SEPTEMBER 22, 2004


            The Advisory Committee met at 10:00 a.m. in the Versailles Ballroom of the Holiday Inn, 8120 Wisconsin Avenue, Bethesda, Maryland, Dr. Gary D. Overturf, Chair, presiding.




GARY D. OVERTURF, M.D.       Chair

PETER DENSEN, M.D.           Temporary Voting Member

MONICA M. FARLEY, M.D.       Member

BRUCE GELLIN, M.D., M.P.H.   Temporary Voting Member

RUTH A. KARRON, M.D.         Member


PAMELA McINNES, D.D.S.       Temporary Voting Member

STEPHEN PETTEWAY, Jr., Ph.D. Acting Industry



Consumer Representative

WALTER ROYAL III, M.D.       Member

STEVEN SELF, Ph.D.           Member

DAVID STEPHENS, M.D.         Temporary Voting Member

RICHARD WHITLEY, M.D.        Member

BONNIE M. WORD, M.D.         Member

CHRISTINE WALSH, R.N.        Executive Secretary


This transcript has not been edited or corrected, but appears as received from the commercial transcribing service.  Accordingly the Food and Drug Administration makes no representation as to its accuracy.
















Call to Order, Dr. Gary Overturf                   4


Announcements, Christine Walsh                     4


Introduction to the License Application,

  Dr. Carl Frasch                                 10


Clinical Data in Support of Menactra              20


Clinical Review of Safety and Efficacy            34


Questions of Clarification for Applicant        81


Questions of Clarification for FDA              90


Open Public Hearing                            127


Presentation of Questions for Committee        141


Committee Discussion/Voting on Questions       145


Adjourn                                        174


10:00 a.m.

            CHAIRMAN OVERTURF:  Good morning.  I'm Gary Overturf, the Chair of the VRBPAC.  And I'd like to call the meeting to order.  This is the 100th meeting of VRBPAC so it's a momentous occasion.

            I'd like to turn the meeting now over to Christine Walsh who has the requisite announcements.

            MS. WALSH:  Good morning.  I'm Christine Walsh, the Executive Secretary for today's meeting of the Vaccines and Related Biological Products Advisory Committee.

            I would like to welcome you all to the 100th meeting of this Advisory Committee.

            Today's session will consist of presentations that are open to the public.  We did not hold a closed session today as described in the Federal Register notice of September 3, 2004.  Tomorrow's meeting will consist of both open and closed sessions.

            I will ask that during our meeting all committee members identify themselves each time they speak.  We have a transcriber present who will need your assistance in order to accurately transcribe all comments to the appropriate committee member.

            I would now like to read into the public record the conflict of interest statement for today's meeting.

            The following announcement addresses conflict of interest issues associated with the Vaccines and Related Biological Products Advisory Committee Meeting on September 22 and 23, 2004.

            The Director of the Center of Biologics Evaluation and Research has appointed Drs. Peter Densen, Bruce Gellin, Pamela McInnes, and David Stephens as temporary voting members for this meeting.

            To determine if any conflicts of interest existed, the Agency reviewed the submitted agenda and all relevant financial interests reported by the meeting participants.

            As a result of this review, and based on the FDA Draft Guidance on disclosure of conflict of interest for special government employees participating in an FDA product-specific Advisory Committee meeting, the following disclosures are being made.

            Dr. David Stephens has been granted a waiver under 21 U.S.C. 355(n)(4) of Section 505 of the Food and Drug Administration Modernization Act for unrelated royalties of less than 5,001 dollar per year from a competing firm.

            Dr. Stephens may participate fully in the discussion of the safety and efficacy of Menactra and the Phase III Thai Trial for the prevention of HIV-1 infection.

            We would like to note for the record that Dr. Stephen Petteway is the Acting Non-Voting Industry Representative for this committee representing regulated industry.  Dr. Petteway's appointment is not subject to 18 U.S.C. 208.  He is employed by Bayer and thus has a financial interest in his employer.

            Dr. Peter Palese recused himself from this meeting.

            Also Dr. Steven Self recused himself from the discussion on September 23 regarding the Phase III Thai Trial for the prevention of HIV-1 infection.  He is participating fully in the discussion on September 22nd regarding the safety and efficacy of Menactra manufactured by Aventis.

            Members and consultants are aware of the need to exclude themselves from the discussions involving specific products or firms for which they have not been screened for conflict of interest.  Their exclusion will be noted for the public record.

            With respect to all other meeting participants, we ask in the interest of fairness that you address any current or previous financial involvement with any firm whose products you wish to comment upon.  Waivers are available by written request under the Freedom of Information Act.

            That ends the reading of the conflict of interest statement.

            Dr. Overturf, I turn the meeting back over to you.

            CHAIRMAN OVERTURF:  Again I'd like to welcome the members to the Vaccines and Related Biological Products Advisory Committee and all those in the audience and members of the FDA staff.

            At this time I'd like the members to introduce themselves and we will begin with Dr. Markovitz.  And I would ask that you introduce yourself and who you represent.

            MEMBER MARKOVITZ:  Yes, I'm David Markovitz.  I'm a Professor of Medicine in Infectious Diseases at University of Michigan in Ann Arbor.

            MEMBER ROYAL:  Walter Royal.  I'm an Associate Professor of Medicine at Morehouse School of Medicine in Atlanta, Georgia.

            MEMBER FARLEY:  I'm Monica Farley.  I'm a Professor of Medicine, Infectious Diseases, at Emory University in Atlanta.

            MEMBER McINNES:  Pamela McInnes, Deputy Director of the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases.

            MS. PROVINCE:  I'm Cindy Province.  I'm the Associate Director of the St. Louis Center for Bioethics and Culture and I'm the Consumer Representative.

            MEMBER GELLIN:  I'm Bruce Gellin.  I'm the Director of the National Vaccine Program Office at the Department of Health and Human Services.

            CHAIRMAN OVERTURF:  I'm Gary Overturf.  I'm a Professor of Pediatrics and Pathology and Director of Pediatric Infectious Disease at the University of New Mexico in Albuquerque.

            MEMBER STEPHENS:  I'm David Stephens, Professor of Medicine, head of the Division of Infectious Diseases at Emory University in Atlanta.

            DR. PETTEWAY:  I'm Steve Petteway.  I'm Vice President for Preclinical R&D and Pathogen Safety for Bayer Health Care.

            MEMBER WORD:  I'm Bonnie Word.  I'm Assistant Professor of Pediatrics at Baylor College of Medicine, Texas Children's Hospital.

            MEMBER WHITLEY:  Rich Whitley, University of Alabama at Birmingham, Professor of Pediatrics, Microbiology, Medicine, and Neurosurgery.

            MEMBER DENSEN:  I'm Peter Densen.  I'm a Professor of Internal Medicine and Infectious Diseases at the University of Iowa where I'm also the Executive Associate Dean.

            MEMBER SELF:  Steve Self, Professor of Biostatistics at the University of Washington in Seattle.

            MEMBER KARRON:  Ruth Karron, Associate Professor of International Health and Pediatrics, Johns Hopkins University.

            CHAIRMAN OVERTURF:  Thank you.

            At this time we'll begin the introduction to the license application.  I'll ask Dr. Carl Frasch to take the podium.

            DR. FRASCH:  Okay.  What I would like to do is introduce the license application, give some basic background information about the license, and provide some historical and regulatory context in which this application is being presented today.

            The vaccine is meningococcal (groups A, C, Y, W135) polysaccharide diphtheria toxoid conjugate vaccine and the trade name is Menactra.

            The application was received on December 17th, 2003 as an electronic BLA.  And this is the first meningococcal conjugate vaccine submitted for licensure in the U.S.A. and the first electronic BLA we've handled in my office.

            And the proposed indication is active immunization of adolescents and adults, 11 to 55 years of age, for prevention of invasive disease caused by Neisseria meningitidis serogroups A, C, Y, and W135.

            The vaccine is formulated to contain per 0.5 microgram dose, four micrograms of each of the four meningococcal polysaccharides conjugated to approximately 48 micrograms of diphtheria toxoid.  The vaccine contains no adjuvant.

