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

 

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 ³ 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

 

Since the current standard for seroprotection is based on the serum bactericidal assay with human complement (SBA-HC) titers ³1:4 or HC titers ³1:8 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

 

 

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 &

Serogroup

Menomune

TetraMenD

SBA-BR

SBA-HC

SBA-BR

SBA-HC

 

³4-fold Rise

Titer ³ 1:4

Titer ³ 1:8

³4-fold Rise

Titer ³ 1:4

Titer ³ 1:8

02A

51/52

(98%)

50/52

(96%)

46/52

(88%)

44/50

(88%)

47/50

(94%)

40/50

(80%)

02C

73/81

(90%)

70/81

(86%)

62/81

(77%)

75/84

(89%)

79/84

(94%)

77/84

(92%)

02Y

50/62

(81%)

59/62

(95%)

59/62

(95%)

61/65

(94%)

61/65

(94%)

61/65

(94%)

09Y

36/50

(72%)

50/50

(100%)

50/50

(100%)

40/50

(80%)

48/50

(96%)

48/50

(96%)

02W

56/58

(97%)

54/58

(93%)

53/58

(91%)

59/61

(97%)

60/61

(98%)

58/61

(95%)

09W

47/50

(94%)

50/50

(100%)

49/50

(98%)

48/50

(96%)

50/50

(100%)

49/50

(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 &

Serogroup

Menomune

TetraMenD

SBA-BR

SBA-HC

SBA-BR

SBA-HC

 

³4-fold Rise

Titer ³ 1:4

Titer ³ 1:8

³4-fold Rise

Titer ³ 1:4

Titer ³ 1:8

02A

11/11

(100%)

10/11

(91%)

9/11

(82%)

12/12

(100%)

11/12

(92%)

8/12

(67%)

02C

56/62

(90%)

51/62

(82%)

43/62

(69%)

54/57

(95%)

52/57

(91%)

50/57

(88%)

02Y

35/39

(90%)

36/39

(92%)

36/39

(92%)

38/41

(93%)

38/41

(93%)

38/41

(93%)

09Y

15/17

(88%)

17/17

(100%)

17/17

(100%)

18/18

(100%)

16/18

(89%)

16/18

(89%)

02W

23/23

(100%)

19/23

(83%)

18/23

(78%)

21/22

(95%)

21/22

(95%)

19/22

(86%)

09W

8/9

(89%)

9/9

(100%)

8/9

(89%)

8/8

(100%)

8/8

(100%)

8/8

(100%)

 

 

 

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

 

 

 

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

 

 

2.2 AP’s Conclusion

 

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

 

o       A comparison of the rate of 4-fold rise in titer by SBA-BR to the rate of achieving a titer of ³ 1:4 by SBA-HC between the TetraMenD and Menomune groups was favorably demonstrated for serogroups C, W-135, and Y.

o       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.

o       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 (³ 1:4 or more conservatively ³ 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:

 

 

 

2.3. Reviewer’s Comments on AP’s Results

 

  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. 

 

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

 


2.4. Reviewer’s Analyses

 

 

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

 

Study

Criteria

Menomune

TetraMenD

Diff

(M-T)

p-value

95% CI

 

 

N

Proportion

N

Proportion

 

 

 

02A

BR³4fold

52

0.98

50

0.88

0.10

0.054

-0.002, 0.224

 

HC³1:4

52

0.96

50

0.94

0.02

0.723

-0.078, 0.132

 

HC³1:8

52

0.88

50

0.80

0.08

0.270

-0.067, 0.240

02C

BR³4fold

81

0.90

84

0.89

0.01

0.924

-0.091, 0.108

 

HC³1:4

81

0.86

84

0.94

-0.08

0.106

-0.177, 0.017

 

HC³1:8

81

0.77

84

0.92

-0.15

0.008

-0.267, -0.031

02Y

BR³4fold

62

0.81

65

0.94

-0.13

0.026

-0.260, -0.015

 

HC³1:4

62

0.95

65

0.94

0.01

0.834

-0.080, 0.110

 

HC³1:8

62

0.95

65

0.94

0.01

0.834

-0.080, 0.110

09Y

BR³4fold

50

0.72

50

0.80

-0.08

0.508

-0.251, 0.091

 

HC³1:4

50

1.00

50

0.96

0.04

0.209

-0.034, 0.137

 

HC³1:8

50

1.00

50

0.96

0.04

0.209

-0.034, 0.137

02W

BR³4fold

58

0.97

61

0.97

-0.00

1.000

-0.090, 0.083

 

HC³1:4

58

0.93

61

0.98

-0.05

0.159

-0.152, 0.029

 

HC³1:8

58

0.91

61

0.95

-0.04

0.549

-0.146, 0.063

09W

BR³4fold

50

0.94

50

0.96

-0.02

0.751

-0.130, 0.084

 

HC³1:4

50

1.00

50

1.00

0.00

1.000

-0.073, 0.072

 

HC³1:8

50

0.98

50

0.98

0.00

1.000

-0.088, 0.088

 

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

 

Comments:

 

  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.

