-----------+
| FHA      | Pre  | 741  | 18.13 | 80    | 5.21  | 3.48  | (2.68,    |
| (EU/mL)  | Post | 741  | 1     |       |       |       | 4.52)     |
|          |      |      | 92.91 | 80    | 39.95 | 4.83  | (3.94,    |
|          |      |      |       |       |       |       | 5.92)     |
+----------+------+------+-------+-------+-------+-------+-----------+
| FIM      | Pre  | 741  | 28.56 | 80    | 13.26 | 2.15  | (1.63,    |
| (EU/mL)  | Post | 741  | 8     |       | 3     |       | 2.84)     |
|          |      |      | 52.72 | 80    | 41.10 | 2.50  | (1.77,    |
|          |      |      |       |       |       |       | 3.54)     |
+----------+------+------+-------+-------+-------+-------+-----------+
| PRN      | Pre  | 741  | 8.45  | 80    | 2.15  | 3.94  | (2.89,    |
| (EU/mL)  | Post | 741  | 3     |       | 1     |       | 5.36)     |
|          |      |      | 41.89 | 80    | 08.12 | 3.16  | (2.25,    |
|          |      |      |       |       |       |       | 4.44)     |
+----------+------+------+-------+-------+-------+-------+-----------+

> \* Per-Protocol Immunogenicity Population is defined as all
> participants who were randomized, received assigned vaccine, and were
> bled to have the data according to the protocol.

# 

# Booster Response Rates

As per the primary hypothesis 2b that booster response rates for
pertussis antigens were comparable to the booster response observed in
the supportive trials with Tdap vaccine, Table 9 shows that the lower
limit (LCL) of the 95% CI for booster response rate for each antigen in
the PPI population is higher than the pre-defined booster rates
established from the supportive studies. The acceptable booster response
rates are: 81.2% for PT, 77.6% for FHA, 82.4% for FIM, and 86.4% for
PRN.

Table 9: Booster Response Rates of Pertussis Antigens (PPI Population)

+------------+-------+-------+-------+------+------+---------+--------+
| Antigen    | Age   | Group | 1     |      |      |         |        |
|            | in    |       | Month |      |      |         |        |
|            | Years |       | P     |      |      |         |        |
|            |       |       | ost-V |      |      |         |        |
|            |       |       | accin |      |      |         |        |
|            |       |       | ation |      |      |         |        |
+------------+-------+-------+-------+------+------+---------+--------+
|            |       |       | M     | n    | \%   | LCL     | UCL    |
+------------+-------+-------+-------+------+------+---------+--------+
| PT (EU/mL) | 11-17 | Tdap  | 524   | 482  | 92.0 | *       | 94.2   |
|            |       | Td    | 515   | 14   | 2.7  | *89.3** |        |
|            |       |       |       |      |      |         | 4.5    |
|            |       |       |       |      |      | **1.5** |        |
+------------+-------+-------+-------+------+------+---------+--------+
|            | 18-64 | Tdap  | 739   | 624  | 84.4 | *       | 87.0   |
|            |       |       |       |      |      | *81.6** |        |
+------------+-------+-------+-------+------+------+---------+--------+
|            |       | Td    | 508   | 11   | 2.2  | **1.1** | 3.8    |
+------------+-------+-------+-------+------+------+---------+--------+
| FHA        | 11-17 | Tdap  | 526   | 450  | 85.6 | *       | 88.4   |
| (EU/mL)    |       | Td    | 515   | 11   | 2.1  | *82.3** |        |
|            |       |       |       |      |      |         | 3.8    |
|            |       |       |       |      |      | **1.1** |        |
+------------+-------+-------+-------+------+------+---------+--------+
|            | 18-64 | Tdap  | 739   | 611  | 82.7 | *       | 85.3   |
|            |       |       |       |      |      | *79.8** |        |
+------------+-------+-------+-------+------+------+---------+--------+
|            |       | Td    | 508   | 11   | 2.2  | **1.1** | 3.8    |
+------------+-------+-------+-------+------+------+---------+--------+
| FIM        | 11-17 | Tdap  | 526   | 499  | 94.9 | *       | 96.6   |
| (EU/mL)    |       | Td    | 515   | 18   | 3.5  | *92.6** |        |
|            |       |       |       |      |      |         | 5.5    |
|            |       |       |       |      |      | **2.1** |        |
+------------+-------+-------+-------+------+------+---------+--------+
|            | 18-64 | Tdap  | 739   | 635  | 85.9 | *       | 88.4   |
|            |       |       |       |      |      | *83.2** |        |
+------------+-------+-------+-------+------+------+---------+--------+
|            |       | Td    | 508   | 11   | 2.2  | **1.1** | 3.8    |
+------------+-------+-------+-------+------+------+---------+--------+
| PRN        | 11-17 | Tdap  | 525   | 496  | 94.5 | *       | 96.3   |
| (EU/mL)    |       | Td    | 515   | 12   | 2.3  | *92.2** |        |
|            |       |       |       |      |      |         | 4.0    |
|            |       |       |       |      |      | **1.2** |        |
+------------+-------+-------+-------+------+------+---------+--------+
|            | 18-64 | Tdap  | 739   | 693  | 93.8 | *       | 95.4   |
|            |       |       |       |      |      | *91.8** |        |
+------------+-------+-------+-------+------+------+---------+--------+
|            |       | Td    | 508   | 15   | 3.0  | **1.7** | 4.8    |
+------------+-------+-------+-------+------+------+---------+--------+

M = Number evaluated, used for calculating the percent.

n = Number of subjects with a post-/pre-titer greater than the
pre-specified level.