            Now for approval of a new vaccine, it must be shown to be both safe and effective.  Concerning the effectiveness requirement, I cite a relevant regulatory standard and I quote:

            "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 substantial effectiveness, 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."

            And I will present more information on the serological response evaluation aspect.

            First, non-inferiority designs are used to evaluate efficacy indirectly when placebo-controlled efficacy designs are not feasible.  Thus, non-inferiority assessments are in reality indirect efficacy evaluations.

            So you need to know that there is an existing polysaccharide vaccine made by the same manufacturer.  The brand name is Menomune and the age indication is the same as for Menactra.  And thus the licensing strategy taken by Aventis Pasteur was to show that Menactra was not inferior to Menomune in terms of immunogenicity and safety.

            Now I want to show that the use of immunogenicity has been used previously.  Thus, the licensing strategy to show that Menactra is not inferior to Menomune in terms of immunogenicity and safety has been used for the approval of Haemophilus polysaccharide-based vaccines and, as I will show shortly, meningococcal vaccines.

            First in December 1987, we approved Haemophilus b conjugate vaccine, then called PRP-D, for the same indication as a previously approved polysaccharide vaccine based on immunogenicity.

            Then in March of 1993, we approved the third Haemophilus b conjugate vaccine called PRP-T, again based on immunogenicity data.

            Now regarding the use of immunological correlates, in September of 1999, CBER presented in front of the VRBPAC a presentation, Use of Immunologic Surrogates for Demonstration of Protective Efficacy of Meningococcal Conjugate Vaccines.

            In brief, the committee concluded that immunological correlates can be used to demonstrate protective efficacy of meningococcal conjugate vaccines for those two years of age and older.

            Now they did not specifically define what they meant by immunological correlates.  So, therefore, I'm going to present some more information relating to that aspect.

            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 upon historical perspective.

            First, how the meningococcal polysaccharide vaccine was licensed, the current meningococcal polysaccharide vaccine, and two, what is known about immunological correlates of protection for meningococcal disease.

            Looking first at the meningococcal polysaccharide vaccines in the mid-1970s, we licensed meningococcal group A, group C, and the A/C polysaccharide vaccines, all based on clinical efficacy trials.

            Then in 1981, we approved the current four-valent or quadrivalent meningococcal polysaccharide vaccine Menomune.  This approval was based upon immunological criteria.  We asked that greater than fourfold rise in the serum bactericidal activity be present in 90 percent of adults three to four weeks after immunization.

            Now looking at the efficacy trials for the group C polysaccharide vaccine, these were done in U.S. Army recruits and you can see at the bottom right corner that the protection was approximately 90 percent.

            Now looking at the group A polysaccharide vaccine, since group A meningococcal disease occurs primarily in Africa, most of these studies were done in Africa except for two done in Finland.  Again, in the bottom righthand corner, we see that the efficacy was 97 percent for the group A polysaccharide vaccine.

            Now based on the efficacy studies and other clinical data, the critical role of bactericidal antibodies in protection against meningococcal disease has been demonstrated.

            First, studies in the U.S. Army recruits in the 1960s showed a direct correlation between susceptibility to meningococcal disease and absence of serum bactericidal antibodies.

            Second, the highest incidence of meningococcal disease occurs in infants between six and twelve months of age.  They have the lowest bactericidal antibody concentrations at this age.

            Third, individuals deficient in serum complement components C5, C6, C7, or C8, the membrane attack complex, have markedly increased susceptibility to systemic meningococcal disease.  And have repeated meningococcal infections.  Thus bactericidal antibody is a surrogate for protective immunity.

            And I will show illustrations of the first two points on this slide now.

            First, we see that the peak incidence of disease occurs in children under two years of age at the time when they have the lowest levels of serum bactericidal antibodies.  This is taken from the classic studies by Goldschneider and Gotschlich published in 1969.

            Now the second illustration is taken from their same publication, and this is an actual table from their publication, and since it's rather complicated, I've summarized the data in the following slide.

            They had the unique opportunity to collect serum on recruits at the point when they entered into training.  They collected serum on 492 recruits at Fort Dix in 1968.  They found that 438 had bactericidal antibody in their blood at the time they started training.  And there was no disease in this population.

            Fifty-four of the 492 initially lacked bactericidal antibodies.  So let's look at those 54 individuals.  Twenty-four became exposed to the group C epidemic strain, 11 developed bactericidal antibody, no disease.

            The other 13 failed to develop bactericidal antibody.  There were five confirmed group C meningococcal cases in this population for an attack rate of 38 percent.  There was a sixth suspected case which would have brought the attack rate to 46 percent in this one population that was initially bactericidal negative.

            Now you will see today data presented using human complement on one hand and rabbit complement on the other.  These studies that I've just shown you used a human serum bactericidal assay using intrinsic complement as the source, the sera were diluted one to four, and they looked at either was it bactericidal or was it not.  And this correlated with protection or susceptibility.

            Then at the time of the approval of the first polysaccharide vaccines, the WHO, in cooperation with then the Bureau of Biologics, developed a standardized bactericidal assay based on using baby rabbit sera.

            This specified that the sera would be taken immediately prior and two to four weeks after immunization.  Baby rabbit serum was to used as the complement source.  The titer would be the reciprocal of the dilution with greater than 50 percent killing and the titers of the sera from at least 90 percent of subjects should show a fourfold or greater rise after immunization indicating that they have responded to the vaccine.

            Thus, based upon the historical record, the primary immunogenicity endpoint for Menactra is determination of percent of vaccinees having a fourfold or greater rise in bactericidal antibody for Menactra compared to the licensed vaccine Menomune using baby rabbit serum as the complement source.

            So to conclude, as part of the review process, CBER investigators conducted a pre-license inspection of Aventis Pasteur manufacturing facility in Swiftwater, Pennsylvania.  And I should say that the inspectional findings were satisfactory.

            And so today, the focus of the presentations are going to be first -- the CBER presentations, first Dr. Lucia Lee will provide the CBER clinical review of safety and efficacy and introduce the questions that will be directed to the committee.

            And second, after lunch, I will present two questions for the committee to vote upon and an additional two items for discussion and comment.

            Thank you.

            CHAIRMAN OVERTURF:  Are there any questions of clarification?

            (No response.)

            CHAIRMAN OVERTURF:  If not, we'll proceed now with the presentation by the sponsor in support of Menactra.

            DR. KUYKENS:  Mr. Chairman, members of the Advisory Committee, ladies and gentlemen, FDA staff, good morning.  My name is Luc Kuykens.  I've Vice President of Regulatory Affairs for Aventis Pasteur.

            Aventis Pasteur is pleased today to have the opportunity to present Menactra, our meningococcal quadrivalent conjugate vaccine to you.

            Please note that during the development of this vaccine, we also used the abbreviation of TetraMen D, a name you may have seen in some of your briefing documents.

            The outline of the sponsor's presentation today is as follows:

            Following my introduction, Dr. Gilmet will review the epidemiology of meningococcal disease and the importance of meningococcal conjugate vaccines for public health.

            Dr. Michael Decker will review the immunogenicity profile of our product.

            And Dr. Gary Chikami will review the safety data.

            While the currently available quadrivalent meningococcal polysaccharide vaccine, Menomune, has been demonstrated to be efficacious and is recommended for use in high-risk groups in outbreak situations, there is a definite public health need for an improved meningococcal vaccine.

            Such vaccine should provide persistent bactericidal antibodies, ability to prime and boost, lack hyporesponsiveness, reduce carriage, and provide  herd immunity.  Menactra has the potential to meet these needs.

            As mentioned by Dr. Frasch, Menactra consists of four polysaccharides, A, C, Y, and W135.  Four micrograms of each polysaccharides is covalently linked to 12 micrograms of diphtheria toxoid for a total of 48 micrograms of diphtheria toxoid.  Note that Menomune contains 50 micrograms of each polysaccharide.

            Menactra is adjuvant and preservative free.  It's presented in a liquid formulation for intramuscular administration.

            Both the polysaccharides and the diphtheria toxoid are currently licensed as part of Menomune and Tripedia respectively.

            The clinical experience was gained with Menactra includes more than 10,000 participants, over 7,600 adolescents and adults and 2,600 children. 

