# FDA Statistical Review and Evaluation

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

September 22, 2004

**Menactra, Meningococcal (Groups A, C, Y, and W135) Polysaccharide**

> **Diphtheria Toxoid Conjugate Vaccine**
>
> **Indication: active immunization of adolescents and adults 11 to 55
> years of age for prevention of invasive meningococcal disease caused
> by *N. meningitidis* serogroups A, C, Y, and W-135.**

**Jingyee Kou, Ph.D.**

FDA/CBER/OBE

**[1. Introduction]{.underline}**

In the application for licensure, Aventis Pasteur (AP) has submitted
information from several clinical trials. In these trials, AP used the
name TetraMenD for this product. It will be the name used in this report
as well.

In order to infer efficacy based on immune response, the primary
immunogenicity hypothesis was non-inferiority of TetraMenD conjugate
vaccine with respect to Menomune polysaccharide vaccine, as measured by
the percentage of participants with a 4-fold rise in serum bactericidal
assay with baby rabbit complement (SBA-BR) titer. The data are in the
form of reciprocal serum dilutions.

The criteria used by AP in demonstrating non-inferiority is that the
upper limit of the two-sided 95% confidence interval of the difference
between the two groups in the proportions of subjects presenting a
4-fold rise from baseline in SBA-BR titers (proportion in Menomune minus
the proportion in TetraMenD) being less than 10 percentage points.

**[2. Comparison of SBA-BR and SBA-HC]{.underline}**

Since the current standard for seroprotection is based on the serum
bactericidal assay with human complement (SBA-HC) titers 1:4 or HC
titers 1:8 for serogroup C, AP has provided the results of a
supplemental study in which the two assay methods were performed on sera
from subsets of subjects from two clinical trials: MTA02 (11 to 18 yrs)
and MTA09 (18 to 55 yrs).

In the original submission, AP presented results of the primary analyses
using geometric mean titer (GMTs), reverse cumulative distribution
curves (RCDC), and seroprotection rates for serogroups C, Y, and W-135.
The results of serogroup A are submitted later in an amendment to the
original BLA submission.

Note: The values of HC titers in serogroups C, Y, and W-135 are
multiples of 2. However, perhaps due to interpolation, the values of HC
titers in serogroup A were not multiples of 2, thus unlike those of
other serogroups.

**[2.1. AP's Results]{.underline}**

-   Seroprotection Rates:

Table 2.1.1. Comparison of SBA-BR 4-fold Rise in Titer with SBA-HC Titer
on Day 28 for Subjects with Both Measurements in all Serogroups in
Studies MTA02 and MTA09.

+--------+----------+--------+--------+----------+--------+--------+
| Study  | Menomune |        |        | T        |        |        |
| &      |          |        |        | etraMenD |        |        |
|        |          |        |        |          |        |        |
| Ser    |          |        |        |          |        |        |
| ogroup |          |        |        |          |        |        |
+--------+----------+--------+--------+----------+--------+--------+
|        | SBA-BR   | SBA-HC |        | SBA-BR   | SBA-HC |        |
+--------+----------+--------+--------+----------+--------+--------+
|        | 4-fold   | Titer  | Titer  | 4-fold   | Titer  | Titer  |
|        | Rise     | 1:4    | 1:8    | Rise     | 1:4    | 1:8    |
+--------+----------+--------+--------+----------+--------+--------+
| 02A    | 51/52    | 50/52  | 46/52  | 44/50    | 47/50  | 40/50  |
|        |          |        |        |          |        |        |
|        | (98%)    | (96%)  | (88%)  | (88%)    | (94%)  | (80%)  |
+--------+----------+--------+--------+----------+--------+--------+
| 02C    | 73/81    | 70/81  | 62/81  | 75/84    | 79/84  | 77/84  |
|        |          |        |        |          |        |        |
|        | (90%)    | (86%)  | (77%)  | (89%)    | (94%)  | (92%)  |
+--------+----------+--------+--------+----------+--------+--------+
| 02Y    | 50/62    | 59/62  | 59/62  | 61/65    | 61/65  | 61/65  |
|        |          |        |        |          |        |        |
|        | (81%)    | (95%)  | (95%)  | (94%)    | (94%)  | (94%)  |
+--------+----------+--------+--------+----------+--------+--------+
| 09Y    | 36/50    | 50/50  | 50/50  | 40/50    | 48/50  | 48/50  |
|        |          |        |        |          |        |        |
|        | (72%)    | (100%) | (100%) | (80%)    | (96%)  | (96%)  |
+--------+----------+--------+--------+----------+--------+--------+
| 02W    | 56/58    | 54/58  | 53/58  | 59/61    | 60/61  | 58/61  |
|        |          |        |        |          |        |        |
|        | (97%)    | (93%)  | (91%)  | (97%)    | (98%)  | (95%)  |
+--------+----------+--------+--------+----------+--------+--------+
| 09W    | 47/50    | 50/50  | 49/50  | 48/50    | 50/50  | 49/50  |
|        |          |        |        |          |        |        |
|        | (94%)    | (100%) | (98%)  | (96%)    | (100%) | (98%)  |
+--------+----------+--------+--------+----------+--------+--------+

Table 2.1.2. Seroprotection Rates for the Naïve Subjects (subjects with
baseline SBA-HC titers \< 1:4) of the Subset with Both Titer Values.