\% = n/M

## Statistical Review Comments

The study protocol was revised and supplemented several times. The study
power and sample size are adequate. The statistical analyses are
appropriate. The results of all four primary analyses meet the
pre-specified criteria. There are no major statistical issues regarding
this study.

# II. **STUDY Td505**

Title: "Safety and Immunogenicity of Three Lots of Tetanus and
Diphtheria Toxoids Adsorbed Combined with Component Pertussis (TdcP)
Vaccine in Adolescents 11-17 Years of Age"

# **Study Design**

This was a Phase 3, randomized, controlled, double-blind, multicenter
study designed to assess the safety and immunogenicity of 3 lots of Tdap
vaccine when given as a booster dose in adolescents 11 to 17 years of
age. Participants enrolled in the study were stratified during
randomization into 2 age groups (11\~13 and 14\~17 years of age).

# **Primary Objective**

To assess the lot consistency of the Tdap vaccine manufacturing process
through evaluation of the immune response elicited by 3 lots when given
as a booster dose.

# **Primary Hypothesis**

The anti-pertussis \[PT, FHA, FIM, PRN\], anti-diphtheria toxin, and
anti-tetanus toxin responses will be similar in recipients of each of 3
Tdap vaccine lots upon completion of a booster vaccination.

The following criteria were used to establish consistency of Lots 1, 2,
and 3. If the two-sided 95% CIs on the difference in post-vaccination
seroprotection rates and booster rates between each 2 lots were within
the interval (-10%, 10%), and the two-sided 90% confidence intervals
(CIs) on post-vaccination GMC ratios were within the interval (0.66,
1.5), it was concluded that the lots are consistent.

# **Determination of Sample Size**

Planned enrollment was 1800 participants, randomized 1:1:1 to receive 1
of the 3 lots of Tdap vaccine. A total of 1170 (389 per lot)
participants were to be bled for immunogenicity assessment. The sample
size for the immunogenicity analysis was determined by taking 10%
attrition into account such that the power for each individual
hypothesis was at least 80%.

In the protocol, it was planned that statistical testing between the
lots use the 90% confidence interval for the difference in rates.
Following the advice of regulatory authorities and to be consistent with
other studies, the 90% confidence interval was replaced with the 95%
confidence interval during the conduct of the trial. Therefore, sample
size calculations for the rates are presented for both 0.05 and 0.025 α
levels.

The calculation of the sample size for the immunogenicity analyses was
based on the

following assumptions:

1.  Log (titer) for each antigen followed a normal distribution.

2.  The expected proportions and GMCs for all lots were equal.

3.  The lot consistency for immunogenicity was assessed by similarity
    criteria:

    -   95%/90% CI for difference in seroprotection rates between 2 lots

    ```{=html}
    <!-- -->
    ```
    -   90% CI for GMC Lot~i~/GMC Lot~j~ for pertussis antigens.

4.  The power to conclude consistency was calculated assuming 3
    comparisons (i.e., Lot 1 vs. Lot 2, Lot 1 vs. Lot 3, and Lot 2 vs.
    Lot 3) for each antigen.

Tables 1 and 2 summarize information used for the sample size
calculation for the immunogenicity endpoints. The sample size is 389 per
each lot and 1167 for all 3 lots. All sample size calculations were
determined using \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-- or
in-house \-\-\-\-\-\-\-\-\-\-- programs.

Table 1: Primary Endpoints, Historical Values (Targeted Response Levels)
for Diphtheria, Tetanus, PT, FHA, FIM, and PRN

+-----------------+-----------+-------------------+---------+--------+
| Antigen         | Primary   | Historical        | Power   |        |
|                 | Endpoints | Values/Targeted   | ^1^     |        |
|                 |           | Response Level    |         |        |
|                 |           | (95% CI)          |         |        |
+-----------------+-----------+-------------------+---------+--------+
|                 |           |                   | ![]     | ![](   |
|                 |           |                   | (media/ | media/ |
|                 |           |                   | image4. | image4 |
|                 |           |                   | jpeg){w | .jpeg) |
|                 |           |                   | idth="0 | {width |
|                 |           |                   | .140277 | ="0.14 |
|                 |           |                   | 7777777 | 027777 |
|                 |           |                   | 7778in" | 777777 |
|                 |           |                   | h       | 778in" |
|                 |           |                   | eight=" | height |
|                 |           |                   | 0.12013 | ="0.12 |
|                 |           |                   | 8888888 | 013888 |
|                 |           |                   | 88889in | 888888 |
|                 |           |                   | "}=0.10 | 889in" |
|                 |           |                   |         | }=0.05 |
+-----------------+-----------+-------------------+---------+--------+
| Diphtheria      | \% ≥0.10  | 95.0%             | \>99%   | \>99%  |
| IU/mL           |           |                   |         |        |
+-----------------+-----------+-------------------+---------+--------+
| Tetanus IU/mL   | \% ≥0.10  | 99%               | \>99%   | \>99%  |
+-----------------+-----------+-------------------+---------+--------+
| PT (EU/mL)      | GMC       | 144               | \>99%   | \-\--  |
|                 |           |                   |         |        |
|                 |           | 95% CI, (132,     |         |        |
|                 |           | 157)              |         |        |
|                 |           |                   |         |        |
|                 |           | N=445             |         |        |
+-----------------+-----------+-------------------+---------+--------+
| FHA (EU/mL)     | GMC       | 328               | \>99%   | \-\--  |
|                 |           |                   |         |        |
|                 |           | 95% CI, (302,     |         |        |
|                 |           | 356)              |         |        |
|                 |           |                   |         |        |
|                 |           | N=446             |         |        |
+-----------------+-----------+-------------------+---------+--------+
| FIM (EU/mL)     | GMC       | 995               | 97.22%  | \-\--  |
|                 |           |                   |         |        |
|                 |           | 95% CI, (883,     |         |        |
|                 |           | 1121)             |         |        |
|                 |           |                   |         |        |
|                 |           | N=446             |         |        |
+-----------------+-----------+-------------------+---------+--------+
| PRN (EU/mL)     | GMC       | 279               | 83.36%  | \-\--  |
|                 |           |                   |         |        |
|                 |           | 95% CI, (241,     |         |        |
|                 |           | 322)              |         |        |
|                 |           |                   |         |        |
|                 |           | N=446             |         |        |
+-----------------+-----------+-------------------+---------+--------+