            However, the indication requested in the BLA submission, which is the subject of this application, is for the prevention of invasive meningococcal disease in adolescents and adults from 11 to 55 years of age for which the clinical database is over 7,600.

            The objective of our clinical program was to demonstrate non-inferiority to the standard of care, our widely-used polysaccharide vaccine Menomune, for both safety and immunogenicity.

            In addition, we started the concomitant administration of Menactra with Td and Typhim Vi vaccines.

            The data to be presented today will show that we met all pre-specified criteria for non-inferiority and that's both for safety and immunogenicity.

            In addition, Dr. Decker will review some important new data that recently became available in a follow-up study, a three-year follow-up study to one of our pivotal trials indicating that Menactra has the characteristics expected from a conjugate vaccine: antibody persistence, immune priming and boosting, and lack of hyporesponsiveness.

            I would like you to note that these data were not part of the initial BLA and have not been reviewed by the FDA.  However, in discussions with the FDA, they have agreed for us to share these data with you today.

            Thank you and I would like to introduce Dr. Gilmet now who will review the epidemiology of meningococcal disease.

            DR. GILMET:  Thank you, Luc.

            I appreciate the opportunity to present the epidemiology of meningococcal disease to the VRBPAC Committee this morning.

            Historically, the epidemiologic situation in the U.S. first drove Aventis Pasteur to begin the development of Menactra over a decade ago.

            In this presentation, I will summarize the following topics: the unique clinical challenge of meningococcal disease, the current epidemiological situation in the U.S., recent European and U.K. epidemiology, benefits of conjugate vaccines when compared to polysaccharide vaccines, data from the recent C conjugate mass vaccination campaign in the U.K., and conclude the presentation with summary statements.

            Meningococcal disease presents a number of unique clinical challenges.  Neisseria meningitidis is the most common cause of bacterial meningitis in children, adolescents, and young adults.  The meningococcus is able to cause disease outbreaks and epidemics.

            The meningococcal sera group distribution continually changes over time and has wide geographic variability.  Meningococcal disease often strikes young, otherwise healthy individuals.  And yet the overall mortality rate has remained in the 10 to 15 percent range for decades despite better understanding of the disease and improved treatment modalities.

            It's estimated that 60 percent of patients with meningococcal disease experience symptoms for less than 24 hours before finally presenting to the hospital for care.

            Lastly, the disease can be difficult to diagnose, has tremendous emotional impact, and causes disproportionate fear and alarm.  Collectively these factors argue for a vaccine-based primary prevention strategy.

            Our initial Menactra application will be for 11 to 55 year olds.  The epidemiology I'm about to show will provide additional evidence to support the public health need for a quadrivalent meningococcal conjugate vaccine in this target age group.

            Let's first look at current U.S. epidemiology.  Now unlike most of the world, meningococcal disease is caused by multiple sera groups in the U.S. and their relative proportions constantly shift over time.  Serogroup Y, for example, increased from nine to 28 percent in the past decade.

            About one-third of disease is caused by serogroup B for which no licensed vaccine is currently available in the U.S.  However, approximately two-thirds is caused by the vaccine-preventable serogroups C, Y, and W135.

            You'll note that serogroup A disease is very rare in the United States although it was responsible for epidemics as recently as World War II.  And it remains a concern for travelers to hyperendemic or epidemic areas such as sub-Saharan Africa.

            Meningococcal disease is also cyclical with the peak endemic incidence as high as 3,500 cases annually.  You'll note on this slide that currently we're at a low point in the cycle, however it is anticipated this will change in the near term based on historical trends.

            Shown here are recent incidence data from CDC national surveillance.  Note that the highest absolute incidence occurs in infants in whom serogroup B is the dominant cause.  However, the next most important group is adolescents and young adults represented by a wide incidence peak.

            The high percent of vaccine-preventable cases in adolescents and young adults relative to younger age groups is demonstrated on this slide.  For clarity, the non-vaccine-preventable cases caused by serogroup B have been grayed out.  The serogroup C, Y, and W135, potentially vaccine-preventable cases, are represented in various colors.

            It's important to note here that the percentage of adolescent and young adult cases that are potentially preventable with a quadrivalent vaccine is in the 70 percent range.  In addition, this CDC Vital Statistics data broken down by age group shows that adolescents and young adults also have the highest number of deaths due to invasive meningococcal disease.

            This slide shows data from Lee Harrison's Maryland study of risk factors and outcomes and is further evidence of lethality in adolescents and young adults.  Note that 15 to 24 year olds are several times more likely to die if they acquire meningococcal disease than those less than 15 years of age.

            Also, the percentage of vaccine-preventable disease in this Maryland sample is significantly higher in the 15- to 24-year-old group and exceeds 80 percent.

            Now historically, the Army was the first to implement the mass vaccination program in military recruits and did so with great success beginning in 1971.  Here you can see the progression for monovalent to bivalent and finally quadrivalent polysaccharide vaccines.

            In this highly controlled setting, a dramatic reduction in both the number of hospitalizations as indicated by the blue bars and rate of hospitalizations, indicated by the solid purple line, was observed.

            College students are another group where  meningococcal vaccination is a consideration.  Like Army recruits, they share a common risk factor such as age and close contact with their peers.

            Not surprisingly then, college freshman, dormitory residents, and to an even greater degree college freshmen living in dormitories, have relative risks several times higher than either all 18 to 23 year olds or all college students highlighting the need for routine vaccination coverage in this population.

            We'll next look at recent epidemiologic data from the U.K. and Europe.  Unlike the situation in the U.S., approximately 95 percent of disease in the U.K. and Europe is caused by serogroup C and B.  Note also the relative absence of serogroup Y in Europe.

            Although only one-third of the disease burden in Europe is vaccine preventable, namely that caused by serogroup C, the decision, nonetheless, was made in the U.K. to pursue a mass vaccination program in adolescents, the group with the highest age-specific mortality rate.

            Data from this U.K. study shows that acquisition of meningococcus increases very rapidly when you put young people in close contact.

            Carriage rates approach 25 percent four days after college matriculation and up to 35 percent one to two months later.  This contrasts with carriage rates in the overall population that are typically reported to be 10 percent in the literature.

            Next I'll summarize important differences between polysaccharide and conjugate vaccines.  Polysaccharide vaccines have several limitations when compared to the newer conjugate vaccines.  Most important, conjugate but not polysaccharide vaccines, elicit a T-cell-dependent immune response.

            And as a consequence of this T-cell activation, only conjugate vaccines induce long-term memory, persistence of protection, and booster responses.  These, in turn, lead to a reduction in bacterial carriage and resultant herd immunity.

            Finally, conjugate vaccines do not result in hyporesponsiveness or immune tolerance after repeat vaccine doses.  These are a well-described phenomenon with polysaccharide vaccines.  Taken together, it's evident that conjugate vaccines confer important immunologic enhancements.

            I'll now address a recent U.K. experience with C conjugate meningococcal vaccines.  Because of the observed benefits of conjugate vaccines we just looked at, the U.K. launched a mass vaccination program with monovalent serogroup C conjugate vaccine.

            The high risk 15 to 17 year old age cohort was initially targeted.  And over the ensuing year, the program was expanded to include younger age groups.  And because the program was so successful, other European countries, Canada, and Australia soon followed suit.

            The impressive U.K. results are highlighted on this and the next four slides.  The baseline data before the program was initiated in November 1999 shows a steady upward trend in cumulative cases.

            During the first year of program implementation, serogroup C disease was nearly halved.  After year two, serogroup C disease is almost entirely eliminated.

            This slide shows serogroup C disease reduction percentages by age group.  And they range from 64 to a high of 89 percent.  Overall disease reduction was 81 percent in the U.K. program.

            Likewise, the important outcome of carriage reduction for serogroup C when comparing pre- and post-program rates was 66 percent in adolescents with no significant change observed in the other serogroups.

            And as a result of that reduction in carriage, there was a dramatic herd immunity effect and reduction in attack rates of 48 to 80 percent in the unvaccinated.  This also parallels the experience seen with the earlier introduction of both Hib and pneumococcal conjugate vaccines.

