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: Singledose 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 largescale safety and immunogenicity study to assess noninferiority 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
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 1164 Years of Age”
This was a Phase 3, randomized, controlled, modified doubleblind*, 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.
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.
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 antidiphtheria toxin and antitetanus toxin responses for participants who receive Tdap vaccine will be noninferior 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 antidiphtheria toxin and antitetanus toxin booster responses for participants who receive Tdap vaccine will be noninferior to the booster responses elicited by the licensed Td vaccine; a booster response is defined as a fourfold response for participants with a prevaccination titer equal to or below the predefined cutoff level and a twofold response for participants with prevaccination titers above the cutoff levels. The cutoff levels are 2.56 IU/mL for diphtheria and 2.7 IU/mL for tetanus.
2a. The antipertussis [PT, FHA, FIM, and PRN] responses for participants who receive Tdap vaccine will be noninferior 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 antipertussis [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 fourfold response for participants with a prevaccination titer equal to or below the predefined cutoff levels and a twofold response for participants with prevaccination titers above the cutoff level. The cutoff levels are: for PT 85 EU/mL, for FHA 170 EU/mL, for FIM 285 EU/mL, for PRN 115 EU/mL, respectively.
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 noninferiority approach. The noninferiority 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 
PreVaccination Titer Cutoff Value 
Predicted Booster Response Level^{*} 
Power ( =
0.025 ) 

Diphtheria IU/mL 
2.56 IU/ 
mL 
92.9% 
>99% 
Tetanus IU/mL 
2.70 IU/ 
mL 
81.6% 
98.9% 
(*) 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 
PreVaccination Titer Cutoff Value 
Predicted^{1} Response Rates 
Acceptable^{2} Response Rates 
Power^{3} α=0.025 
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.
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 noninferiority according to the primary and secondary hypotheses, statistical testing between the groups was performed using twosided 95% confidence intervals on the difference in rates and twosided 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 2sided 95% confidence interval on the difference in rates or ratios of GMCs. To calculate the confidence interval for the difference between two proportions, the MantelHaenszel 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
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:
For ‘Any’ and ‘Moderate and Severe’ Erythema, Swelling, Pain, and Fever rates during Days 014, the noninferiority of Tdap vaccine to Td vaccine will be concluded if the upper limit of the twosided 95% CI for the difference in event rates is <10%.
Per the primary hypotheses 1a and 1b, for diphtheria and tetanus, the noninferiority of Tdap vaccine to Td vaccine will be concluded if the lower limits of the 2sided 95% CIs of the difference in postvaccination 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 noninferiority of Tdap vaccine to DAPTACEL® (Sweden I Efficacy trial) will be concluded if the lower limit of the 2sided 95% CI of the postvaccination 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 twosided 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.
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 IntenttoTreat 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 Information 
n 
% 
n 
% 
n 
% 
1117 
Enrolled and Randomized Completed Visit 2 Completed entire study Terminated the Study (early) 
1225 1208 1194 31 
100.0 98.6 97.5 2.5 
818 812 802 16 
100.0 99.3 98.0 2.0 
20531 20291 20051 48 
100.0 98.8 97.7 2.3 
1864 
Enrolled and Randomized Completed Visit 2 Completed entire study Terminated the Study (early) 
1807 1780 1720 87 
100.0 98.5 95.2 4.8 
600 594 575 25 
100.0 99.0 95.8 4.2 
24272 23942 23152 112 
100.0 98.6 95.4 4.6 
Total 1164 
Enrolled and Randomized Completed Visit 2 Completed entire study Terminated the Study (early) 
3032 2988 2914 118 
100.0 98.5 96.1 3.9 
1418 1406 1377 41 
100.0 99.2 97.1 2.9 
44803 44233 43203 160 
100.0 98.7 96.4 3.6 
As per the primary hypothesis 1a that Tdap vaccine is noninferior 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 1month postvaccination 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 yearold 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 yearold population was 0.10% for tetanus.
Table 4: Seroprotection Rates Between Tdap and Td Groups (PPI Population*)
Antigen 
Age in Years 
1 Month Postvaccination 