^1^ Two-sided α.

N is the sample size used in calculating the 95% CI.

Table 2: Additional Immunogenicity Endpoints - Predicted Booster
Response Rates and Predicted GMC Levels for Diphtheria and Tetanus

  ---------------- ---------------- ------------------- ------------------------------------------------------ ------------------------------------------------------
  Antigen          Endpoint^1^      Predicted^2,3^      Power^4^                                               

                                                        ![](media/image5.jpeg){width="0.14027777777777778in"   ![](media/image5.jpeg){width="0.14027777777777778in"
                                                        height="0.12013888888888889in"}=0.10                   height="0.12013888888888889in"}=0.05

  Diphtheria IU/mL \% booster       92.9%               \-\--                                                  99%
                   response                                                                                    

  Tetanus IU/mL    \% booster       81.6%               \-\--                                                  70%
                   response                                                                                    

                                    7.65                                                                       

  Diphtheria IU/mL GMC              95% CI (6.71, 8.72) 98.79%                                                 \-\--

                                    N=326                                                                      

                                    26.26                                                                      

  Tetanus IU/mL    GMC              95% CI (24.01,      \>99%                                                  \-\--
                                    28.72)                                                                     

                                    N=326                                                                      
  ---------------- ---------------- ------------------- ------------------------------------------------------ ------------------------------------------------------

^1^ The pre-vaccination titer of titer ≤2.56 IU/mL for diphtheria and
≤2.7 IU/mL for tetanus represent the 95^th^ percentile for the
distribution of observed pre-vaccination titers in participants in
clinical trials TC9704 and TD9805.

^2^ Predicted booster response rates were estimated from the observed
data from both adolescents and adults in clinical trials TC9704 and
TD9805.

^3^ For predicted GMC levels, only adolescent data were used.

^4^ Two-sided α.

N is the sample size used in calculating the 95% CI for the predicted
levels.

For the safety profile for the secondary hypothesis, using the sample
size of 600 participants per lot, the power to conclude that Tdap
vaccine was similar for all 3 lots was calculated for Erythema,
Swelling, Pain, and Fever using the criterion that the 95% CI for the
difference in response rates should be less than 10%. Table 3 summarizes
sample size and power calculations for safety endpoints. The sample size
for the combined Tdap lots was 1800 (600 for each lot).

Table 3: Secondary Endpoints Safety Analysis

  -------------------- ---------------------- ------------------------------------------------------ ------------------------------------------------------
  Adverse Event        Expected Response      Power^2^                                               
                       Level^1^                                                                      

                                              ![](media/image6.jpeg){width="0.14027777777777778in"   ![](media/image6.jpeg){width="0.14027777777777778in"
                                              height="0.12013888888888889in"}=0.10                   height="0.12013888888888889in"}=0.05

  Erythema             11.8%                  99.96%                                                 99.84%

  Swelling             16.7%                  99.33%                                                 98.25%

  Pain                 88.6%                  99.99%                                                 99.88%

  Fever                9.4%                   99.99%                                                 99.98%
  -------------------- ---------------------- ------------------------------------------------------ ------------------------------------------------------

^1^ Levels obtained from clinical trial TC9704 (55), in which Tdap was
given to adolescents and adults.

^2^ Two-sided α.

[Change in Statistical Analysis]{.underline}

Following the advice of regulatory authorities and to be consistent with
other studies, the 90% confidence interval specified in the protocol for
the statistical testing of seroprotection rates or adverse event rates
between the 2 lots was replaced with the 95% confidence interval during
the conduct of the trial. Also, comparisons of booster rates and GMCs
for diphtheria and tetanus were added to the immunogenicity analysis.
Cut-off values used to calculate the tetanus booster response rates were
revised from the original protocol to allow for EU to IU conversion as
well as internal site-to-site testing concordance.