            Now traditionally, the existing vaccine standard has been the licensed A, C, Y, W135 polysaccharide vaccine Menomune.  Menomune is indicated for travelers, individuals with potential occupational exposure to meningococcus, household or institutional contacts of cases, college students living in dormitories, immune-compromised individuals, and military recruits.

            Menomune is highly effective, has been available for over 20 years, has an excellent safety profile, and is widely used.  However, polysaccharide vaccines such as Menomune have limitations a conjugate vaccine such as Menactra will overcome.

            The expected benefits of Menactra, if given as part of a universal vaccination program of 11 to 18 year olds in the U.S., include the following: a persistence of protective antibody, an ability to both prime and boost, and a lack of hyporesponsiveness after a booster dose.

            Now in a few minutes, Dr. Decker will show you important data that demonstrate these immunologic attributes of Menactra.  In addition, we expect to see upon further study and experience a reduction in carriage and resultant herd immunity with Menactra.

            And finally, the potential exists to replicate the U.K. findings in the U.S. and broaden the coverage to include serogroups A, Y, and W135.

            Historically, we are approaching a very exciting and important milestone in public health.  Over the past several decades, conjugate vaccines have substantially impacted both Hib and pneumococcal disease.  The last of the triad of major causes of bacterial meningitis in children, adolescents, and young adults is the meningococcus.

            We now have a quadrivalent conjugate vaccine that should greatly impact the meningococcal disease burden in the United States.

            In summary, the key epidemiologic findings are the following.  Meningococcal disease is a serious and challenging public health problem.  Adolescents and young adults are at high risk.  The U.K. program demonstrated the ability to reduce carriage, induce herd immunity, and eradicate serogroup C disease.

            Menactra should prevent meningococcal disease by as much as 70 percent in U.S. adolescents if used as part of a universal immunization program targeting 11 to 18 year olds.

            Thank you for your attention.  I'd now like to introduce Dr. Michael Decker who will present the Menactra immunogenicity data.

            DR. DECKER:  Thanks, Greg.

            I'm Dr. Michael Decker.  And I will present to you the immunogenicity data in support of our application for licensure of Menactra.

            First, I'll discuss the basis for licensure, which is the non-inferiority of Menactra as compared to Menomune.

            Second, I'll talk about how we measure immunogenicity.

            Third, I'll provide an overview of the clinical trials and then show you the results of the comparative clinical trials in adolescents followed by the results of the comparative clinical trials in adults.

            And then I'll close with a review of the results of studies of the concomitant administration of Menactra with other vaccines.

            First, a brief word on the non-inferiority approach.  Non-inferiority studies are particularly suitable when a standard of care exists such as Menomune.

            In order to conduct the comparative evaluation of the candidate product versus the standard of care, it is necessary to define a threshold, a non-inferiority margin.

            Even two exactly equal products will not return exactly the same results in two populations under study.  These sample results will have some difference.

            And the non-inferiority criteria place a bound on the uncertainly concerning this comparison so that one then knows that if shown non-inferior, the candidate product is a suitable alternative.  And as I said, the evaluation of Menactra involves demonstrating its non-inferiority with respect to Menomune.

            There are a number of ways to measure immunogenicity.  And in the clinical laboratory, the most common measurements involve assays that measure the quantity of antibody present such as ELISAs or RIAs and produce results that typically are measured in milligrams or micrograms per ml.

            And although useful, these assays tell us nothing about the performance of the antibody that is being measured, only its quantity.

            Other assays called functional assays actually tell us about the performance of the antibody but typically these are more burdensome to conduct and are not generally available in clinical laboratories.  These include assays such as CHO cell assays, serum bactericidal assays, and so on.

            Now as Dr. Frasch mentioned, some 35 years ago, Gotschlich, Goldschneider, and colleagues conducted a seminal study at Fort Dix, New Jersey.  They drew serum samples from about 15,000 Army recruits arriving at Fort Dix for basic training.  And then followed them for about eight weeks to observe the occurrence of invasive meningococcal disease.

            Over that period of time, 54 cases occurred.  They analyzed the sera from those 54 persons as well as 10 control samples for each case.

            And what they found was that there was an extraordinarily high predictive value of having serum bactericidal assay titers of one to four or greater in your serum.  Having that amount of SBA conferred 98.4 percent protection from invasive meningococcal disease.

            They also showed that this protective property could be absorbed from the serum by group-specific polysaccharides demonstrating the specificity of this association.

            And as Dr. Frasch mentioned, in 1999, VRBPAC considered these issues and endorsed the use of serologic data, immunogenicity data, in support of the licensure of specifically conjugate meningococcal vaccines for those indications where a polysaccharide is licensed.

            We will present to you serum bactericidal assay results.  This is the standard approach for meningococcal assays.  The results are directly relevant to protection from the disease.

            It was the basis for licensure not only of Menomune several decades ago but also in the U.K. for the licensure of their currently used conjugate C vaccines.

            Our assay conforms to CDC and WHO standards and we participated in the Inter-Laboratory  Collaborative Study.  Our assays fully validated.

            Now when one measures immunogenicity, there are a variety of endpoints that could be looked at.  We'll present to you several different analyses.

            First we'll look at fourfold rises which are defined as the proportion of those participants whose post-immunization titers are at least four times their pre-immunization titers.

            This was specifically the basis for Menomune licensure and for licensure of the vaccines in the U.K.  And it's the primary non-inferiority outcome measure in all of the core clinical trials that I'll be presenting to you.

            I'll also show you geometric mean titer results, the normalized average of the post-immunization titers.  And this measure was a co-primary outcome in some of the core clinical trials and in the remainder, it's a descriptive measure.

            We also calculated seroconversion rates, which represents the proportion of those who were initially seronegative, defined as less than 1:8, who then have a fourfold or greater rise.  These analyses are descriptive and for the interest of time, I won't show them to you in the slides today but they are in your handouts.

            And finally, I'll show you some reverse cumulative distribution curves, which provide a graphical depiction of the overall distribution of antibody in the population participating.  And these, again, are descriptive.

            We have a number of clinical trials to present to you.

            MTA02 is the primary comparative trial between Menactra and Menomune in adolescents.

            MTA19 is a recently completed follow-up study in a subset of that same population who were given Menactra again three years later.

            MTA04 is a safety comparison in adolescents.  I'll not be presenting to you results from that study but my colleague, Dr. Chikami, will.

            MTA09 is the analogous trial to MTA02 but in adults.  It's the primary comparative trial between Menactra and Menomune in those 18 to 55 years of age.

            MTA14 is the lot consistency trial also conducted in adults.

            MTA12 is a study of the concomitant administration of Menactra and Td vaccine conducted in adolescents.

            And MTA11 is a study of the concomitant administration of Menactra and Typhim VI typhoid vaccine conducted in adults.

            In the aggregate, these clinical trials enrolled 7,642 persons to receive Menactra and 3,041 persons to receive Menomune, for a total of over 10,000, nearly 11,000 participants in the clinical trials.

            The gender distribution of those receiving Menactra and the racial ethnic distribution is shown on this slide.

            As you see, for the adolescents there was an approximately even balance between males and females whereas for adults, there was approximately a two to one ratio of females to males.  And in each case, those distributions reflect the patient populations of the clinics and centers that participated in the clinical trials.

            Overall 86.2 percent of the participants were white, non-Hispanic.  And 14 percent were other than white, non-Hispanic.

            MTA02 is the first study that I'd like to show you.  This was a multicenter, randomized, comparative clinical trial in U.S. adolescents; 881 healthy 11 to 18 year olds participated, approximately half of whom received Menactra and half Menomune.

            The hypothesis was that the short-term immune response of Menactra was not inferior to that of Menomune.  And I emphasize here short term for two reasons.  First, that is what we measured.  We looked at the antibody responses 28 days after immunization.

            But secondly, the short-term aspect is important to consider because polysaccharide vaccines, including Menactra, raise excellent antibody responses in full grown persons in the short term.

            The deficiencies of polysaccharide vaccines lie in the durability of their responses, their inability to prime, and the fact that they are not very effective in very young persons.

            I'll show you a number of slides that look like this.  This one shows you the fourfold rises.  Others will show you similar data.  For each of these, the four serogroups are rated across the slide.