 

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

 

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

 

 

 

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.

 


 

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

Ratio2

95% CI of ratio3

02A

BR

Treatment

-0.46

-1.07, 0.15

0.14

0.73

0.47, 0.90

 

 

Baseline

0.18

0.08, 0.27

0.00

 

 

 

HC

Treatment

0.01

-0.49, 0.51

0.96

1.09

0.71, 1.43

 

 

Baseline

0.51

0.32, 0.70

0.00

 

 

02C

BR

Treatment

-0.12

-0.74, 0.49

0.70

0.92

0.60, 1.41

 

 

Baseline

0.22

0.12, 0.33

0.00

 

 

 

HC

Treatment

-0.45

-1.23, 0.33

0.26

0.73

0.42, 1.26

 

 

Baseline

1.19

0.57, 1.81

0.00

 

 

02Y

BR

Treatment

-0.55

-1.12, 0.02

0.06

0.68

0.46, 1.01

 

 

Baseline

0.34

0.22, 0.46

0.00

 

 

 

HC

Treatment

-0.19

-1.04, 0.66

0.66

0.88

0.48, 1.58

 

 

Baseline

0.34

0.15, 0.52

0.00

 

 

09Y

BR

Treatment

-0.20

-1.07, 0.68

0.66

0.87

0.48, 1.60

 

 

Baseline

0.35

0.21, 0.49

0.00

 

 

 

HC

Treatment

0.58

-0.28, 1.43

0.18

1.49

0.82, 2.70

 

 

Baseline

0.36

0.21, 0.51

0.00

 

 

02W

BR

Treatment

-0.05

-0.63, 0.52

0.86

0.96

0.65, 1.44

 

 

Baseline

0.34

0.21, 0.46

0.00

 

 

 

HC

Treatment

0.20

-0.48, 0.89

0.55

1.15

0.72, 1.85

 

 

Baseline

0.39

0.26, 0.51

0.00

 

 

09W

BR

Treatment

0.36

-0.28, 0.99

0.27

1.28

0.82, 1.99

 

 

Baseline

0.19

0.06, 0.32

0.01

 

 

 

HC

Treatment

-0.08

-0.78, 0.62

0.82

0.94

0.58, 1.54

 

 

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.

 

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

 

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

 

  1. 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).

 

  1. 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.

 

 

 

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 ³ 4-fold rise with HC ³ 1:4 and HC ³ 1:8 at day 28, as well as comparisons of BR ³ 1:128, BR ³ 1:256 with HC ³ 1:4, HC³ 1:8 at both day 0 and day 28)

 

(a) BR ³ 4-fold rise vs HC ³ 1:4 at day 28

 

Study

Vaccine

BR+

within HC+

Sensitivity

BR-

within HC-

Specificity

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 ³ 4-fold rise vs HC ³ 1:8 at day 28

 

Study

Vaccine

BR+

within HC+

Sensitivity

BR-

within HC-

Specificity

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 ³ 1:128 vs HC ³ 1:4 at day 0

 

Study

Vaccine

BR+

within HC+

Sensitivity

BR-

within HC-

Specificity

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 ³ 1:128 vs HC ³ 1:8 at day 0

 

 

Study

Vaccine

BR+

within HC+

Sensitivity

BR-

within HC-

Specificity

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 ³ 1:256 vs HC ³ 1:4 at day 0

 

Study

Vaccine

BR+

within HC+

Sensitivity

BR-

within HC-

Specificity

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 ³ 1:256 vs HC ³ 1:8 at day 0

 

Study

Vaccine

BR+

within HC+

Sensitivity

BR-

within HC-

Specificity

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 ³ 1:128 vs HC ³ 1:4 at day 28

 

 

Study

Vaccine

BR+

within HC+

Sensitivity

BR-

within HC-

Specificity

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 ³ 1:128 vs HC ³ 1:8 at day 28

 

Study

Vaccine

BR+

within HC+

Sensitivity

BR-

within HC-

Specificity

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 ³ 1:256 vs HC ³ 1:4 at day 28

 

Study

Vaccine

BR+

within HC+

Sensitivity

BR-

within HC-

Specificity

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 ³ 1:256 vs HC ³ 1:8 at day 28

 

Study

Vaccine

BR+

within HC+

Sensitivity

BR-

within HC-

Specificity

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

 

  1. From the first two tables, comparisons of the criteria of BR ³ 4-fold rise with HC ³ 1:4 and HC ³ 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 ³ 4-fold rise should be used as an alternative definition of seroprotection with the current data.

 

  1. Further exploratory analyses were performed by the reviewer to compare the possible alternative definitions such as BR ³ 1:128 or BR ³ 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). 

 

  1. 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.

 

  1. From the seroprotection rate and ANCOVA analyses in comparing the two assay methods, the conclusions reached by using the criteria of BR titer ³ 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

 

 


3.1 Reviewer’s Comments

 

  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.

 

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

 

  1. 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.  

           


4. Reviewer’s Summary Comments

 

  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.

 

  1. 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.

 

  1. 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