**[Statistical Methods]{.underline}**

In general, the continuous variables were presented by summary
statistics (i.e., mean, standard deviation, geometric mean
concentrations (GMCs) and their confidence intervals) and the
categorical variables by frequency distributions (i.e., frequency
counts, percentages and their confidence intervals). It was assumed that
log (antibody titer) for each antigen follows the normal distribution.
To establish consistency among the lots, statistical testing between 2
lots by the equivalence approach was performed using two-sided 95%
confidence intervals on the difference in rates and two-sided 90%
confidence intervals on ratios of GMCs.

The following hypotheses were tested between any 2 lots:

For the difference between 2 proportions, at a significance level of a
two-sided α=0.05:

Null Hypothesis, H~o~ : \| p~i~ -- p~j~ \| ≥ δ i,j =1,2,3, i≠j

Alternative Hypothesis, H~a~ : \| p~i~ -- p~j~ \| \< δ

where δ was 10%.

For the ratio between 2 GMCs, at a significance level of a two-sided
α=0.10:

Null Hypothesis, H~o~ : logGMC~i~ -- logGMC~j~ ≥ log(3/2)

> or logGMC~i~ -- logGMC~j~ ≤ log(2/3), i,j =1,2,3, i≠j

Alternative Hypothesis, H~a~: log(2/3) \< logGMC~i~ -- logGMC~j~ \<
log(3/2).

Confidence intervals for the outcome measures where the sample size was
not justified were used only for descriptive purposes to investigate
trends in the data. Baseline variables (age and gender) were compared
between the study groups using the analysis

of variance technique for continuous variables and the chi-square test
for categorical variables. As stated above, there were 2 age strata
defined in this study: 11 to 13 years and 14 to 17 years. For each age
stratum, there are only descriptive comparisons between the study groups
due to the insufficient sample size. In this submission, only data for
combined age strata, 11 to 17 years, are analyzed.

[Analysis Populations]{.underline}

Three analysis populations were used in this study. The intent-to-treat
safety (ITTS) population included all participants who were randomized
and received a Tdap vaccination. Participants who were randomized to
receive one Tdap lot but received another Tdap lot were included and
analyzed according to the lot they actually received. The
intent-to-treat immunogenicity (ITTI) population included all
participants who were randomized and received a vaccination. Note that
the subset of randomized participants who were bled for immunogenicity
analysis was included in the ITTI population. The per-protocol
immunogenicity (PPI) population included all ITTI participants who had
no major study violations. Some participants with protocol deviations,
such as a delay in the Day 4 or Day 14 telephone call, that were judged
to have no impact on their immunologic response were included in the PPI
population.

[Immunogenicity]{.underline}

The statistical criterion for concluding consistency in the serology
responses among

the 3 lots, that supports the primary hypothesis, was based on the
comparisons of GMCs for diphtheria, tetanus, and pertussis antigens and
on the comparison of seroprotection rates (at a level ≥ 0.1 IU/mL) and
booster rates for diphtheria and tetanus for the Per-Protocol
Immunogenicity (PPI) population. Lots were determined to be consistent
if the two-sided 90% confidence intervals for Lot 1/Lot 2, Lot 1/Lot 3,
and Lot 2/Lot 3 post-vaccination GMC ratios were within the boundaries
of (0.67, 1.5) and the 2-sided 95% CIs of the difference in
postvaccination seroprotection rates and booster rates between each 2
lots (Lots 1 and 2, Lots 2 and 3, Lots 1 and 3) were within the interval
(--10%, 10%).

[Safety]{.underline}

The statistical criterion for concluding consistency in the safety
responses in the secondary hypothesis was based on the comparisons of
Erythema, Swelling, Pain, and Fever rates Days 0-14 for the
Intent-to-Treat Safety population. Per the secondary study hypothesis,
if the two-sided 95% CIs on the difference between Lots 1, 2, and 3 (Lot
1 vs. Lot 2, Lot 1 vs. Lot 3, and Lot 2 vs. Lot 3) in rates of Erythema,
Swelling, Pain, and Fever were within the interval (--10%, 10%), this
was determined to be evidence of consistency in safety among the 3 lots
with respect to these events.

**[Results and Conclusions]{.underline}**

A total of 1811 participants were enrolled, of which 1791 (98.9%)
completed the study. A total of 1806 randomized participants received
vaccine in the Intent-to-Treat Safety (ITTS) population, and a subset of
these (1175) were bled for immunogenicity assessment in the
intent-to-treat immunogenicity (ITTI) population. A total of 10.1%
(119/1175) participants were excluded from the per-protocol
immunogenicity (PPI) population. All three groups were comparable in
participant disposition (Table 4) and demographic characteristics.

Table 4: Participant Disposition

  -------------------------------- --------- --------- --------- ----------
                                   Tdap1     Tdap2     Tdap3     Total

  Randomized                       603       605       603       1811

  Did Not Receive Vaccine          3         1         1         5

  ITTS                             600       604       602       1806

                                                                 

  Completed Study                  596       599       596       1791

  Discontinued Study Early         7         6         7         20

                                                                 

  Participants with Blood Samples  393       390       392       1175

  Protocol Violators               1         0         0         1

  ITTI                             392       390       392       1174

                                                                 

  Protocol Violators Not in PPI    42        40        37        119

  PPI                              351       350       355       1056
  -------------------------------- --------- --------- --------- ----------

> ITTS -- Intent-to-Treat Safety Population
>
> ITTI -- Intent-to-Treat Immunogenicity Population
>
> PPI -- Per-Protocol Immunogenicity Population

[Comparisons of Seroprotection Rates of Diphtheria and Tetanus
Toxoids]{.underline}

The primary hypothesis states that the anti-diphtheria toxin and
anti-tetanus toxin responses will be similar in recipients of 3 Tdap
vaccine lots upon completion of a booster vaccination. As part of the
evaluation of lot consistency, seroprotection rates between lots of Tdap
vaccine for the PPI population were compared using the 95% CI on the
difference in rates between any two lots. As shown in Table 5, for both
diphtheria and tetanus the 95% CIs for the differences in 1-month
post-vaccination seroprotection rates (at a level of ≥0.1 IU/mL) between
any 2 lots are within the interval (--10%, 10%).