            For each serogroup Menactra is compared to Menomune, Menactra will always be in the powder blue and Menomune in the pale yellow.  And below each of the bars, you find the data that support those bars.

            In this case, these are the fourfold rises among adolescents given Menactra or Menomune by serogroup.  And what you see is a very close correlation between the responses for the Menactra and the Menomune recipients.  And so not surprisingly, all the non-inferiority criteria were met.

            Now I'll also show you a number of slides that look this.  In each case, there's a vertical dash line or perhaps two vertical dash lines indicating the bounds of the non-inferiority margin that was defined.

            Within, or hopefully within those bounds, one will find the results of the four serogroups or whatever else the comparison might be, a little vertical line and a number indicating the point estimate, and the 95 percent confidence interval.

            If the entire 95 percent confidence interval lies within the non-inferiority margin, then the criteria for non-inferiority have been met.  If any part falls outside, then for that comparison, the criteria were not met.  And as you see here, all the non-inferiority criteria were met for fourfold rises among adolescents.

            This slide shows you the geometric mean titers from that same study.  For groups C, Y, and W, you see again a close correlation between the Menactra and the Menomune geometric mean titers whereas for serogroup A, it appears that the Menactra group has substantially higher geometric mean titers than the Menomune group.

            This is a reverse cumulative distribution curve.  Along the X axis are arrayed in ascending order various antibody titers.  Along the Y axis are the percentages of the overall population who achieved any given titer.

            So for the very lowest titer, four, the percentage is 100 percent.  And as the titer value rises, the proportion of the population that achieved that level or greater declines.

            Now on this slide, there are four lines drawn.  The two that are the pale pastels here are the pre-titers for Menactra and Menomune respectively.  And the bolder pastels are the post-immunization, the 28-day titers for Menactra and Menomune.

            This is serogroup A, which was the serogroup that you saw in the prior slide where the Menactra and the Menomune results looked different.  And one of the virtues of a reverse cumulative distribution curve is it enables you to understand the sources of difference.

            In this case, what you see is that the two vaccines appear identical up to this point here, titer of 256 or 512.  And then they start to diverge with the Menactra value superior, particularly in this range of titers from 4,000 through 32,000 or 64,000.

            And from this I conclude that although the geometric mean titers for Menactra were substantially higher than those for Menomune, the two vaccines  actually are identical in the range that is predictive of protection from disease.

            The human complement value 1:4 that was identified by Gotschlich and Goldschneider in their study 35 years ago, has been viewed to be equivalent to a titer of 1:128 by baby rabbit complement based on studies conducted both on laboratory validation studies and on studies out of the U.K. looking at their experience with their vaccine program.

            And as you see, both vaccines are achieving 100 percent coverage at 1:128 and even above that.  The difference lies in these high titers.

            So from that, I conclude that the difference in GMTs that was shown on the prior slide for A is probably of no clinical importance with respect to the performance of these two vaccines in the population.

            Here are the RCD curves for serogroup C, for serogroup Y, and for serogroup W135.

            Next I'd like to show you the results from study MTA19.  MTA19, which was recently completed and was not part of the submission to the FDA, enrolled a subset of participants in MTA02 and then offered them Menactra immunization.

            Seventy-six persons from MTA02 who received Menactra, 77 who had received Menomune, and an additional 88 persons enrolled at this point in time for this study who had never received any prior meningococcal vaccine participated in MTA19.  All received one dose of Menactra.

            And the objectives of our study were first to evaluate the persistence of antibody over the three-year interval from the initial vaccination MTA02 to the time of this second vaccination in MTA19.

            Secondly, to evaluate the ability of Menactra to prime and to boost.

            And third, to evaluate the response of Menomune recipients to a subsequent dose of Menactra.

            Now the inset slide here looks very much like the GMT, the geometric mean titer slide that I showed you a few moments ago for MTA02.  Indeed it differs only in that this version of the slide contains only those persons who went on to participate in MTA19.

            So it therefore provides the proper backdrop for this graph which shows you the level of antibody that these persons had three years after this point in time.  So if you compare these bar pairs to these bar pairs, what you see is substantially better persistence of the antibody in the Menactra than in the Menomune recipients.

            And indeed, although the study was not powered to achieved statistical significance for these comparisons, two of these four comparisons are statistically significant and the other two are borderline.

            Now recall we also enrolled at the time of MTA19 a vaccine-naive population to provide a further comparison.  These in coral here are shown the antibody levels of persons of the same age who have never received vaccine.  And so the difference between the Menactra vaccinated, the Menomune vaccinated, and the naive, I think, is clear.

            These reverse cumulative distribution curves further demonstrate the antibody levels prior to re-immunization.  These are the antibody levels three years after Menactra, three years after Menomune, or in a naive population that's never been vaccinated.

            These are the curves for serogroup A, for serogroup C, for serogroup Y, and for serogroup W135.

            Now on this particular scale, the pre-titers prior to re-vaccination look very similar here although you've just seen that they are not, in fact, similar.  Upon administration of Menactra, those who had previously received Menactra had a rapid and very high increase in their antibody levels.

            In the case of serogroup C here, up to about 18,000 within eight days following re-immunization.

            The naive population not previously vaccinated also had an excellent antibody response to Menactra but substantially lower than that of those who were previously primed, thus demonstrating the benefit of prior Menactra administration and the fact that Menactra does prime the immune system.

            Here are the results for serogroup Y, for the Menactra-primed, and for the naive.

            The results from serogroup W135 for the Menactra-primed and the naive.

            And the results of serogroup A for the Menactra-primed and the naive.  In this case, the naive responded equally well to the Menactra-primed, probably reflecting the fact that most of the population is already pre-primed for serogroup A due to cross-reacting antibodies.

            Then the last question we wanted to evaluate was what happens when you give Menactra to a person previously immunized with Menomune?

            Now this was the initial Menomune pre-titer and the antibody response after initial Menomune administration.  This is the antibody level of this group three years later.

            The literature tells us pretty clearly that if given Menomune at this point, because of the phenomenon of hyporesponsiveness associated with polysaccharide vaccine re-administration, the post-re-administration antibody level would be expected to be in this range down here and would not be expected to reach the level seen previously.

            What we found was that when this population was given Menactra, here you see it for serogroup C, there was an antibody response that exceeded that that would have been expected.

            Here you see serogroup A, serogroup Y, and serogroup W135.

            So from these repeat administration study data, we conclude that Menactra is associated with superior persistence of antibody.  At three years, the Menactra SBA geometric mean titers are higher than seen following Menomune or in naive controls.  And you see that clearly in the RCD curves also.

            We believe this study demonstrates the ability of Menactra to prime and to boost because we see a rapid, high anamnestic response that far exceeds the response of naive controls for all serogroups except A where they are equal.

            And we see the prior Menomune recipients who were given Menactra demonstrate a rapid increase in bactericidal antibody to levels that exceed those that would be expected were they re-immunized with Menomune.

            And we conclude, therefore, the Menactra demonstrates the important immunological characteristics that are expected of a conjugate vaccine.

            Now I'd like to turn to results in adults.

            MTA09 is the primary comparative trial in adults; 2,554 healthy U.S. adults 18 to 55 years of age of whom approximately 60 percent received Menactra and 40 percent received Menomune.  And, again, the hypothesis was that the short-term immune response of Menactra is not inferior to that of Menomune.

            We begin again with the fourfold rises.  And you see, again, close correlation between the Menactra and the Menomune responses for all four serogroups.  And the non-inferiority criteria are met.

            Here are the geometric mean titers, reasonably close correlation, less so for serogroups Y and W135, however, take note that even the lowest geometric mean titer is well over a 1,000.  All the non-inferiority criteria were met.

            And here are the reverse cumulative distribution curves.  For serogroup C and A, the curves closely compare.  For serogroups Y and W135, the curves diverge here as we saw earlier when we looked at the MTA02 study.

            And once again, as in that study, the two vaccines appear to perform identically up to a titer of well over the 128 benchmark for clinical protection.  Probably up to 256, it appears they are identical.  And the real divergence in the curves is in the range of titers above a 1,000, from 2,000 or 4,000 up to 16,000 or so.

            So we conclude again that although the GMTs differ, this difference probably has no relevance to clinical protection from disease.