+--------+----------+--------+--------+----------+--------+--------+
| Study  | Menomune |        |        | T        |        |        |
| &      |          |        |        | etraMenD |        |        |
|        |          |        |        |          |        |        |
| Ser    |          |        |        |          |        |        |
| ogroup |          |        |        |          |        |        |
+--------+----------+--------+--------+----------+--------+--------+
|        | SBA-BR   | SBA-HC |        | SBA-BR   | SBA-HC |        |
+--------+----------+--------+--------+----------+--------+--------+
|        | 4-fold   | Titer  | Titer  | 4-fold   | Titer  | Titer  |
|        | Rise     | 1:4    | 1:8    | Rise     | 1:4    | 1:8    |
+--------+----------+--------+--------+----------+--------+--------+
| 02A    | 11/11    | 10/11  | 9/11   | 12/12    | 11/12  | 8/12   |
|        |          |        |        |          |        |        |
|        | (100%)   | (91%)  | (82%)  | (100%)   | (92%)  | (67%)  |
+--------+----------+--------+--------+----------+--------+--------+
| 02C    | 56/62    | 51/62  | 43/62  | 54/57    | 52/57  | 50/57  |
|        |          |        |        |          |        |        |
|        | (90%)    | (82%)  | (69%)  | (95%)    | (91%)  | (88%)  |
+--------+----------+--------+--------+----------+--------+--------+
| 02Y    | 35/39    | 36/39  | 36/39  | 38/41    | 38/41  | 38/41  |
|        |          |        |        |          |        |        |
|        | (90%)    | (92%)  | (92%)  | (93%)    | (93%)  | (93%)  |
+--------+----------+--------+--------+----------+--------+--------+
| 09Y    | 15/17    | 17/17  | 17/17  | 18/18    | 16/18  | 16/18  |
|        |          |        |        |          |        |        |
|        | (88%)    | (100%) | (100%) | (100%)   | (89%)  | (89%)  |
+--------+----------+--------+--------+----------+--------+--------+
| 02W    | 23/23    | 19/23  | 18/23  | 21/22    | 21/22  | 19/22  |
|        |          |        |        |          |        |        |
|        | (100%)   | (83%)  | (78%)  | (95%)    | (95%)  | (86%)  |
+--------+----------+--------+--------+----------+--------+--------+
| 09W    | 8/9      | 9/9    | 8/9    | 8/8      | 8/8    | 8/8    |
|        |          |        |        |          |        |        |
|        | (89%)    | (100%) | (89%)  | (100%)   | (100%) | (100%) |
+--------+----------+--------+--------+----------+--------+--------+

-   Geometric Mean Titers (GMTs):

Table 2.1.3. Comparison of the Geometric Mean Titers (GMTs) on Day 28
for Serogroup A from Subjects who Had Both Measurements.

  -------- ---------- --------- ----------------- ----------- --------- -----------------
  02A      Menomune                               TetraMenD             

           N          GMT       95% CI            N           GMT       95% CI

  Day 0    52         51.71     28.19, 94.86      50          119.43    67.31, 211.91

  Day 28   52         2568.88   1848.85, 3569.32  50          4096.00   3087.71, 5433.55
  -------- ---------- --------- ----------------- ----------- --------- -----------------

-   Reverse Cumulative Distribution Curves (RCDCs):

Please see the Appendix for RCDC figures from AP's documents.

**[2.2 AP's Conclusion]{.underline}**

1\. For serogroups C, Y, and W-135:

-   The concordance observed in the bactericidal response patterns
    between the human complement assay (SBA-HC) results and the rabbit
    complement assay (SBA-BR) results in a subset comparison confirms
    the reliability of the SBA-BR for evaluating protective immune
    responses to serogroups C, Y, and W-135 meningococcal vaccines.

```{=html}
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```
-   A comparison of the rate of 4-fold rise in titer by SBA-BR to the
    rate of achieving a titer of 1:4 by SBA-HC between the TetraMenD and
    Menomune groups was favorably demonstrated for serogroups C, W-135,
    and Y.

-   Both sets of RCDCs (SBA-BR and SBA-HC) overlap for the two vaccine
    groups from both clinical results for serogroups C, Y, and W-135.

-   The agreement in the seroconversion rates measured by the fold rise
    in SBA-BR titers to the proportion of subjects having
    post-vaccination titers above the putative protective level ( 1:4 or
    more conservatively 1:8), coupled to the overlapping RCDC (SBA-BR
    and SBA-HC) provides strong evidence that the SBA-BR yields reliable
    results for assessing non-inferiority between the TetraMenD
    conjugate vaccine and the licensed polysaccharide vaccine Menomune.

2\. For serogroup A:

-   The proportion of subjects achieving a 4-fold rise in titer by
    SBA-BR was similar to the proportion of subjects achieving a titer
    of 1:4 by SBA-HC between the TetraMenD and Menomune groups for
    serogroup A.

-   Both sets of Day 28 RCDCs (SBA-BR and SBA-HC) have a similar profile
    for the two vaccine groups for serogroup A.

-   The agreement in the seroconversion rates measured by the fold rise
    in SBA-BR titers to the proportion of subject having
    post-vaccination titers above the putative protective level (SBA-HC
    titer 1:4), coupled to the similar RCDCs (SBA-BR and SBA-HC)
    provides strong evidence that the SBA-BR yields relevant results for
    assessing non-inferiority between the TetraMenD conjugate vaccine
    and the licensed polysaccharide vaccine Menomune for response to
    serogroup A.

-   By analogy with the correlate of immunity established for serogroup
    C, these data provide support for extrapolation of AP results
    demonstrateing a 4-fold rise in SBA-BR titer to protection against
    serogroup A.

**[2.3. Reviewer's Comments on AP's Results]{.underline}**

1.  The reverse cumulative distribution curves (RCDCs) were provided and
    they are included as an attachment. The conclusions drawn from these
    RCDCs are by visual comparisons only.

2.  The results presented are all descriptive in nature. No statistical
    analysis was provided by AP.

**[2.4. Reviewer's Analyses]{.underline}**

-   Seroprotection Rates:

Table 2.4.1. Results from an Analysis of Differences in the
Seroprotection Rates between Menomune and TetraMenD from all Three
Criteria^\*^

+-----+--------+---+---------+---+---------+-----+------+------------+
| St  | Cr     | M |         | T |         | D   | p-v  | 95% CI     |
| udy | iteria | e |         | e |         | iff | alue |            |
|     |        | n |         | t |         |     |      |            |
|     |        | o |         | r |         | (M  |      |            |
|     |        | m |         | a |         | -T) |      |            |
|     |        | u |         | M |         |     |      |            |
|     |        | n |         | e |         |     |      |            |
|     |        | e |         | n |         |     |      |            |
|     |        |   |         | D |         |     |      |            |
+-----+--------+---+---------+---+---------+-----+------+------------+
|     |        | N | Pro     | N | Pro     |     |      |            |
|     |        |   | portion |   | portion |     |      |            |
+-----+--------+---+---------+---+---------+-----+------+------------+
| 02A | B      | 5 | 0.98    | 5 | 0.88    | 0   | 0    | -0.002,    |
|     | R4fold | 2 |         | 0 |         | .10 | .054 | 0.224      |
+-----+--------+---+---------+---+---------+-----+------+------------+
|     | HC1:4  | 5 | 0.96    | 5 | 0.94    | 0   | 0    | -0.078,    |
|     |        | 2 |         | 0 |         | .02 | .723 | 0.132      |
+-----+--------+---+---------+---+---------+-----+------+------------+
|     | HC1:8  | 5 | 0.88    | 5 | 0.80    | 0   | 0    | -0.067,    |
|     |        | 2 |         | 0 |         | .08 | .270 | 0.240      |
+-----+--------+---+---------+---+---------+-----+------+------------+
| 02C | B      | 8 | 0.90    | 8 | 0.89    | 0   | 0    | -0.091,    |
|     | R4fold | 1 |         | 4 |         | .01 | .924 | 0.108      |
+-----+--------+---+---------+---+---------+-----+------+------------+
|     | HC1:4  | 8 | 0.86    | 8 | 0.94    | -0  | 0    | -0.177,    |
|     |        | 1 |         | 4 |         | .08 | .106 | 0.017      |
+-----+--------+---+---------+---+---------+-----+------+------------+
|     | HC1:8  | 8 | 0.77    | 8 | 0.92    | -0  | 0    | -0.267,    |
|     |        | 1 |         | 4 |         | .15 | .008 | -0.031     |
+-----+--------+---+---------+---+---------+-----+------+------------+
| 02Y | B      | 6 | 0.81    | 6 | 0.94    | -0  | 0    | -0.260,    |
|     | R4fold | 2 |         | 5 |         | .13 | .026 | -0.015     |
+-----+--------+---+---------+---+---------+-----+------+------------+
|     | HC1:4  | 6 | 0.95    | 6 | 0.94    | 0   | 0    | -0.080,    |
|     |        | 2 |         | 5 |         | .01 | .834 | 0.110      |
+-----+--------+---+---------+---+---------+-----+------+------------+
|     | HC1:8  | 6 | 0.95    | 6 | 0.94    | 0   | 0    | -0.080,    |
|     |        | 2 |         | 5 |         | .01 | .834 | 0.110      |
+-----+--------+---+---------+---+---------+-----+------+------------+
| 09Y | B      | 5 | 0.72    | 5 | 0.80    | -0  | 0    | -0.251,    |
|     | R4fold | 0 |         | 0 |         | .08 | .508 | 0.091      |
+-----+--------+---+---------+---+---------+-----+------+------------+
|     | HC1:4  | 5 | 1.00    | 5 | 0.96    | 0   | 0    | -0.034,    |
|     |        | 0 |         | 0 |         | .04 | .209 | 0.137      |
+-----+--------+---+---------+---+---------+-----+------+------------+
|     | HC1:8  | 5 | 1.00    | 5 | 0.96    | 0   | 0    | -0.034,    |
|     |        | 0 |         | 0 |         | .04 | .209 | 0.137      |
+-----+--------+---+---------+---+---------+-----+------+------------+
| 02W | B      | 5 | 0.97    | 6 | 0.97    | -0  | 1    | -0.090,    |
|     | R4fold | 8 |         | 1 |         | .00 | .000 | 0.083      |
+-----+--------+---+---------+---+---------+-----+------+------------+
|     | HC1:4  | 5 | 0.93    | 6 | 0.98    | -0  | 0    | -0.152,    |
|     |        | 8 |         | 1 |         | .05 | .159 | 0.029      |
+-----+--------+---+---------+---+---------+-----+------+------------+