Table 5: Seroprotection Rates at a Level of ≥0.1 IU/mL

+----------+----------------+---------+---------+-------+-----+-----+
| Antigen  | Comparison     | 1 Month |         |       |     |     |
|          |                | Post    |         |       |     |     |
|          |                | Vacc    |         |       |     |     |
|          |                | ination |         |       |     |     |
+----------+----------------+---------+---------+-------+-----+-----+
|          |                | Rate1 % | Rate2 % | Diff  | LCL | UCL |
|          |                |         |         | %     |     |     |
+----------+----------------+---------+---------+-------+-----+-----+
| Di       | Tdap1 vs.      | 100.0   | 99.4    | 0.57  | -0  | 1   |
| phtheria | Tdap2          | 100.0   |         | 0.28  | .22 | .36 |
|          |                |         | 99.7    |       | -0  | 1   |
|          | Tdap1 vs.      |         |         |       | .50 | .07 |
|          | Tdap3          |         |         |       |     |     |
+----------+----------------+---------+---------+-------+-----+-----+
|          | Tdap2 vs.      | 99.4    | 99.7    | -0.29 | -1  | 0   |
|          | Tdap3          |         |         |       | .08 | .50 |
+----------+----------------+---------+---------+-------+-----+-----+
| Tetanus  | Tdap1 vs.      | 100.0   | 100.0   | ----  | -   | -   |
|          | Tdap2          |         |         |       | --- | --- |
+----------+----------------+---------+---------+-------+-----+-----+
|          | Tdap1 vs.      | 100.0   | 100.0   | ----  | -   | -   |
|          | Tdap3          |         |         |       | --- | --- |
+----------+----------------+---------+---------+-------+-----+-----+
|          | Tdap2 vs.      | 100.0   | 100.0   | ----  | -   | -   |
|          | Tdap3          |         |         |       | --- | --- |
+----------+----------------+---------+---------+-------+-----+-----+

Rate 1, Rate 2 : Seroprotection rates in first and second group,
respectively, involved in the comparison.

Diff% : Difference between 2 lots in the proportion of participants with
a titer ≥0.1 IU/mL.

LCL, UCL : Lower and upper limits of the two-sided 95% confidence
interval for the difference in rates.

## Comparison of Booster Response Rates of Diphtheria and Tetanus Toxoids

As part of the additional evaluation of lot consistency, booster
response rates between lots of Tdap vaccine were compared for the PPI
population using 95% CI on the

difference in rates between any two lots. As shown in Table 6, for both
diphtheria and tetanus the 95% CIs for the differences in 1-month
post-vaccination booster rates between any 2 lots are within the
interval (-10%, 10%).

Table 6: Comparison of Booster Response Rates

+------------+---------------+---------+--------+-------+------+-----+
| Antigen    | Comparison    | 1 Month |        |       |      |     |
|            |               | Po      |        |       |      |     |
|            |               | st-Vacc |        |       |      |     |
|            |               | ination |        |       |      |     |
+------------+---------------+---------+--------+-------+------+-----+
|            |               | Rate1 % | Rate2  | Diff  | LCL  | UCL |
|            |               |         | %      | %     |      |     |
+------------+---------------+---------+--------+-------+------+-----+
| Diphtheria | Tdap1 vs.     | 96.0    | 95.7   | 0.31  | -    | 3   |
|            | Tdap2 Tdap1   |         |        | 1.11  | 2.75 | .37 |
|            | vs. Tdap3     | 96.0    | 94.9   |       |      | 4   |
|            |               |         |        |       | -    | .16 |
|            |               |         |        |       | 1.94 |     |
+------------+---------------+---------+--------+-------+------+-----+
|            | Tdap2 vs.     | 95.7    | 94.9   | 0.80  | -    | 3   |
|            | Tdap3         |         |        |       | 2.25 | .86 |
+------------+---------------+---------+--------+-------+------+-----+
| Tetanus    | Tdap1 vs.     | 92.6    | 93.7   | -1.12 | -    | 2   |
|            | Tdap2         |         |        |       | 4.99 | .74 |
+------------+---------------+---------+--------+-------+------+-----+
|            | Tdap1 vs.     | 92.6    | 91.8   | 0.79  | -    | 4   |
|            | Tdap3         |         |        |       | 3.06 | .64 |
+------------+---------------+---------+--------+-------+------+-----+
|            | Tdap2 vs.     | 93.7    | 91.8   | 1.91  | -    | 5   |
|            | Tdap3         |         |        |       | 1.94 | .77 |
+------------+---------------+---------+--------+-------+------+-----+

Rate 1, Rate 2 : Seroprotection rates in first and second group,
respectively, involved in the comparison.

