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

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 &

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%)

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

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.

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:

The proportion of subjects achieving a ³ 4-fold rise in titer by SBA-BR was similar to the proportion of subjects achieving a titer of ³ 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 ³ 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 ³ 4-fold rise in SBA-BR titer to protection against serogroup A.

2.3. Reviewer’s Comments on AP’s Results

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.

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

2.4. Reviewer’s Analyses

Seroprotection Rates:

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:

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.

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

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	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:

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.

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

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

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).

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 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

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