|     | HC1:8  | 5 | 0.91    | 6 | 0.95    | -0  | 0    | -0.146,    |
|     |        | 8 |         | 1 |         | .04 | .549 | 0.063      |
+-----+--------+---+---------+---+---------+-----+------+------------+
| 09W | B      | 5 | 0.94    | 5 | 0.96    | -0  | 0    | -0.130,    |
|     | R4fold | 0 |         | 0 |         | .02 | .751 | 0.084      |
+-----+--------+---+---------+---+---------+-----+------+------------+
|     | HC1:4  | 5 | 1.00    | 5 | 1.00    | 0   | 1    | -0.073,    |
|     |        | 0 |         | 0 |         | .00 | .000 | 0.072      |
+-----+--------+---+---------+---+---------+-----+------+------------+
|     | HC1:8  | 5 | 0.98    | 5 | 0.98    | 0   | 1    | -0.088,    |
|     |        | 0 |         | 0 |         | .00 | .000 | 0.088      |
+-----+--------+---+---------+---+---------+-----+------+------------+

^\*^ P-values and exact 2-sided 95% confidence intervals (CI) obtained
from the \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-- software.

[Comments:]{.underline}

1.  In non-inferiority comparisons, the upper confidence bounds of the
    95% CI are required to be within 10 percentage points. However, the
    sample size is not sufficient for testing the non-inferiority
    hypothesis with regard to the two assay methods.

2.  Except for serogroup A, the upper bounds of the 95% CI on the
    difference in proportions are under 15%.

3.  Except for serogroup Y in study MTA02, all results show general
    agreement between the conclusions drawn from HC or BR assays.

-   Geometric Mean Titers:

Table 2.4.2. GMTs for Both Methods and for All 4 Serogroups^\*^

\(a\) SBA-BR

  ------- ------- ---------- --------- ---------------- ----------- --------- ----------------
  Study           Menomune                              TetraMenD             

                  N          GMT       95% CI           N           GMT       95% CI

  02A     Day 0   52         51.71     27.77, 96.27     50          119.43    66.34, 215.00

          Day 28  52         2568.88   1834.13, 3597.96 50          4096.00   3065.70, 5472.55

  02C     Day 0   81         39.30     24.82, 62.21     84          30.96     20.03, 47.86

          Day 28  81         1682.10   1219.37, 2320.43 84          1736.42   1265.44, 2382.70

  02Y     Day 0   62         125.17    86.08, 182.01    65          77.54     49.86, 120.59

          Day 28  62         1184.18   893.43, 1569.57  65          1471.50   1053.54, 2055.29

  09Y     Day 0   50         85.63     43.99, 166.68    50          133.44    76.50, 232.75

          Day 28  50         1428.22   862.98, 2363.67  50          1910.85   1215.42, 3004.18

  02W     Day 0   58         30.51     20.28, 45.88     61          26.38     17.28, 40.26

          Day 28  58         1364.16   974.57, 1909.48  61          1345.05   998.88, 1811.18

  09W     Day 0   50         39.40     24.15, 64.27     50          29.04     18.58, 45.40

          Day 28  50         2225.63   1589.13, 3117.07 50          1640.59   1200.94, 2241.19
  ------- ------- ---------- --------- ---------------- ----------- --------- ----------------

\(b\) SBA-HC

  ------- -------- ---------- -------- --------------- ----------- -------- --------------
  Study            Menomune                            TetraMenD            

                   N          GMT      95% CI          N           GMT      95% CI

  02A     Day 0    52         6.25     4.80, 8.15      50          5.86     4.58, 7.48

          Day 28   52         18.65    14.27, 24.38    50          17.88    13.35, 23.94

  02C     Day 0    81         2.44     2.24, 2.65      84          2.71     2.44, 3.02

          Day 28   81         29.88    19.38, 46.09    84          46.39    32.20, 66.83

  02Y     Day 0    62         6.26     4.06, 9.63      65          5.57     3.85, 8.04

          Day 28   62         108.24   70.52, 166.13   65          118.79   75.63, 186.58

  09Y     Day 0    50         21.11    11.67, 38.20    50          18.64    10.81, 32.13

          Day 28   50         216.77   132.59, 354.39  50          139.10   89.20, 216.92

  02W     Day 0    58         14.54    8.62, 24.52     61          15.46    9.58, 24.96

          Day 28   58         89.43    58.37, 137.03   61          79.42    55.89, 112.86

  09W     Day 0    50         21.41    13.43, 34.11    50          27.47    17.18, 43.94

          Day 28   50         85.63    59.32, 123.61   50          99.73    66.11, 150.46
  ------- -------- ---------- -------- --------------- ----------- -------- --------------

^\*^ For serogroup A, the values for the 95% CI obtained from the
\-\-\-\-\-\-- software are different from those provided by AP. This
difference is due to \-\-\-\-\-\-- using the t-distribution instead of
the normal distribution in calculating the confidence intervals.

-   Analysis of Covariance on GMTs with Treatment and Baseline as
    Covariates:

Table 2.4.3. Results of Analysis of Covariance Performed on the Log
(Base 2) Transformed Titers with Treatment group and Transformed
Baseline Titers as Covariates^\*^

  ------- ------- ----------- ----------- ---------- --------- ---------- ---------------
  Study   Assay   Covariate   Coeff.^1^   95% CI     p-value   Ratio^2^   95% CI of
                                                                          ratio^3^

  02A     BR      Treatment   -0.46       -1.07,     0.14      0.73       0.47, 0.90
                                          0.15                            

                  Baseline    0.18        0.08, 0.27 0.00                 

          HC      Treatment   0.01        -0.49,     0.96      1.09       0.71, 1.43
                                          0.51                            

                  Baseline    0.51        0.32, 0.70 0.00                 

  02C     BR      Treatment   -0.12       -0.74,     0.70      0.92       0.60, 1.41
                                          0.49                            

                  Baseline    0.22        0.12, 0.33 0.00                 

          HC      Treatment   -0.45       -1.23,     0.26      0.73       0.42, 1.26
                                          0.33                            

                  Baseline    1.19        0.57, 1.81 0.00                 

  02Y     BR      Treatment   -0.55       -1.12,     0.06      0.68       0.46, 1.01
                                          0.02                            

                  Baseline    0.34        0.22, 0.46 0.00                 

          HC      Treatment   -0.19       -1.04,     0.66      0.88       0.48, 1.58
                                          0.66                            

                  Baseline    0.34        0.15, 0.52 0.00                 

  09Y     BR      Treatment   -0.20       -1.07,     0.66      0.87       0.48, 1.60
                                          0.68                            