Tdap Rate % 
Td Rate % 
Diff % 
LCL 
UCL 

Diphtheria 
1117 1864 1164 
99.8 94.1 96.7 
99.8 95.1 97.3 
0.00 1.01 0.54 
0.53 3.55 1.92 
0.54 1.53 0.85 
Tetanus 
1117 1864 1164 
100.0 100.0 100.0 
100.0 99.8 99.9 
0.00 0.20 0.11 
0.00 0.19 0.10 
0.00 0.58 0.31 
* PerProtocol Immunogenicity Population is defined
as all participants who were
randomized, received assigned vaccine, and were bled
to have the data according to the protocol.
As per the primary hypothesis 1b that Tdap vaccine is noninferior to the Td vaccine with respect to the 4fold rise booster rates, both diphtheria and tetanus meet the –10% criterion. That is, the lower limits of the 95% CIs for the differences in 1month postvaccination 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 Rate % 
Td Rate % 
Difference % 
LCL 
UCL 
Diphtheria 
1117 
95.1 
95.0 
0.11 
2.53 
2.76 

1864 
87.4 
83.4 
4.02 
0.01 
8.04 

1164 
91.0 
88.8 
2.20 
0.28 
4.69 
Tetanus 
1117 
91.7 
91.3 
0.37 
3.02 
3.76 

1864 
63.1 
66.8 
3.72 
9.09 
1.64 

1164 
76.3 
78.1 
1.83 
5.11 
1.45 
* PerProtocol Immunogenicity Population is defined
as all participants who were
randomized, received assigned vaccine, and were bled
to have the data according to the protocol.
Statistical comparisons of diphtheria and tetanus GMCs using
the 95% confidence interval for the GMC ratio between Tdap vaccine and Td
vaccine showed noninferiority of Tdap vaccine to Td vaccine. Table 6 below
shows that the lower limits (LCL) of the 95% CIs of GMC ratios 1month
postvaccination 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 GMC 
Td GMC2 
GMC Ratio 
LCL 
UCL 
Diphtheria 
1117 
8.462 
7.096 
1.19 
1.03 
1.39 

1864 
2.487 
2.368 
1.05 
0.86 
1.29 

1164 
4.137 
4.119 
1.12 
0.98 
1.27 
Tetanus 
1117 
12.869 
14.346 
0.90 
0.84 
0.96 

1864 
7.651 
8.179 
0.94 
0.86 
1.01 

1164 
9.495 
10.853 
0.92 
0.87 
0.97 
* PerProtocol Immunogenicity Population is defined as all participants who were
randomized, received assigned vaccine, and were bled to have the data according to the protocol.
As per the primary hypothesis 2a that the pertussis immune responses to Tdap vaccine are noninferior 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
Antigens 
Time 
Tdap Td506 Trial 
DAPTACEL
Sweden I Efficacy Trial 
Tdap vs. DAPTACEL 

n 
GMC 
n 
GMC 
GMC Ratio 
95% CI 

PT (EU/mL)

Pre
Post 
527 524 
14.46 309.26 
80 80 
5.24 86.55

2.76 3.57 
(2.06, 3.70) (2.83, 4.52) 
FHA
(EU/mL)

Pre
Post 
527 526 
19.49 214.83 
80 80 
5.21 39.95

3.74 5.38 
(2.81, 4.99) (4.46, 6.49) 
FIM
(EU/mL)

Pre
Post 
527 526 
25.80 1792.40 
80 80 
13.26 341.10 
1.94 5.25 
(1.52, 2.50) (3.90, 7.09) 
PRN
(EU/mL)