            MTA14 was the lot consistency trial conducted in adults.  Approximately 2,000 healthy U.S. 18 to 55 year olds participated.  Three-quarters of these received Menactra, one-quarter respectively to each of three consistency lots of Menactra.  And the remaining quarter of the participants receive Menomune.

            The hypothesis was that the three Menactra lot geometric mean titers would be equivalent as reflected by a maximum ratio between any two GMTs of 1.5.

            Here are those geometric mean titers by serogroup, by lot.  You see some variation amongst the three.  In this particular case, there is no titer lower than 2,000.  So all of these anti-responses are very high.

            There are 12 non-inferiority comparisons to be made of which nine passed and three failed.  For the three failures, their point estimates are contained within the bounds but one end of the 95 percent confidence interval crosses the boundaries.  And as noted in the FDA briefing document, all of these confidence intervals are fully contained within a 2.0 ratio.

            Here are the geometric mean titers for serogroup A, C, Y, and let me pause here.  You note again the same thing we've seen before, that up to a titer well above the putative protective level, the two vaccines -- I mean in this case the three lots perform virtually identically.

            And it's only for the titers that are well above 1,000 that we see any differences.  So although these three did not meet the consistency criteria for the GMTs, slightly exceeding the margin, we believe that difference is of no clinical relevance.

            And serogroup W135.

            Here is another view of the results of this lot consistency trial.  In this table, you see the various lots by serogroup and the GMTs that you've just seen graphically.  But also shown are the percent achieving a fourfold rise and the proportion who had titers of 128 or greater.

            Now what you see is that there is substantially less variation in the percent achieving fourfold rise and virtually no variation, no more than plus or minus one percent, in the proportion achieving a titer of 128 or greater.

            Now I'd like to turn to the studies of concomitant administration of Menactra with another vaccine.

            First, we looked at the co-administration of Menactra and Td vaccine in adolescents.  We enrolled approximately 1,000 healthy adolescents to receive either Menactra and Td simultaneously or Td and placebo initially followed by Menactra 28 days later.

            And we looked at this question because it seemed likely to us that if licensed, Menactra might be given concomitantly with Td since the first Td booster for adolescents is recommended at about the same age that Menactra might well be given.

            The hypothesis was that the concomitant administration of the two vaccines would not be inferior in any way to the sequential administration of the two vaccines.

            Here you see the fourfold rises in SBA titer by serogroup.  Now the colors have changed because the vaccines represented are different.  The green bars represent Menactra plus the concomitant vaccine, in this case Td.  And the pale yellow bar here is Menactra alone 28 days after Td.

            So the question is are the green bars non-inferior to the yellow bars?  I think you see graphically that they are.  And indeed the statistical analysis demonstrates their non-inferiority.

            You saw there that the results 28 days later tended to be a little lower than the results with concomitant administration, which might raise in your minds the question of well, perhaps concomitant is okay but there's some problem with sequential administration.

            So to lay that question to rest, I've put on this slide the results from MTA02, which was the primary comparative trial in the same age group.  And what you see is that for three of the four serogroups, the sequential administration and the primary comparative trial Menactra results are essentially identical.  And for the fourth serogroup, they are superior.

            So from this we conclude that neither the sequential nor the simultaneous administration of Menactra and Td in any way interferes with Menactra antibody responses.

            Now with respect to the tetanus and diphtheria antibody responses, I need to show you a slide that is structured a little bit differently because antibody levels to tetanus and diphtheria can vary widely in the population and persons who already have very high antibody levels are much less likely to achieve a fourfold rise upon re-vaccination.

            So by agreement with FDA, we analyzed these data by separating the population into those who had very high pre-titers, in this case to tetanus, which is the blue group, and were held to the standard of requiring a twofold rise and person who did not have very high pre-titers, which is the group shown in green, for which we calculated fourfold rise percentages.  And then the pale yellow bar shows the aggregate information.

            Now the first block of three bars is the Menactra and Td group.  And the second block of three is the person who received only Td along with placebo.  And the question is how each bar compares to its companion color bar in the other group.

            And what you see here clearly is that there's no difference at all.  So that administering Menactra with Td and administering Td alone produce identical proportions of fourfold or twofold response and identical overall results.

            For the diphtheria antibody levels, the results are similar.  They differ only in that the proportion achieving a twofold response is greater in the concomitant administration than in the Td alone group.

            And for both tetanus and diphtheria, all pre-specified non-inferiority criteria were met.

            Finally, I'd like to show you the results of trial MTA11, which was a study of the concomitant administration of Menactra and Typhim Vi typhoid vaccine in adults.

            We looked at this because it occurred to us that many adults who receive Menactra might be travelers or military or others who would be simultaneously receiving a travel vaccine such as Typhim Vi.

            We enrolled in this study 945 healthy adults of whom approximately half received Typhim Vi and Menactra simultaneously and half receive Typhim Vi and placebo initially with Menactra given a month later.

            And the hypothesis again was that the concomitant administration of these two vaccines would not produce results that were inferior to the sequential administration.

            Here you see the geometric mean titers at Day 28 following either receipt of Menactra and Typhim Vi together or Menactra 28 days after Typhim Vi.  Once again, the results are very similar for the two groups.

            Here are the fourfold rises in SBA titer by serogroup.  And the results, again, are very similar or if different, the concomitant administration group is a little bit higher than the sequential administration group.

            All non-inferiority criteria were met.

            As far as the response to the Typhim Vi vaccine, we analyzed these data by looking at the proportion in which either titered greater than 1.0, a Typhim titer.  Here's the proportion for the concomitant administration group.  And here's the proportion for the sequential.  And clearly the concomitant is not inferior to the sequential as supported by this statistical analysis.

            So based on all these data, we conclude that Menactra is consistently immunogenic in adults and adolescents and satisfied all non-inferiority criteria.

            Menactra serum bactericidal antibody levels three years after administration are superior to those seen following Menomune or in naive controls.  One dose of Menactra primes from memory as demonstrated by a rapid and very high booster response upon re-immunization.

            Menactra offers a superior re-immunization pathway for prior Menomune recipients.

            And finally, Menactra demonstrates the important immunologic characteristics that are expected from a conjugate vaccine.

            At this time, I'd like to ask Dr. Gary Chikami to present to you the safety results from our studies.

            DR. CHIKAMI:  Thank you, Michael.

            The overall results from these studies demonstrate that Menactra was safe and well tolerated among adolescents and adults.  All the pre-specified safety criteria were met.  And the safety profile of Menactra is consistent with what would be expected from a diphtheria toxoid conjugate vaccine.

            The clinical safety program was designed to meet the requirements for regulatory approval and to establish the clinical impact of the overall safety profile for the product.

            The main objectives were one, to compare the safety profile of Menactra to the safety profile of Menomune.  The primary objective was to demonstrate that the rate of severe systemic reactions was similar between Menactra and Menomune recipients.  The comparison was based on severe systemic reactions because these were felt to be the most clinically significant.

            It's important to note that the local reactogenicity profile was expected to be different between Menactra, a protein conjugate vaccine containing diphtheria toxoid, and Menomune, a polysaccharide vaccine.

            The second major objective was to characterize the overall safety profile of the product.  The following safety data were collected: immediate reactions were collected for the 30 minutes post-vaccination.

            Solicited and systemic local reactions were selected because they are clinically significant to the characterization of the overall safety profile of Menactra.  These lists were developed with input from the FDA Review Division.

            Unsolicited reactions were collected during two time periods.  All adverse events were collected from Day Zero through Day 28.  From Day 29 through Month 6 in studies which included a six-month follow up, any adverse event that included a new onset of a sign, symptom, laboratory abnormality that promoted medical intervention were collected.

            And finally, serious adverse events were collected throughout the entire follow-up period for each study.

            The overall rates for immediate reactions were similar across the vaccine groups; .3 percent Menactra recipients and .2 percent of Menomune recipients reported an immediate reaction.

            We looked more closely at the eight cases that were coded as syncope in the Menactra recipients.  We found that five of the eight cases were described as vasovagal reactions, two were described as syncope in one as a syncopal episode.

            None were reported as a serious adverse event, and none required medical intervention, and all were covered on the same day without sequelae.  Based

on these descriptions, we conclude that there are no significant concerns regarding these cases.

