cber introduction to license application:
DESCRIPTION
TRANSCRIPT
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
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 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
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 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
Meningococcal Polysaccharide VaccinesAn Historical Prospective
Meningococcal Polysaccharide VaccinesAn 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
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
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 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