# Presentation: 307883

## CBER Introduction to license application:

- Aventis Pasteur license application for **Meningococcal (groups A, C, Y, and W135) ****Polysaccharide Diphtheria Toxoid Conjugate Vaccine**

- Trade name: **Menactra**

## Tetravalent Meningococcal Polysaccharide Diphtheria Toxoid Conjugate Vaccine, Menactra

**Application received:**  December 17, 2003 as an e-BLA
- This is the first meningococcal conjugate submittedfor licensure in the USA .

**Proposed indication:**  Active immunization of adolescents and adults ( 11 to 55 yr of age) for** **prevention of  invasive disease caused by *Neisseria meningitidis*  serogroups A, C, Y and W135

## Tetravalent Meningococcal Polysaccharide Diphtheria Toxoid Conjugate Vaccine, Menactra

- Vaccine is formulated to contain per 0.5 ml dose

-    4 g of polysaccharide - serogroup A
-    4 g of polysaccharide - serogroup C
-    4 g of polysaccharide - serogroup Y
-    4 g of polysaccharide - serogroup W135
-    Approx. 48 g of diphtheria toxoid
-    0.6 mg sodium phosphate
-    4.4 mg sodium chloride

## For approval of a new vaccine it must be shown to be both safe and effective

- Concerning the effective requirement:

**21 CFR 601.25 (d) *****Standards for safety, effectiveness and labeling***

- Proof of effectiveness shall consist of controlled clinicalinvestigations as defined in 314.126, unless this requirementis waived on the basis of a showing  that it is not reasonablyapplicable to the biological product and that an alternative method of investigation is adequate to substantiate effectiveness

- Continued >>>

## 21 CFR 601.25 (d) Standards for safety, effectiveness and labeling

- Alternate methods, such as serological response evaluation inclinical studies and other laboratory evaluations may be adequate to substantiate effectiveness where a previouslyaccepted correlation between data generated in this way andclinical effectiveness already exists.

## “Non-inferiority designs are used to evaluateefficacy indirectly when placebo-controlled ‘efficacy’ designs are not feasible. Thus, non-inferiority assessments are really indirect efficacy evaluations.” 

- FDA/CBER Biostatistics

## Tetravalent Meningococcal Polysaccharide Diphtheria Toxoid Conjugate Vaccine, Menactra

**Existing polysaccharide vaccine:**
-  There is an existing licensed tetravalent meningococcal polysaccharide vaccine, Menomune,for use in the same age indication.
- The licensing strategy taken by  Aventis Pasteur was therefore to show that  Menactra was ***not inferior***  to Menomune  in terms of immunogenicity and safety.

## The licensing strategy to show that Menactra is  not inferior to Menomune in terms of immunogenicity and safety has been used in the approval of Haemophilus polysaccharide based vaccines

**Approval Date                         Vaccine**

- December 1987            **Haemophilus b conjugate**
**                                  ****(PRP-D)** was approved for same                                   indication as the previously                                    approved polysaccharide vaccine
- March 1993                  **Haemophilus b conjugate**
**                                  ****(PRP-T)** was approved as a third                                   Hib conjugate vaccine

## Use of immunological correlates of protection

- _The September 1999 VRBPAC presentation:_ “Use of immunologic surrogates for demonstration of protective efficacy of meningococcal conjugate vaccines”
- The committee concluded that **immunological correlates** can be used to demonstrate protective efficacy of  meningococcal conjugate vaccines for those 2 years
-  of age and older.

## During the IND process CBER and Aventis Pasteur agreed upon the path to be taken  to demonstrate the effectiveness of Menactra.

- This path was based in part upon **an historical perspective**:1.  How the polysaccharide vaccine was licensed2.  What is known about immunological      correlates of protection.

**       **
**     ****Immunological correlates of protection:**

## Meningococcal Polysaccharide VaccinesAn Historical Prospective

| Vaccine | Date
 | License Criteria | Manufacturer |
| --- | --- | --- | --- |
| Group C | 02-Apr-1974 | Efficacy | Merck & Co. Inc. |
|  | 11-Jul-1975 | Efficacy | Merrell-National Laboratories Div. |
| Group A | 11-Jul-1975 | Efficacy | Merck & Co. Inc. |
|  | 19-Sep-1975 | Efficacy | Merrell-National Laboratories Div. |
| Group A/C | 6-Oct-1975 | Efficacy | Merck & Co. Inc. |
|  | 13-Dec-1976 | Efficacy | Merrell-National Laboratories Div. |
| Group A/C/Y/ W135 | 23-Nov-1981 |  4 fold rise in SBA in 90% of adults 3-4 wks | Connaught Laboratories, Inc. |
|  | 14-Dec-1982 |  4 fold rise in SBA in 90% of adults 3-4 wks | Merck & Co. Inc. |