                  Baseline    0.35        0.21, 0.49 0.00                 

          HC      Treatment   0.58        -0.28,     0.18      1.49       0.82, 2.70
                                          1.43                            

                  Baseline    0.36        0.21, 0.51 0.00                 

  02W     BR      Treatment   -0.05       -0.63,     0.86      0.96       0.65, 1.44
                                          0.52                            

                  Baseline    0.34        0.21, 0.46 0.00                 

          HC      Treatment   0.20        -0.48,     0.55      1.15       0.72, 1.85
                                          0.89                            

                  Baseline    0.39        0.26, 0.51 0.00                 

  09W     BR      Treatment   0.36        -0.28,     0.27      1.28       0.82, 1.99
                                          0.99                            

                  Baseline    0.19        0.06, 0.32 0.01                 

          HC      Treatment   -0.08       -0.78,     0.82      0.94       0.58, 1.54
                                          0.62                            

                  Baseline    0.38        0.23, 0.53 0.00                 
  ------- ------- ----------- ----------- ---------- --------- ---------- ---------------

^\*^ The analysis was performed with the software Stata version-8.

Notes:

1.  The coefficient for treatment was calculated using TetraMenD as the
    reference. It is equivalent to testing the difference of the mean
    log base 2 titer of Menomune minus the mean log base 2 titer of
    TetraMenD, after adjusting for the baseline titers.

2.  The ratios were calculated by taking the antilog (base 2) of the
    coefficients for treatment from the ANCOVA results.

3.  The 95% confidence limits for the ratios were obtained by taking the
    antilog (base 2) of the 95% confidence limits on the treatment
    coefficients.

4.  From the results above, it is clear that the baseline titer plays an
    important role in predicting the final titer for a subject (baseline
    p-values are all very small).

5.  Again, because of how the ratios were defined, only the upper
    confidence limits are used to evaluate non-inferiority of Menomune
    compared to TetraMenD. The upper bounds on the ratios of Menomune to
    TetraMenD are all under 2, except for study 09 with the HC assay,
    where the upper bound is 2.70.

-   Sensitivity and Specificity: a Paired Analysis

In general, when a new method is compared to a "gold standard",
sensitivity is the proportion of the subjects correctly classified as
"positive" by the new method among the group of subjects defined as
"positive" by the "gold standard." Specificity is the proportion of the
subjects correctly classified as "negative" by the new method among the
group of subjects defined as "negative" by the "gold standard." When
sensitivity and specificity are both one, it means the new method is
exactly as good as the "gold standard."

To compare the BR and HC methods using paired data, sensitivity and
specificity of the BR assay was investigated by treating the HC assay as
the "gold standard." In this setting, sensitivity of the BR assay is the
proportion of the subjects who are classified as seroprotected by the BR
method out of the ones classified as seroprotected by the HC method.
Specificity is the proportion of the subjects who are classified as not
seroprotected by the BR method out of the ones classified as not
seroprotected by the HC method.

It is difficult to interpret the cases of 0/0, which indicates that no
subject is classified in that category by either method. Such result
could be due to the small sample sizes of these studies.

Table 2.4.4 Results from Direct Comparison of SBA-BR to SBA-HC using
SBA-HC as the "Gold Standard" (includes comparisons of the BR 4-fold
rise with HC 1:4 and HC 1:8 at day 28, as well as comparisons of BR
1:128, BR 1:256 with HC 1:4, HC 1:8 at both day 0 and day 28)

\(a\) BR 4-fold rise vs HC 1:4 at day 28

+---------+------------+------------+---------+------------+---------+
| Study   | Vaccine    | BR+        | Sens    | BR-        | Spec    |
|         |            |            | itivity |            | ificity |
|         |            | within HC+ |         | within HC- |         |
+---------+------------+------------+---------+------------+---------+
| 02A     | Menomune   | 49/50      | 0.98    | 0/2        | 0.00    |
+---------+------------+------------+---------+------------+---------+
|         | TetraMenD  | 42/47      | 0.89    | 1/3        | 0.33    |
+---------+------------+------------+---------+------------+---------+
| 02C     | Menomune   | 63/70      | 0.90    | 1/11       | 0.09    |
+---------+------------+------------+---------+------------+---------+
|         | TetraMenD  | 70/79      | 0.89    | 0/5        | 0.00    |
+---------+------------+------------+---------+------------+---------+
| 02Y     | Menomune   | 48/59      | 0.81    | 1/3        | 0.33    |
+---------+------------+------------+---------+------------+---------+
|         | TetraMenD  | 57/61      | 0.93    | 0/4        | 0.00    |
+---------+------------+------------+---------+------------+---------+
| 09Y     | Menomune   | 36/50      | 0.72    | 0/0        | ?       |
+---------+------------+------------+---------+------------+---------+
|         | TetraMenD  | 38/48      | 0.79    | 0/2        | 0.00    |
+---------+------------+------------+---------+------------+---------+
| 02W     | Menomune   | 52/54      | 0.96    | 0/4        | 0.00    |
+---------+------------+------------+---------+------------+---------+
|         | TetraMenD  | 58/60      | 0.97    | 0/1        | 0.00    |
+---------+------------+------------+---------+------------+---------+
| 09W     | Menomune   | 47/50      | 0.94    | 0/0        | ?       |
+---------+------------+------------+---------+------------+---------+
|         | TetraMenD  | 48/50      | 0.96    | 0/0        | ?       |
+---------+------------+------------+---------+------------+---------+

\(b\) BR 4-fold rise vs HC 1:8 at day 28

+-----------+-----------+-----------+-----------+-----------+-----------+
| Study     | Vaccine   | BR+       | Se        | BR-       | Sp        |
|           |           |           | nsitivity |           | ecificity |
|           |           | within    |           | within    |           |