Diff% : Difference between 2 lots in the proportion of participants with
a post-/pre-titer titer fold rise.

LCL, UCL : Lower and upper limits of the two-sided 95% confidence
interval for the difference in rates.

## Comparison of Geometric Mean Concentrations of Diphtheria and Tetanus Toxoids

As part of the additional evaluation of lot consistency, GMCs were
compared for the PPI population between groups receiving 1 of the 3 lots
of Tdap vaccine using the 90% CI on the GMC ratios between any two lots.
As shown in Table 7, for both diphtheria and tetanus, the 90% CIs for
the pre- and 1-month post-vaccination GMC ratios between any 2 lots are
within the interval (0.67, 1.5). In addition, GMC comparisons using the
95% CI for the ratio of GMCs are also presented in Table 7 for the PPI
population.

Table 7: Comparison of Geometric Mean Concentrations (GMCs) (PPI
Population)

+---------+--------------+-----+-----+-----+-----+-----+-----+-----+
| Antigen | Groups       | One |     |     |     |     |     |     |
|         |              | Mo  |     |     |     |     |     |     |
|         |              | nth |     |     |     |     |     |     |
|         |              | P   |     |     |     |     |     |     |
|         |              | ost |     |     |     |     |     |     |
|         |              | -Va |     |     |     |     |     |     |
|         |              | cci |     |     |     |     |     |     |
|         |              | nat |     |     |     |     |     |     |
|         |              | ion |     |     |     |     |     |     |
+---------+--------------+-----+-----+-----+-----+-----+-----+-----+
|         |              | G   | G   | GMC | 90% |     | 95% |     |
|         |              | MC1 | MC2 | Ra  | CI  |     | CI  |     |
|         |              |     |     | tio |     |     |     |     |
+---------+--------------+-----+-----+-----+-----+-----+-----+-----+
|         |              |     |     |     | LCL | UCL | LCL | UCL |
+---------+--------------+-----+-----+-----+-----+-----+-----+-----+
| Dip     | Tdap1 vs.    | 7   | 7   | 1   | 0   | 1   | 0   | 1   |
| htheria | Tdap2 Tdap1  | .74 | .16 | .08 | .96 | .22 | .94 | .25 |
|         | vs. Tdap3    | 7   | 7   |     | 0   | 1   | 0   | 1   |
|         |              | .74 | .52 | 1   | .91 | .16 | .89 | .18 |
|         |              |     |     | .03 |     |     |     |     |
+---------+--------------+-----+-----+-----+-----+-----+-----+-----+
|         | Tdap2 vs.    | 7   | 7   | 0   | 0   | 1   | 0   | 1   |
|         | Tdap3        | .16 | .52 | .95 | .85 | .07 | .83 | .10 |
+---------+--------------+-----+-----+-----+-----+-----+-----+-----+
| Tetanus | Tdap1 vs.    | 16  | 16  | 0   | 0   | 1   | 0   | 1   |
|         | Tdap2        | .27 | .72 | .97 | .91 | .04 | .90 | .06 |
+---------+--------------+-----+-----+-----+-----+-----+-----+-----+
|         | Tdap1 vs.    | 16  | 17  | 0   | 0   | 1   | 0   | 1   |
|         | Tdap3        | .27 | .22 | .95 | .88 | .01 | .87 | .03 |
+---------+--------------+-----+-----+-----+-----+-----+-----+-----+
|         | Tdap2 vs.    | 16  | 17  | 0   | 0   | 1   | 0   | 1   |
|         | Tdap3        | .72 | .22 | .97 | .91 | .04 | .89 | .05 |
+---------+--------------+-----+-----+-----+-----+-----+-----+-----+

GMC1, GMC2 : GMCs for first and second group, respectively, involved in
the comparison.

GMC Ratio : Ratio of GMCs for 2 groups.

LCL, UCL: Lower and upper limits of the two-sided confidence interval
for the GMC ratio.

## Comparison of Geometric Mean Concentrations of Pertussis

The primary hypothesis states that the anti-pertussis -- PT, FHA, FIM,
PRN -- responses will be similar in recipients of 3 Tdap vaccine lots
upon completion of a booster vaccination. As part of the evaluation of
lot consistency, GMCs were compared for the PPI population between
groups receiving the 3 lots of Tdap vaccine using the 90% CI on the GMC
ratios between any two lots. As shown in Table 8, for PT, FHA, and PRN,
the 90% CIs for the one-month post-vaccination GMC ratios between any 2
lots are within the equivalence margins (0.67, 1.5). For FIM, the 90%
CIs for the one-month postvaccination GMC ratios between Lots 1 and 2
and Lots 1 and 3 in the PPI population are within the margins while the
90% CI for the GMC ratio between Lots 2 and 3, having an upper limit of
1.55, is marginally outside the margins (0.67, 1.5). In addition, the
comparisons using the 95% CI for the ratio of GMCs are also presented in
Table 8 for the PPI population.