## Meningococcal Polysaccharide VaccinesAn Historical Prospective

| Group C Vaccine trial | Vaccinees/
Group C cases | Controls/
Group C cases | Reference |
| --- | --- | --- | --- |
| Army Recruits | 13,763/ 1 | 54,309/ 38 | N.Engl.J.Med. 282:417, 1970 |
| Army Recruits | 14,482/ 1 | 60,172/ 35 | Bull.W.H.O.
45:279, 1971 |
|  | 28,245/ 2 | 114,481/ 73 |  |
| Group C cases/100,000 | 7.1 | 63.8 | Protection:
89.9% |

**Adapted from Sippel, Crit.Rev.Microbiol. 8:267, 1981**

- Meningococcal Polysaccharide VaccinesAn Historical Prospective

## Meningococcal Polysaccharide VaccinesAn Historical Prospective

| Group A Vaccine trial | Vaccinees/
Group A cases | Controls/
Group A cases | Reference |
| --- | --- | --- | --- |
| Egypt
School children | 62,295/ 0 | 62,054/ 8 | Bull.W.H.O.
48:667, 1973 |
| Egypt
School children | 88,263/ 1 | 88,383/ 9 | Bull.W.H.O.
55:645, 1977 |
| Sudan
School children | 10,891/ 0 | 10,749/ 7 | Bull.W.H.O.
49:301, 1973 |
| Finland
3 mth – 5 yrs | 49,295/ 0 | 48,977/ 6 | N.Engl.J.Med. 297:686, 1977 |
| Finland
Army Recruits | 16,458/ 1 | 20,748/ 11 | Lancet, ii, 883, 1975 |
| Upper Volta | 17,300/ 0 | 25,700/ 43 | Med.Trop. 37:225, 1977 |
|  | 244,502/ 2 | 256,611/ 84 |  |
| Group A cases/100,000 | 0.9 | 32.7 | Protection:
97.2% |

**Adapted from Sippel, Crit.Rev.Microbiol. 8:267, 1981**

## The critical role of bactericidal antibodies in protection against meningococcal disease has been demonstrated in a number of ways

-     Studies in the US Army recruits in the 1960’s showed a direct     correlation between susceptibility to meningococcal disease and     absence of serum bactericidal antibodies.
-    The highest incidence of meningococcal disease occurs in infants      between 6 months and 12 months of age.  They have the lowest      bactericidal antibody concentrations.
-    Individuals deficient in serum complement components C5, C6     C7, or C8 have markedly increased susceptibility to systemic     meningococcal disease, and have repeated meningococcal      infections.

- Thus, bactericidal antibody is a surrogate for protective efficacy

## Highest incidence of meningococcal meningitisoccurs at lowest bactericidal antibody prevalence

- Ref: Goldscneider et al  J Exp Med 127: 1969

**Disease**

**Bactericidal****antibody**

**Highest incidence of meningococcal meningitis****occurs at lowest bactericidal antibody prevalence**

## Protection is afforded by naturally acquired

- Goldschneider et al.  J. Exp. Med. 129:1307, 1969

**Protection is afforded by naturally acquired**
** ****bactericidal antibodies**

## Bactericidal activity in an Army recruit populationand susceptibility to group C meningococcal disease 

- Goldschneider et al.  J. Exp. Med. 129:1307, 1969

**492 **recruits in at Fort Dix, NJ – 1968
-        **438** had bactericidal antibody  -      **No disease**
-           **54** were initially lacked bactericidal antibody

_**Fate of the initially bactericidal negative individuals**_
-    ** ****24** became exposed to the group C epidemic strain
-             ** ****11**  developed bactericidal antibody -  No disease
-              **13**  failed to develop bactericidal antibody
-                       **5/13** –  group C meningococal disease                                  **(38.5 % attack rate)**

## The bactericidal assay:  Historical Prospective

-  Serum diluted 1:4
-   Pos/neg assay correlated with protection or susceptibility

**The bactericidal assay: ** Historical Prospective

*    **W.H.O. Tech. Rep. Ser. 594:51, 1976*
-   Paired sera taken immediately prior and 2-4 wks after immunization
-   SBA performed with baby rabbit sera as C’ source and titer     expressed as the reciprocal of the dilution with  50% killing
-    Titers of the sera from at least 90% of the subjects should      show a **fourfold or greater rise** after immunization

## Tetravalent Meningococcal Polysaccharide Diphtheria Toxoid Conjugate Vaccine, Menactra

**Primary immunogenicity endpoint for Menactra**:
- Determine percent of vaccinees having a 4-fold or greater increase in bactericidal antibodyfor Menactra compared to Menomune
- Baby rabbit serum was used as the source of complement

## Tetravalent Meningococcal Polysaccharide Diphtheria Toxoid Conjugate Vaccine, Menactra

- As part of the review process CBER investigators conducteda pre-license inspection of Aventis Pasteur manufacturing facility in Swiftwater, Pennsylvania .
- The inspectional findings were satisfactory

##   Focus of today’s CBER presentations   

**First:**
- Dr. Lucia Lee, M.D. will provide the CBER clinicalreview of safety and efficacy
**Second:**
- I will present two questions for the committee to voteupon and an additional two items for discussion and comment