Pre
Post 
526 526 
10.01 344.52 
80 80 
2.15 108.12 
4.67 3.19 
(3.46, 6.30) (2.48, 4.10) 
* PerProtocol 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 1864 Years, PPI Population*) and DAPTACEL in the Sweden I Efficacy Trial
Antigens 
Time 
Tdap Td506 Trial 
DAPTACEL
Sweden I Efficacy Trial 
Tdap vs. DAPTACEL 

n 
GMC 
n 
GMC 
GMC Ratio 
95% CI 

PT (EU/mL) 
Pre Post 
741 741 
12.54 178.84 
80 80 
5.24 86.55

2.39 2.07 
(1.80, 3.18) (1.58, 2.70) 
FHA (EU/mL) 
Pre Post 
741 741 
18.13 192.91 
80 80 
5.21 39.95

3.48 4.83 
(2.68, 4.52) (3.94, 5.92) 
FIM (EU/mL) 
Pre Post 
741 741 
28.56 852.72 
80 80 
13.26 341.10 
2.15 2.50 
(1.63, 2.84) (1.77, 3.54) 
PRN (EU/mL) 
Pre Post 
741 741 
8.45 341.89 
80 80 
2.15 108.12 
3.94 3.16 
(2.89, 5.36) (2.25, 4.44) 
* PerProtocol Immunogenicity
Population is defined as all participants who were randomized, received
assigned vaccine, and were bled to have the data according to the protocol.
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 predefined 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 in Years 
Group 
1 Month PostVaccination 

M 
n 
% 
LCL 
UCL 

PT (EU/mL) 
1117 
Tdap Td 
524 515 
482 14 
92.0 2.7 
89.3 1.5 
94.2 4.5 
1864 
Tdap 
739 
624 
84.4 
81.6 
87.0 



Td 
508 
11 
2.2 
1.1 
3.8 
FHA (EU/mL) 
1117 
Tdap Td 
526 515 
450 11 
85.6 2.1 
82.3 1.1 
88.4 3.8 
1864 
Tdap 
739 
611 
82.7 
79.8 
85.3 



Td 
508 
11 
2.2 
1.1 
3.8 
FIM (EU/mL) 
1117 
Tdap Td 
526 515 
499 18 
94.9 3.5 
92.6 2.1 
96.6 5.5 
1864 
Tdap 
739 
635 
85.9 
83.2 
88.4 



Td 
508 
11 
2.2 
1.1 
3.8 
PRN (EU/mL) 
1117 
Tdap Td 
525 515 
496 12 
94.5 2.3 
92.2 1.2 
96.3 4.0 
1864 
Tdap 
739 
693 
93.8 
91.8 
95.4 



Td 
508 
15 
3.0 
1.7 
4.8 
M = Number evaluated, used for
calculating the percent.
n = Number of subjects with a
post/pretiter greater than the prespecified level.
% = n/M
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 prespecified criteria. There are no major statistical issues regarding this study.
Title: “Safety and Immunogenicity of Three Lots of Tetanus and Diphtheria Toxoids Adsorbed Combined with Component Pertussis (TdcP) Vaccine in Adolescents 1117 Years of Age”
This was a Phase 3, randomized, controlled, doubleblind, 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).
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.
The antipertussis [PT, FHA, FIM, PRN], antidiphtheria toxin, and antitetanus 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 twosided 95% CIs on the difference in postvaccination seroprotection rates and booster rates between each 2 lots were within the interval (10%, 10%), and the twosided 90% confidence intervals (CIs) on postvaccination GMC ratios were within the interval (0.66, 1.5), it was concluded that the lots are consistent.
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
· 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 inhouse  programs.
Table 1: Primary Endpoints, Historical Values (Targeted Response Levels) for Diphtheria, Tetanus, PT, FHA, FIM, and PRN
Antigen 
Primary Endpoints 
Historical Values/Targeted Response Level (95% CI) 
Power ^{1} 

=0.10 
=0.05 

Diphtheria IU/mL 
% ≥0.10 
95.0% 
>99% 
>99% 
Tetanus IU/mL 
% ≥0.10 
99% 
>99% 
>99% 
PT (EU/mL) 
GMC 
144 95% CI, (132, 157) N=445 
>99% 
 