Table 8: Pertussis Antigens: Geometric Mean Concentrations (PPI
Population)

  --------- --------------- ------------------ --------- ------- ------ ------ ------ ------
  Antigen   Groups          One Month                                                 
                            Post-Vaccination                                          

                            GMC1               GMC2      GMC     90% CI        95% CI 
                                                         Ratio                        

                                                                 LCL    UCL    LCL    UCL

  PT        Tdap1 vs. Tdap2 343.65             347.36    0.99    0.87   1.13   0.85   1.16

            Tdap1 vs. Tdap3 343.65             323.89    1.06    0.93   1.21   0.91   1.24

            Tdap2 vs. Tdap3 347.36             323.89    1.07    0.94   1.22   0.92   1.25

  FHA       Tdap1 vs. Tdap2 285.10             264.98    1.08    0.98   1.19   0.96   1.21

            Tdap1 vs. Tdap3 285.10             247.76    1.15    1.04   1.27   1.02   1.29

            Tdap2 vs. Tdap3 264.98             247.76    1.07    0.97   1.18   0.95   1.20

  FIM       Tdap1 vs. Tdap2 1901.60            2025.38   0.94    0.80   1.10   0.78   1.13

            Tdap1 vs. Tdap3 1901.60            1528.75   1.24    1.06   1.45   1.03   1.50

            Tdap2 vs. Tdap3 2025.38            1528.75   1.32    1.13   1.55   1.10   1.60

  PRN       Tdap1 vs. Tdap2 366.14             394.69    0.93    0.81   1.07   0.79   1.10

            Tdap1 vs. Tdap3 366.14             343.21    1.07    0.93   1.23   0.90   1.26

            Tdap2 vs. Tdap3 394.69             343.21    1.15    1.00   1.32   0.97   1.36
  --------- --------------- ------------------ --------- ------- ------ ------ ------ ------

GMC1, GMC2 : GMCs for first and second group, respectively, involved in
the comparison.

GMC Ratio : Ratio of GMCs for 2 groups.

LCL, UCL: Lower and upper limits of the two-sided confidence interval
for the GMC ratio.

[Four-Fold Response Rates of Pertussis Antigens]{.underline}

As part of the additional evaluation of lot consistency, four-fold
response rates for the pertussis antigens one-month post-vaccination
were analyzed for the PPI population. Most participants achieved
four-fold rise in titer to all antigens at one-month post-vaccination:
87.4% (304/348), 80.4% (283/352), 92.5% (322/348), and 93.1% (324/348)
for PT, FHA, FIM, and PRN, respectively. Table 9 shows that these rates
are similar in participants receiving Lots 1, 2, and 3. The 95% CI for
the differences in 4-fold rise rates at one- month following vaccination
between groups are mostly within the 10% range, except for two
comparisons involving the FHA antigen.

Table 9: Comparisons of Pertussis Antigens: Four-Fold Rates

  ------------ --------------- ------------------ --------- -------- ------- -------
  Antigen      Comparison      1 Month                                       
                               Post-Vaccination                              

                               Rate1 %            Rate2 %   Diff %   LCL     UCL

  PT (EU/mL)   Tdap1 vs. Tdap2 92.0               87.4      4.67     0.06    9.28

               Tdap1 vs. Tdap3 92.0               88.1      3.95     -0.64   8.55

               Tdap2 vs. Tdap3 87.4               88.1      -0.71    -5.32   3.90

  FHA (EU/mL)  Tdap1 vs. Tdap2 86.3               81.0      5.34     -0.28   10.97

               Tdap1 vs. Tdap3 86.3               80.4      5.93     0.32    11.54

               Tdap2 vs. Tdap3 81.0               80.4      0.58     -5.04   6.21

  FIM (EU/mL)  Tdap1 vs. Tdap2 93.4               92.5      0.90     -2.83   4.63

               Tdap1 vs. Tdap3 93.4               93.8      -0.32    -4.04   3.39

               Tdap2 vs. Tdap3 92.5               93.8      -1.22    -4.94   2.50

  PRN (EU/mL)  Tdap1 vs. Tdap2 95.4               93.1      2.34     -1.16   5.83

               Tdap1 vs. Tdap3 95.4               93.8      1.69     -1.79   5.17

               Tdap2 vs. Tdap3 93.1               93.8      -0.65    -4.14   2.84
  ------------ --------------- ------------------ --------- -------- ------- -------

Rate 1, Rate 2 : Seroprotection rates in first and second group,
respectively, involved in the comparison.

Diff% : Difference between 2 lots in the proportion of participants with
a post-/pre-titer titer fold rise.

LCL, UCL : Lower and upper limits of the two-sided 95% confidence
interval for the difference in rates.

[Safety Analysis: Comparison of Adverse Event Rates]{.underline}

The secondary hypothesis states that the Erythema, Swelling, and Pain
rates will be similar between the 3 consistency lots of Tdap vaccine
when given as a booster dose. To evaluate consistency between the lots,
rates of Erythema, Swelling, and Pain between groups receiving the 3
different lots of Tdap vaccine were compared for 'Any' and 'Moderate &
Severe' intensities for Days 0--14 using the 95% CI on the difference in
rates between any 2 lots. As shown in Table 10 based on the
Intent-to-Treat Safety (ITTS) Population, the 95% CIs for the
differences in Erythema, Swelling, and Pain rates between any 2 lots are
within the interval (--10%, 10%) for all intensity categories.