            The categories of events included in the list of systemic reactions was based on experience with Menomune and other conjugate vaccines.

            A pre-established list of medical conditions was defined that meet study protocol.  The clinical severity of the reported events were documented as mild, moderate, or severe according to a defined rating scale.

            Information was collected on participant diary cards from Day Zero through Day Seven.  The presence or absence of an event and the intensity of the event were collected on a daily basis.  This allowed us to determine the duration of the event as well as the duration of the most intense portion of any reported event.

            The safety comparison objective was to demonstrate that Menactra was non-inferior compared to Menomune with regard to participants who reported a serious systemic adverse event.

            For MTA04 and MTA09, the criteria for non-inferiority was based on the ratio of the 95 percent confidence interval of subjects presenting at least one severe systemic reaction.  The upper limit of the 95 percent confidence interval was set at three.

            For MTA02 and MTA14, the criteria for non-inferiority was based on the 95 confidence interval of the difference in the percentage of subjects reporting at least one severe systemic reaction.  In this case, the upper limit of the confidence interval was set at 10 percent.

            The difference in the non-inferiority criteria used across the two groups of studies were the result of ongoing discussions with the Review Division.

            For MTA02 and MTA14, in addition to the criteria specified in the protocol, we applied the stricter criteria used in MTA04 and MTA09 and those are the results that I'll present to you this morning.

            For solicited systemic reactions in the studies in adults, all of the non-inferiority criteria were met.

            MTA04 was a comparative study in adolescents and a total of 3,235 participants were evaluated for safety.  Ninety-nine percent of the participants completed the six-month follow up.

            The frequency of any systemic reaction was 55 percent in the Menactra group and 48.7 in the Menomune group.  The rates for severe solicited systemic reactions were 4.3 percent and 2.6 percent in the Menactra and Menomune groups respectively.

            In the assessment of the primary safety endpoint, the ratio of the percentage of participants with any severe solicited systemic reaction is 1.66.  And the upper bound of the 95 percent confidence interval is 2.56, meeting the criteria for non-inferiority.

            While the upper bound of the confidence interval does fall within the specified criteria for non-inferiority, there was a higher rate of reactions on the Menomune subjects in this one study.

            For each of the solicited systemic reactions, we assessed frequency, intensity, and duration.  The most common systemic reactions reported were headache, fatigue, malaise, and arthralgia.  Most events were classified as mild.  The median duration for any solicited systemic event was three days in the Menactra group and two days in the Menomune group.

            With regard to severe reactions, the rates for headache, fatigue, malaise, and diarrhea were higher in the Menactra recipients.  As I'll show you in subsequent slides, those same events were not significantly higher in Menactra recipients in the other comparative studies.  And none of these reactions were reported as severe adverse reactions.

            There were no other significant differences between the rates of severe events between the two groups.  And for events that were reported as severe, the duration of the severe component was one day.

            MTA02 was the second comparative immunogenicity and safety study in adolescents; 880 participants were evaluated for safety and 98.9 percent completed the study.

            The rates for any solicited systemic reaction were 57.2 percent in the Menactra recipients, 51.9 percent in Menomune recipients.  And for severe reactions, 3.9 percent and 4.1 percent in the Menactra and Menomune recipients respectively.

            The ratio of the percentage of participants with any severe solicited systemic reaction is .95 and the upper limit of the confidence interval is 1.82, again meeting the criteria for non-inferiority.

            In this study, the most common systemic reactions were headache, fatigue, anorexia, and diarrhea.  Again, most events were classified as mild.  Overall, the median duration for the solicited systemic events was three days in both vaccine groups.

            In contrast to MTA04, the other study in adolescents, there were no significant differences in the rates for any of the severe systemic reactions for the Menactra and Menomune recipients.  The median duration for the severe component of these events was one day.

            The rate of systemic reactions observed in MTA12 provide a useful context for the rates that I've shown you in MTA04 and MTA02.  In MTA12, Menactra was given concomitantly with or 28 days after Td vaccine in healthy adolescents, a population similar to MTA04 and MTA02.

            In this study, the rates of systemic reactions were similar in the groups that received Td concomitantly with Menactra or Td with placebo.  The rates of systemic reactions observed in MTA04 and MTA02 were similar to those observed in MTA12 for Td vaccine.

            Overall the rates in the adult studies were comparable to the results seen in the adolescent studies and the non-inferiority criteria for each study were met.

            MTA09 was a comparative study in healthy adults and a total of 2,530 participants were evaluated for safety.  Ninety-four percent completed the six-month follow up.  The rates of any solicited systemic reaction was 61.9 percent in the Menactra recipients and 60.3 percent in the Menomune recipients.

            The rates for severe systemic reactions were 3.8 percent and 2.6 percent in the Menactra and Menomune recipients respectively.

            The ratio of percentage of participants with any severe solicited systemic reaction was 1.47.  And the upper limit of the confidence interval is 2.28, meeting the criteria for non-inferiority.

            The most commonly reported systemic reactions were headache, fatigue, malaise, and arthralgia.  And the rates were similar across the vaccine groups.

            Most systemic reactions were classified as mild and the median duration was three days in both groups.

            Except for chills, which were higher in the Menactra recipients, there were no significant differences in the rates of any of the severe systemic reactions reported in the Menomune and Menactra recipients.

            In MTA14, comparative safety was evaluated in Menactra and Menomune recipients in a total of 1,140 adults.  Ninety-four percent completed the six-month follow up.  The rates of any solicited systemic reaction was 53.4 percent compared to 49.2 percent.

            And in this study, the rate of severe systemic reactions were lower in the Menactra recipients at 2.2 percent versus 5.5 percent in the Menomune group.

            The ratio in the percentage of participants with any severe solicited systemic reaction was .4.  And the upper limit of the confidence interval .75, meeting the criteria for non-inferiority.

            The most commonly reported systemic reactions were headache, fatigue, malaise, and arthralgia.  Again, most systemic reactions were classified as mild and the median duration of the reactions was three days in both vaccine groups.

            Except for malaise, which in this case was reported higher in the Menomune group as compared to the Menactra group, there were no significant differences between the rates of any of the severe systemic reactions reported.

            To put the rates of systemic reactions in the two adult studies in context, this slide shows the results from MTA11.  In this study, Menactra was given either concomitantly with or 28 days after Typhim Vi vaccine in healthy adults, populations similar to those enrolled in MTA09 and MTA14.

            The rates for solicited systemic reactions reported in MTA09 and MTA14 were in the same range as those seen with Typhim Vi whether given concomitantly with Menactra or with placebo.

            It was anticipated that the local reactogenicity profile of Menactra, a protein conjugate vaccine containing diphtheria toxoid, would be different from Menomune, a polysaccharide vaccine.  While this was observed in the clinical studies, data from the concomitant use studies with Td and Typhim Vi vaccine show that the local reactogenicity profile of Menactra was similar to that for these other licensed vaccines.

            Solicited local reactions were defined in the protocol for each study and included redness, swelling, induration, and pain at the injection site.  Information was recorded on participant diary cards on Day Zero through Day Seven.

            Clinical intensity was documented as mild, moderate, or severe according to predefined rating scales.  For induration, swelling, and redness reported as severe, the measurements of the actual event were to be recorded.

            In the adolescent studies, local reactions were higher in the Menactra recipients as compared to the Menomune recipients.  Pain at the injection site was the most frequent local reaction reported and were reported in the ranges shown on this slide.

            While the rates of injection site pain were higher in the Menactra recipients as compared to the Menomune recipients, the observed rates were similar to those or lower than the rates observed for Td vaccine in MTA12.

            For all groups, the majority of pain was reported as mild.  The median duration of pain was two days in the Menactra recipients compared to one day in the Menomune recipients and one to two days in the Td recipients.

            Severe pain was uncommon and was reported in 0 to .8 percent of Menactra recipients and .2 percent of the Td recipients.  The median duration of the severe component was one day.

            As with pain at the injection site, the reported rates of induration, swelling, and redness were higher in the Menactra recipients compared to the Menomune recipients.  The rates in the Menactra recipients were in the same range as those reported by Td recipients in MTA12.