FHA (EU/mL) 
GMC 
328 95% CI, (302, 356) N=446 
>99% 
 
FIM (EU/mL) 
GMC 
995 95% CI, (883, 1121) N=446 
97.22% 
 
PRN (EU/mL) 
GMC 
279 95% CI, (241, 322) N=446 
83.36% 
 
^{1} Twosided 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 } 

=0.10 
=0.05 

Diphtheria IU/mL 
% booster response 
92.9% 
 
99% 
Tetanus IU/mL 
% booster response 
81.6% 
 
70% 


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, 28.72) 
>99% 
 


N=326 


^{1} The prevaccination 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 prevaccination
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} Twosided
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 Level^{1}

Power^{2} 

=0.10 
=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} Twosided α.
Change in Statistical Analysis
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. Cutoff 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 sitetosite testing concordance.
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 consistency among the lots, statistical testing between 2 lots by the equivalence approach was performed using twosided 95% confidence intervals on the difference in rates and twosided 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 twosided 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 twosided 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 chisquare 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
Three analysis populations were used in this study. The intenttotreat 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 intenttotreat 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 perprotocol 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
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 PerProtocol Immunogenicity (PPI) population. Lots were determined to be consistent if the twosided 90% confidence intervals for Lot 1/Lot 2, Lot 1/Lot 3, and Lot 2/Lot 3 postvaccination GMC ratios were within the boundaries of (0.67, 1.5) and the 2sided 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
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 014 for the IntenttoTreat Safety population. Per the secondary study hypothesis, if the twosided 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
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 IntenttoTreat Safety (ITTS) population, and a subset of these (1175) were bled for immunogenicity assessment in the intenttotreat immunogenicity (ITTI) population. A total of 10.1% (119/1175) participants were excluded from the perprotocol 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 –
IntenttoTreat Safety Population
ITTI –
IntenttoTreat Immunogenicity Population
PPI –
PerProtocol Immunogenicity Population
Comparisons of Seroprotection Rates of Diphtheria and Tetanus Toxoids
The primary hypothesis states that the antidiphtheria toxin and antitetanus 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 1month postvaccination 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 Vaccination 

Rate1 % 
Rate2 % 
Diff % 
LCL 
UCL 

Diphtheria 
Tdap1 vs. Tdap2 Tdap1 vs. Tdap3 
100.0 100.0 
99.4 99.7 
0.57 0.28 
0.22 0.50 
1.36 1.07 

Tdap2 vs. Tdap3 
99.4 
99.7 
0.29 
1.08 
0.50 
Tetanus 
Tdap1 vs. Tdap2 
100.0 
100.0 
–– 
–– 
–– 

Tdap1 vs. Tdap3 
100.0 
100.0 
–– 
–– 
–– 

Tdap2 vs. Tdap3 
100.0 
100.0 
–– 
–– 
–– 
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 twosided 95% confidence interval for the difference in rates.
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 1month postvaccination booster rates between any 2 lots are within the interval (10%, 10%).
Table 6: Comparison of Booster Response Rates
Antigen 
Comparison 
1 Month PostVaccination 

Rate1
% 
Rate2
% 
Diff
% 
LCL 
UCL 

Diphtheria

Tdap1
vs. Tdap2 Tdap1 vs. Tdap3 
96.0 96.0 
95.7 94.9 
0.31 1.11 
2.75 1.94 
3.37 4.16 

Tdap2
vs. Tdap3 
95.7 
94.9 
0.80 
2.25 
3.86 
Tetanus

Tdap1
vs. Tdap2 
92.6 
93.7 
1.12 
4.99 
2.74 

Tdap1
vs. Tdap3 
92.6 
91.8 
0.79 
3.06 
4.64 

Tdap2
vs. Tdap3 
93.7 
91.8 
1.91 
1.94 
5.77 
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 1month postvaccination 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 Month PostVaccination 