|           |           | HC+       |           | HC-       |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02A       | Menomune  | 45/46     | 0.98      | 0/6       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 36/40     | 0.90      | 2/10      | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02C       | Menomune  | 55/62     | 0.89      | 1/19      | 0.05      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 68/77     | 0.88      | 0/7       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02Y       | Menomune  | 48/59     | 0.81      | 1/3       | 0.33      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 57/61     | 0.93      | 0/4       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09Y       | Menomune  | 36/50     | 0.72      | 0/0       | ?         |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 38/48     | 0.79      | 0/2       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02W       | Menomune  | 51/53     | 0.96      | 0/5       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 56/58     | 0.96      | 0/3       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09W       | Menomune  | 46/49     | 0.94      | 0/1       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 47/49     | 0.96      | 0/1       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+

\(c\) BR 1:128 vs HC 1:4 at day 0

+-----------+-----------+-----------+-----------+-----------+-----------+
| Study     | Vaccine   | BR+       | Se        | BR-       | Sp        |
|           |           |           | nsitivity |           | ecificity |
|           |           | within    |           | within    |           |
|           |           | HC+       |           | HC-       |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02A       | Menomune  | 24/41     | 0.58      | 10/11     | 0.91      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 30/38     | 0.79      | 8/12      | 0.67      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02C       | Menomune  | 7/19      | 0.37      | 41/62     | 0.66      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 11/27     | 0.41      | 42/57     | 0.74      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02Y       | Menomune  | 18/23     | 0.78      | 19/39     | 0.49      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 16/24     | 0.67      | 18/41     | 0.44      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09Y       | Menomune  | 22/33     | 0.67      | 12/17     | 0.70      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 22/32     | 0.69      | 9/18      | 0.50      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02W       | Menomune  | 12/35     | 0.34      | 19/23     | 0.83      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 11/39     | 0.28      | 17/22     | 0.77      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09W       | Menomune  | 14/41     | 0.34      | 4/9       | 0.44      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 14/42     | 0.33      | 6/8       | 0.75      |
+-----------+-----------+-----------+-----------+-----------+-----------+

\(d\) BR 1:128 vs HC 1:8 at day 0

+-----------+-----------+-----------+-----------+-----------+-----------+
| Study     | Vaccine   | BR+       | Se        | BR-       | Sp        |
|           |           |           | nsitivity |           | ecificity |
|           |           | within    |           | within    |           |
|           |           | HC+       |           | HC-       |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02A       | Menomune  | 16/19     | 0.84      | 24/33     | 0.73      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 18/20     | 0.90      | 14/30     | 0.47      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02C       | Menomune  | 2/4       | 0.50      | 51/77     | 0.66      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 2/10      | 0.20      | 50/74     | 0.68      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02Y       | Menomune  | 17/22     | 0.77      | 19/40     | 0.48      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 16/24     | 0.67      | 18/41     | 0.44      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09Y       | Menomune  | 22/33     | 0.67      | 12/17     | 0.70      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 22/32     | 0.69      | 9/18      | 0.50      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02W       | Menomune  | 11/31     | 0.35      | 2/27      | 0.07      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 7/34      | 0.20      | 18/27     | 0.67      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09W       | Menomune  | 14/39     | 0.36      | 6/11      | 0.54      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 14/40     | 0.35      | 8/10      | 0.80      |
+-----------+-----------+-----------+-----------+-----------+-----------+

\(e\) BR 1:256 vs HC 1:4 at day 0

+-----------+-----------+-----------+-----------+-----------+-----------+
| Study     | Vaccine   | BR+       | Se        | BR-       | Sp        |
|           |           |           | nsitivity |           | ecificity |
|           |           | within    |           | within    |           |
|           |           | HC+       |           | HC-       |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02A       | Menomune  | 22/41     | 0.54      | 10/11     | 0.91      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 23/38     | 0.60      | 9/12      | 0.75      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02C       | Menomune  | 6/19      | 0.32      | 49/62     | 0.79      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 11/27     | 0.41      | 46/57     | 0.81      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02Y       | Menomune  | 15/23     | 0.65      | 28/39     | 0.72      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 12/24     | 0.50      | 27/41     | 0.66      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09Y       | Menomune  | 17/33     | 0.52      | 13/17     | 0.76      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 19/32     | 0.59      | 11/18     | 0.61      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02W       | Menomune  | 6/35      | 0.17      | 21/23     | 0.91      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 5/39      | 0.13      | 21/22     | 0.95      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09W       | Menomune  | 8/41      | 0.20      | 6/9       | 0.67      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 8/42      | 0.19      | 7/8       | 0.88      |
+-----------+-----------+-----------+-----------+-----------+-----------+

\(f\) BR 1:256 vs HC 1:8 at day 0

+-----------+-----------+-----------+-----------+-----------+-----------+
| Study     | Vaccine   | BR+       | Se        | BR-       | Sp        |
|           |           |           | nsitivity |           | ecificity |
|           |           | within    |           | within    |           |
