CBER Introduction to license application:

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 submitted

for 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


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 clinical

investigations as defined in 314.126, unless this requirement

is waived on the basis of a showing that it is not reasonably

applicable 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 in

clinical studies and other laboratory evaluations may be

adequate to substantiate effectiveness where a previously

accepted correlation between data generated in this way and

clinical 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


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 licensed

2. What is known about immunological

correlates of protection.

Immunological correlates of protection:

Meningococcal Polysaccharide VaccinesAn 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.

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



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

o 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.

o The highest incidence of meningococcal disease occurs in infants between 6 months and 12 months of age. They have the lowest bactericidal antibody concentrations.

o 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

Ref: Goldscneider et al J Exp Med 127: 1969

Disease

Bactericidalantibody

Highest incidence of meningococcal meningitisoccurs at lowest bactericidal antibody prevalence

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

Protection is afforded by naturally acquired bactericidal antibodies

Bactericidal activity in an Army recruit populationand 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)

• Human SBA with intrinsic C’ source– 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


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


As part of the review process CBER investigators conducted

a 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

CBER Introduction to license application:

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