1. 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

2. 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

3. 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

4. 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 >>>

5. 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.

6. “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

7. 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.

8. 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

9. 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.

10. 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:

11. Meningococcal Polysaccharide Vaccines An Historical Prospective VaccineDateLicense CriteriaManufacturer Group C02-Apr-1974EfficacyMerck & Co. Inc. 11-Jul-1975EfficacyMerrell-National Laboratories Div. Group A11-Jul-1975EfficacyMerck & Co. Inc. 19-Sep-1975EfficacyMerrell-National Laboratories Div. Group A/C6-Oct-1975EfficacyMerck & Co. Inc. 13-Dec-1976EfficacyMerrell-National Laboratories Div. Group A/C/Y/ W13523-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.

12. Group C Vaccine trial Vaccinees/ Group C cases Controls/ Group C cases Reference Army Recruits13,763/ 154,309/ 38N.Engl.J.Med. 282:417, 1970 Army Recruits14,482/ 160,172/ 35Bull.W.H.O. 45:279, 1971 28,245/ 2114,481/ 73 Group C cases/100,000 7.163.8Protection: 89.9% Adapted from Sippel, Crit.Rev.Microbiol. 8:267, 1981 Meningococcal Polysaccharide Vaccines An Historical Prospective

13. Group A Vaccine trialVaccinees/ Group A cases Controls/ Group A cases Reference Egypt School children 62,295/ 062,054/ 8Bull.W.H.O. 48:667, 1973 Egypt School children 88,263/ 188,383/ 9Bull.W.H.O. 55:645, 1977 Sudan School children 10,891/ 010,749/ 7Bull.W.H.O. 49:301, 1973 Finland 3 mth – 5 yrs 49,295/ 048,977/ 6N.Engl.J.Med. 297:686, 1977 Finland Army Recruits 16,458/ 120,748/ 11Lancet, ii, 883, 1975 Upper Volta17,300/ 025,700/ 43Med.Trop. 37:225, 1977 244,502/ 2256,611/ 84 Group A cases/100,000 0.932.7Protection: 97.2% Adapted from Sippel, Crit.Rev.Microbiol. 8:267, 1981

14. 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

15. Ref: Goldscneider et al J Exp Med 127: 1969 Disease Bactericidal antibody Highest incidence of meningococcal meningitis occurs at lowest bactericidal antibody prevalence

16. Goldschneider et al. J. Exp. Med. 129:1307, 1969 Protection is afforded by naturally acquired bactericidal antibodies

17. 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)

18. 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

19. 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 antibody for Menactra compared to Menomune Baby rabbit serum was used as the source of complement

20. 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

21. Focus of today’s CBER presentations First: Dr. Lucia Lee, M.D. will provide the CBER clinical review of safety and efficacy Second: I will present two questions for the committee to vote upon and an additional two items for discussion and comment