|           |           | HC+       |           | HC-       |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02A       | Menomune  | 14/19     | 0.74      | 24/33     | 0.73      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 15/20     | 0.75      | 19/30     | 0.63      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02C       | Menomune  | 2/4       | 0.50      | 60/77     | 0.78      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 2/10      | 0.20      | 54/74     | 0.73      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02Y       | Menomune  | 15/22     | 0.68      | 29/40     | 0.72      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 12/24     | 0.50      | 27/41     | 0.66      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09Y       | Menomune  | 17/33     | 0.52      | 13/17     | 0.76      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 19/32     | 0.59      | 11/18     | 0.61      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02W       | Menomune  | 6/31      | 0.19      | 25/27     | 0.93      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 3/34      | 0.09      | 24/27     | 0.89      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09W       | Menomune  | 8/39      | 0.20      | 8/11      | 0.73      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 8/40      | 0.20      | 9/10      | 0.90      |
+-----------+-----------+-----------+-----------+-----------+-----------+

\(g\) BR 1:128 vs HC 1:4 at day 28

+-----------+-----------+-----------+-----------+-----------+-----------+
| Study     | Vaccine   | BR+       | Se        | BR-       | Sp        |
|           |           |           | nsitivity |           | ecificity |
|           |           | within    |           | within    |           |
|           |           | HC+       |           | HC-       |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02A       | Menomune  | 50/50     | 1.00      | 0/2       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 47/47     | 1.00      | 0/3       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02C       | Menomune  | 70/70     | 1.00      | 2/11      | 0.18      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 79/79     | 1.00      | 0/5       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02Y       | Menomune  | 59/59     | 1.00      | 1/3       | 0.33      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 60/61     | 0.98      | 0/4       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09Y       | Menomune  | 49/50     | 0.98      | 0/0       | ?         |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 47/48     | 0.98      | 0/2       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02W       | Menomune  | 53/54     | 0.98      | 0/4       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 60/60     | 1.00      | 0/1       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09W       | Menomune  | 50/50     | 1.00      | 0/0       | ?         |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 50/50     | 1.00      | 0/0       | ?         |
+-----------+-----------+-----------+-----------+-----------+-----------+

\(h\) BR 1:128 vs HC 1:8 at day 28

+-----------+-----------+-----------+-----------+-----------+-----------+
| Study     | Vaccine   | BR+       | Se        | BR-       | Sp        |
|           |           |           | nsitivity |           | ecificity |
|           |           | within    |           | within    |           |
|           |           | HC+       |           | HC-       |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02A       | Menomune  | 46/46     | 1.00      | 0/6       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 40/40     | 1.00      | 0/10      | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02C       | Menomune  | 62/62     | 1.00      | 2/19      | 0.10      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 77/77     | 1.00      | 0/7       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02Y       | Menomune  | 59/59     | 1.00      | 1/3       | 0.33      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 60/61     | 0.98      | 0/4       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09Y       | Menomune  | 49/50     | 0.98      | 0/0       | ?         |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 47/48     | 0.98      | 0/2       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02W       | Menomune  | 52/53     | 0.98      | 0/5       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 58/58     | 1.00      | 0/3       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09W       | Menomune  | 49/49     | 1.00      | 0/1       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 49/49     | 1.00      | 0/1       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+

\(i\) BR 1:256 vs HC 1:4 at day 28

+-----------+-----------+-----------+-----------+-----------+-----------+
| Study     | Vaccine   | BR+       | Se        | BR-       | Sp        |
|           |           |           | nsitivity |           | ecificity |
|           |           | within    |           | within    |           |
|           |           | HC+       |           | HC-       |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02A       | Menomune  | 47/50     | 0.94      | 0/2       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 47/47     | 1.00      | 0/3       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02C       | Menomune  | 69/70     | 0.98      | 3/11      | 0.27      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 73/79     | 0.92      | 0/5       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02Y       | Menomune  | 59/59     | 1.00      | 1/3       | 0.33      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 58/61     | 0.95      | 1/4       | 0.25      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09Y       | Menomune  | 44/50     | 0.88      | 0/0       | ?         |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 45/48     | 0.98      | 0/2       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02W       | Menomune  | 51/54     | 0.94      | 1/4       | 0.25      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 56/60     | 0.93      | 0/1       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09W       | Menomune  | 50/50     | 1.00      | 0/0       | ?         |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 49/50     | 0.98      | 0/0       | ?         |
+-----------+-----------+-----------+-----------+-----------+-----------+

\(j\) BR 1:256 vs HC 1:8 at day 28

+-----------+-----------+-----------+-----------+-----------+-----------+
| Study     | Vaccine   | BR+       | Se        | BR-       | Sp        |
|           |           |           | nsitivity |           | ecificity |
|           |           | within    |           | within    |           |