Table 10: Erythema (Redness), Swelling, and Pain: Comparison of Rates
Between Groups (ITTS Population), Days 0--14

<table style="width:100%;">
<colgroup>
<col style="width: 9%" />
<col style="width: 16%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2">Adverse Event</td>
<td rowspan="2">Groups Compared</td>
<td colspan="5">Any</td>
<td colspan="5">Moderate &amp; Severe</td>
</tr>
<tr class="even">
<td>Rate 1%</td>
<td>Rate 2 %</td>
<td>Diff %</td>
<td>LCL</td>
<td>UCL</td>
<td><p>Rate 1</p>
<p>%</p></td>
<td>Rate 2 %</td>
<td>Diff %</td>
<td>LCL</td>
<td>UCL</td>
</tr>
<tr class="odd">
<td>Erythema (Redness)</td>
<td>Tdap1 vs. Tdap2 Tdap1 vs. Tdap3</td>
<td>23.66 23.66</td>
<td>24.21 25.08</td>
<td><p>-0.55</p>
<p>-1.43</p></td>
<td><p>-5.41</p>
<p>-6.29</p></td>
<td><p>4.32</p>
<p>3.44</p></td>
<td>12.08 12.08</td>
<td>11.02 11.37</td>
<td>1.06 0.71</td>
<td><p>-2.55</p>
<p>-2.91</p></td>
<td>4.68 4.33</td>
</tr>
<tr class="even">
<td></td>
<td>Tdap2 vs. Tdap3</td>
<td>24.21</td>
<td>25.08</td>
<td>-0.88</td>
<td>-5.74</td>
<td>3.98</td>
<td>11.02</td>
<td>11.37</td>
<td>-0.35</td>
<td>-3.97</td>
<td>3.26</td>
</tr>
<tr class="odd">
<td>Swelling</td>
<td>Tdap1 vs. Tdap2</td>
<td>20.97</td>
<td>22.20</td>
<td>-1.23</td>
<td>-5.97</td>
<td>3.51</td>
<td>13.59</td>
<td>12.85</td>
<td>0.74</td>
<td>-3.29</td>
<td>4.77</td>
</tr>
<tr class="even">
<td></td>
<td>Tdap1 vs. Tdap3</td>
<td>20.97</td>
<td>24.41</td>
<td>-3.44</td>
<td>-8.18</td>
<td>1.30</td>
<td>13.59</td>
<td>18.06</td>
<td>-4.47</td>
<td>-8.50</td>
<td>-0.44</td>
</tr>
<tr class="odd">
<td></td>
<td>Tdap2 vs. Tdap3</td>
<td>22.20</td>
<td>24.41</td>
<td>-2.21</td>
<td>-6.94</td>
<td>2.52</td>
<td>12.85</td>
<td>18.06</td>
<td>-5.21</td>
<td>-9.23</td>
<td>-1.18</td>
</tr>
<tr class="even">
<td>Pain</td>
<td>Tdap1 vs. Tdap2</td>
<td>80.70</td>
<td>78.80</td>
<td>1.91</td>
<td>-2.64</td>
<td>6.45</td>
<td>20.97</td>
<td>20.87</td>
<td>0.11</td>
<td>-4.63</td>
<td>4.84</td>
</tr>
<tr class="odd">
<td></td>
<td>Tdap1 vs. Tdap3</td>
<td>80.70</td>
<td>80.27</td>
<td>0.44</td>
<td>-4.11</td>
<td>4.98</td>
<td>20.97</td>
<td>25.75</td>
<td>-4.78</td>
<td>-9.52</td>
<td>-0.04</td>
</tr>
<tr class="even">
<td></td>
<td>Tdap2 vs. Tdap3</td>
<td>78.80</td>
<td>80.27</td>
<td>-1.47</td>
<td>-6.01</td>
<td>3.07</td>
<td>20.87</td>
<td>25.75</td>
<td>-4.88</td>
<td>-9.62</td>
<td>-0.15</td>
</tr>
</tbody>
</table>

Rate 1, Rate 2 :Adverse event rates for first and second groups,
respectively, involved in the comparison.

Diff % : Difference in event rates between the groups being compared.

LCL, UCL : Lower and upper limits of the two-sided 95% confidence
interval for the difference.

Erythema and Swelling: Any, \>0 mm; Moderate & Severe, ≥10 mm.

Days 0--14: Maximum intensity of events reported during the time period.

Tdap1 (N=600), Tdap2 (N=604), Tdap3 (N=602) -- Tdap Vaccine Lots C0192,
C0614, and C0632, respectively, administered at Day 0.

## Statistical Review Comments

The study protocol for lot consistency was revised and supplemented
several times. The study power and sample size are adequate. The
statistical analyses are appropriate. The results of primary analyses of
immunogenicity meet the pre-specified criteria, except for a few
comparisons noted above. In the safety analysis, comparisons of local
adverse event rates are within the pre-specified criterion. There are no
major statistical issues regarding this study.

Note that for comparisons of rates (proportions), 95% confidence
intervals have been used in order to be consistent with CBER's current
general statistical preference. The two-sided lot consistency
comparisons involving ratios of GMCs, however, are based in this
submission on 90% confidence intervals. These confidence levels, though
inconsistent with CBER's current general statistical preference, may be
viewed as being consistent with drug pharmacokinetic bioequivalence
evaluations which are customarily based on 2-sided 90% confidence
intervals. In this latter case, the alpha (significance ) level is 5%,
not 10%, due to the intersection-union nature of equivalence testing.