GMC1

GMC2

GMC
Ratio 
90% CI 
95% CI 

LCL 
UCL 
LCL 
UCL 

Diphtheria

Tdap1
vs. Tdap2 Tdap1 vs. Tdap3 
7.74 7.74 
7.16 7.52 
1.08 1.03 
0.96 0.91 
1.22 1.16 
0.94 0.89 
1.25 1.18 

Tdap2
vs. Tdap3 
7.16 
7.52 
0.95 
0.85 
1.07 
0.83 
1.10 
Tetanus

Tdap1
vs. Tdap2 
16.27 
16.72 
0.97 
0.91 
1.04 
0.90 
1.06 

Tdap1
vs. Tdap3 
16.27 
17.22 
0.95 
0.88 
1.01 
0.87 
1.03 

Tdap2
vs. Tdap3 
16.72 
17.22 
0.97 
0.91 
1.04 
0.89 
1.05 
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 twosided confidence interval for the GMC ratio.
The primary hypothesis states that the antipertussis – 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 onemonth postvaccination GMC ratios between any 2 lots are within the equivalence margins (0.67, 1.5). For FIM, the 90% CIs for the onemonth 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 PostVaccination 

GMC1 
GMC2 
GMC Ratio 
90% CI 
95% CI 

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
twosided confidence interval for the GMC ratio.
FourFold Response Rates of Pertussis Antigens
As part of the additional evaluation of lot consistency, fourfold response rates for the pertussis antigens onemonth postvaccination were analyzed for the PPI population. Most participants achieved fourfold rise in titer to all antigens at onemonth postvaccination: 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 4fold 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: FourFold Rates
Antigen 
Comparison 
1 Month PostVaccination 

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 
Table 10: Erythema (Redness), Swelling, and Pain: Comparison of Rates Between Groups (ITTS Population), Days 0–14
Adverse Event 
Groups Compared 
Any 
Moderate & Severe 

Rate 1% 
Rate 2 % 
Diff % 
LCL 
UCL 
Rate 1 % 
Rate 2 % 
Diff % 
LCL 
UCL 

Erythema (Redness) 
Tdap1 vs. Tdap2 Tdap1 vs.
Tdap3 
23.66 23.66 
24.21 25.08 
0.55 1.43 
5.41 6.29 
4.32 3.44 
12.08 12.08 
11.02 11.37 
1.06 0.71 
2.55 2.91 
4.68 4.33 

Tdap2 vs. Tdap3 
24.21 
25.08 
0.88 
5.74 
3.98 
11.02 
11.37 
0.35 
3.97 
3.26 
Swelling 
Tdap1 vs. Tdap2 
20.97 
22.20 
1.23 
5.97 
3.51 
13.59 
12.85 
0.74 
3.29 
4.77 

Tdap1 vs. Tdap3 
20.97 
24.41 
3.44 
8.18 
1.30 
13.59 
18.06 
4.47 
8.50 
0.44 

Tdap2 vs. Tdap3 
22.20 
24.41 
2.21 
6.94 
2.52 
12.85 
18.06 
5.21 
9.23 
1.18 
Pain 
Tdap1 vs. Tdap2 
80.70 
78.80 
1.91 
2.64 
6.45 
20.97 
20.87 
0.11 
4.63 
4.84 

Tdap1 vs. Tdap3 
80.70 
80.27 
0.44 
4.11 
4.98 
20.97 
25.75 
4.78 
9.52 
0.04 

Tdap2 vs. Tdap3 
78.80 
80.27 
1.47 
6.01 
3.07 
20.87 
25.75 
4.88 
9.62 
0.15 
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 twosided 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.
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 prespecified criteria, except for a few comparisons noted above. In the safety analysis, comparisons of local adverse event rates are within the prespecified 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 twosided 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 2sided 90% confidence intervals. In this latter case, the alpha (significance ) level is 5%, not 10%, due to the intersectionunion nature of equivalence testing.