|           |           | HC+       |           | HC-       |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02A       | Menomune  | 45/46     | 0.98      | 2/6       | 0.33      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 40/40     | 1.00      | 0/10      | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02C       | Menomune  | 61/62     | 0.98      | 3/19      | 0.16      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 71/77     | 0.92      | 0/7       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02Y       | Menomune  | 59/59     | 1.00      | 1/3       | 0.33      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 58/61     | 0.95      | 1/4       | 0.25      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09Y       | Menomune  | 44/50     | 0.88      | 0/0       | ?         |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 45/48     | 0.94      | 0/2       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 02W       | Menomune  | 50/53     | 0.94      | 1/5       | 0.20      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 54/58     | 0.93      | 0/3       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 09W       | Menomune  | 49/49     | 1.00      | 0/1       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | TetraMenD | 48/49     | 0.98      | 0/1       | 0.00      |
+-----------+-----------+-----------+-----------+-----------+-----------+

**[2.5. Reviewer's Overall Comments for SBA-BR and SBA-HC]{.underline}**

1.  From the first two tables, comparisons of the criteria of BR 4-fold
    rise with HC 1:4 and HC 1:8 at day 28, indicate that the sensitivity
    results are mostly above 80%. However, the specificity results are
    mostly around 0%. Although this could be due to the small number of
    subjects who were not seroprotected as defined by HC assays, these
    results nonetheless do not provide enough evidence that BR titer
    4-fold rise should be used as an alternative definition of
    seroprotection with the current data.

2.  Further exploratory analyses were performed by the reviewer to
    compare the possible alternative definitions such as BR 1:128 or BR
    1:256. The comparisons were made at both day 0 and day 28. In
    general, the sensitivities and specificities are both higher for day
    0 (indicating greater similarity of the two methods) but
    specificities are very low for day 28 (indicating disagreement).

3.  Although an individual clearly responds differently with the two
    assays (BR and HC), the responses of the two groups with different
    vaccines appear to be 'similar' within each assay method. However,
    these studies were not sufficiently powered to permit drawing a
    definitive conclusion. A study of larger sample size may provide
    more information on the relationship between the two assay methods.

4.  From the seroprotection rate and ANCOVA analyses in comparing the
    two assay methods, the conclusions reached by using the criteria of
    BR titer 4-fold rise do not contradict those drawn using the
    criteria of HC titers. Therefore, it may be accepted as a method for
    judging non-inferiority of immunogenicity of the investigational ,
    TetraMenD to the licensed Menomune but not as an alternative
    definition of seroprotection.

**[3. Clinical Studies Performed by AP]{.underline}**

![](media/image1.png){width="5.998611111111111in"
height="7.341666666666667in"}

**[3.1 Reviewer's Comments]{.underline}**

1.  The non-inferiority with respect to immunogenicity of TetraMenD
    compared to Menomune, using the 4-fold rise in SBA-BR complement,
    has been demonstrated in studies MTA02 for 11-18 years olds and
    MTA09 for 18 -55 years olds.

2.  There are no statistical concerns regarding studies 603-01, MTA02,
    MTA04, MTA09, MTA12, and MTA11.

3.  In study MTA14, the primary objective is to demonstrate lot
    consistency of 3 lots of the investigational vaccine, TetraMenD.

> The primary hypothesis:

Twenty-eight days after vaccination, the immune responses elicited by
the three consistency lots of TetraMenD, as measured by the geometric
mean titer (GMT), are equivalent for each of the four serogroups.

> This hypothesis will be supported by the data if the upper limit of
> the two-sided 90% confidence interval of the difference between the
> maximum and the minimum effect among the three lot responses is \<
> log2 (1.5); these effects are estimated by analysis of covariance of
> the log base 2 of the response at Day 28. In order to avoid
> disparities between groups due to imbalanced baseline titer, responses
> at Day 28 are adjusted by subtracting the responses at baseline and
> using the baseline as one of the covariates.
>
> Results submitted by AP from study MTA14 are listed in the following
> table. These results have been verified by the reviewer. Note that for
> serogroups C and Y, the upper limits of the 90% confidence intervals
> have exceeded the pre-determined value of 1.5.
>
> ![](media/image2.png){width="4.927083333333333in"
> height="2.4166666666666665in"}

**[4. Reviewer's Summary Comments]{.underline}**

1.  The criterion of at least a 4-fold rise at day 28 after the
    vaccination by the serum bactericidal assay with the baby rabbit
    complement (SBA-BR) appears acceptable as a method for
    non-inferiority immune comparability for the 11-55 age group, but
    not acceptable as an alternative measure for definition of
    seroprotection unless more definitive evidence is provided.

2.  The results of the clinical trials demonstrated non-inferiority
    (with respect to immunogenicity) of TetraMenD compared to Menomune
    by the SBA-BR method for the11-55 age group.

3.  The results of the lot consistency evaluation indicate that
    serogroups C and Y did not meet the primary objective of the
    predefined equivalence limit of 1.5 for the GMT ratios. The C and Y
    values 1.637 and 1.734, respectively, are within a 2-fold
    difference.

**Appendix**

![](media/image3.png){width="5.9944444444444445in"
height="3.5340277777777778in"}

![](media/image4.png){width="5.645833333333333in"
height="3.1041666666666665in"}

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height="3.3020833333333335in"}

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height="3.2916666666666665in"}

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height="3.4166666666666665in"}

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height="3.3229166666666665in"}

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height="3.4479166666666665in"}

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height="3.3645833333333335in"}

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height="3.3958333333333335in"}

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height="3.3854166666666665in"}

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height="3.3256944444444443in"}

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