            The majority of the events were mild in intensity for all vaccine groups and the median duration was one day in the Menomune recipients, one to two days in the Menactra and Td recipients.  Severe induration, swelling, and redness were uncommon.

            Overall, these rates show while the rates of local reactions were higher in the Menactra recipients as compared to Menomune recipients, the local reactogenicity profile of Menomune is comparable to that of Td.

            Within MTA12, the overall rates for local reactions observed at the Menactra injection sites, the two bars in the center of the graph, were lower than those observed at the Td injection sites, the two bars on the extreme left of the graph.

            While the overall local reaction rates observed in MTA02 at 72.4 percent and MTA04, at 62.7 percent, were higher than those observed at the Menactra injection sites in MTA12, they were similar to or lower than the rates observed at the Td injection sites.

            Similar to the studies in adolescents, the rates of local reactions were higher in Menactra recipients compared to Menomune recipients in the adult studies.  Pain at the injection site was the most frequent local reaction and was more frequently reported among Menactra recipients compared to Menomune recipients.  The rates of pain among Menactra recipients was less than those observed in Typhim Vi recipients in MTA11.

            Most injection site pain was reported as mild and the overall median duration of pain was two days.

            Severe pain was reported in 0 to 1.8 percent of Menactra recipients compared to 0 to .1 percent of Menomune recipients and .4 to .8 percent of Typhim Vi recipients.  The duration of severe pain was one and one-half to two days for the Menactra recipients compared to one day for Menomune recipients and two and one-half days for Typhim Vi recipients.

            Again, the rates of induration, swelling, and redness were higher in the Menactra recipients compared to Menomune recipients however these rates were lower than those observed at the Typhim Vi injection sites in MTA11.

            The majority of the events were mild in intensity and the median duration was one to two days in Menomune recipients, two days in Menactra recipients, and one day in the Typhim Vi recipients.  Severe induration, swelling, and redness were uncommon.

            The overall results from these studies in adults show that while the rates of local reactions for Menactra were higher compared to Menomune, these rates were lower than observed for Typhim Vi vaccine.

            Within MTA11, the rates of local reactions reported at the Menactra injection sites, the two center bars, were lower than those reported at the Typhim Vi injection sites, the two bars on the extreme left of the graph.

            The local reaction rates reported in MTA09 and MTA14 were in the same range as those rates reported for Menactra injection sites in MTA11.  But again, these rates were lower than those reported at the Typhim Vi injection sites.

            Unsolicited adverse events and serious adverse events were reported at similar rates across the two vaccine groups in the clinical studies.  This table shows the most frequent unsolicited adverse events that occurred in at least one percent of participants.  And there were no differences in the nature of frequencies of events across the two vaccine groups.

            We found similar results for the six-month follow-up period in studies that included that follow up.

            A total of 5.8 percent and 5.7 percent of Menomune recipients reported at least one unsolicited adverse event.  There were no differences between the nature or frequency of these events.  None of the events was considered either probably or definitely related to study vaccine by the investigators.

            And there was no apparent increase in the frequency of new-onset asthma, diabetes mellitus, or autoimmune disease.

            With regard to SAEs, there were 77 participants in the Menactra group who reported a serious adverse event and 39 among the Menomune recipients.  All except one were categorized as unrelated to study vaccine by the investigator.

            Across the six studies, there were two deaths reported in study participants.  Both were in study MTA14, one a motor vehicle accident occurring 109 days after study vaccination in the Menactra group, the other a drug overdose occurring 79 days after vaccination in the Menactra group.  Both were classified as unrelated to study vaccine by the investigators.

            Overall, the safety data from the clinical trials demonstrate that Menactra was safe and well tolerated among adolescents and adults.  Menactra met all agreed non-inferiority criteria with respect to safety.

            Specifically Menactra was demonstrated non-inferior to Menomune with respect to the proportion of subjects reporting at least one severe systemic reaction.

            While the rates of local reactions seen with Menactra are higher than those reported with Menomune, they are comparable or less than the rates seen with Td vaccine and are consistent with expectations for a protein conjugate vaccine.

            And Menactra may be administered either concomitantly with or one month after Td vaccine or Typhim Vi vaccine.

            Thank you.  And I'll turn the podium back to Dr. Kuykens.

            DR. KUYKENS:  Thank you, Gary.

            Let me know briefly present the conclusions of the sponsor.

            In our immunogenicity presentation we have shown data indicating that Menactra is highly immunogenic both in adults and adolescents, that Menactra's immune response is non-inferior to Menomune's, our widely-licensed polysaccharide vaccine, and that Menactra can be administered concomitantly with Td and Typhim Vi vaccines.

            Dr. Decker reviewed important recent data  from a three-year follow-up study to our pivotal MTA02 trial indicating that Menactra has the characteristics expected from a conjugate vaccine, antibody persistence, immune priming and boosting, and lack of hyporesponsiveness.

            Dr. Chikami presented the safety data indicating Menactra is safe and well tolerated, has a non-inferior safety profile in regards to severe systemic reactions compared to Menomune, and a local reactogenicity profile similar to Td vaccine.

            Menactra can be administered concomitantly with Td and Typhim Vi vaccines.

            In conclusion, from a risk/benefit point of view, the local reactogenicity rates for Menactra were as expected for a diphtheria-containing conjugate vaccine, somewhat higher than those of Menomune.  But were similar to those seen with Td vaccine.

            The benefits shows for Menactra include the excellent immunogenicity profile in both populations of adults and adolescents, the improved antibody persistence versus the polysaccharide vaccine, the priming and boosting capabilities, and the lack of hyporesponsiveness.

            This concludes the presentation of the sponsor and the presenters will be happy to take any clarifying questions at this point.

            CHAIRMAN OVERTURF:  Thank you.  I'd like to thank Drs. Kuykens, Gilmet, Decker, and Chikami for the presentation.  And I open the floor for any questions or clarifications.

            MEMBER MARKOVITZ:  Yes, David Markovitz, University of Michigan.  I have a question probably for Dr. Decker.  Michael, do I understand correctly that when Menomune priming data are strictly historical?  You don't have a direct comparison?

            DR. DECKER:  No, we did not enroll a group in that study to receive Menomune again.  That would have raised ethical questions because the literature, I think, are really very -- pretty uniform on the hyporesponsiveness.

            For example, I'm reminded of Dr.  Granoff's study because I'm looking right at him.  And in his study he found no improvement in antibody whatsoever from baseline upon re-administration of Menomune.  Now that's probably the most pessimistic study out there.  Others have shown some improvement in antibody.

            But I think we already know that if you re-administer Menomune, you're happy to see any increase in antibodies compared to the prior value.  You really get your benefit out of a polysaccharide vaccine with the first administration.

            MEMBER MARKOVITZ:  Okay, thanks.

            CHAIRMAN OVERTURF:  Yes, Dr. Karron?

            MEMBER KARRON:  Two questions.  The first is really a follow on to that question.  And it's that although clearly the people who got Menomune and then Menactra had much higher antibody responses than you'd expect with two doses of Menomune, if I'm reading the data correctly, all of the antibody titers were lower than in people who only received placebo.

            And that was particularly true with group C where I think the placebo recipients had titers of about 2,000 whereas the people who got Menomune and then Menactra had titers of about 500.

            And my question is do you think that Menomune is blunting the response to Menactra?

            DR. DECKER:  Well, let me clarify for a moment.  No one received placebo.  There was --

            MEMBER KARRON:  I'm sorry.  I misspoke.  So people in that study who received a first dose of Menactra compared to people who received Menomune followed by Menactra.

            DR. DECKER:  Yes, I saw what you did that those who had previously received -- those who were naive --

            MEMBER KARRON:  Yes.

            DR. DECKER:  -- and received Menactra had superior antibody responses apparently than those who were previously vaccinated with Menomune and then received Menactra.

            Although I think that's probably a correct observation, I think it's not the key question because those people in the U.S. population who previously received Menomune received it for good reason and they cannot go back and become vaccine naive.

            And the real public health question is what's the best thing to do for them if they again or continue to need protection from invasive meningococcal disease.  And heretofore we've had only  the limited choice of do nothing or received the polysaccharide again.

            And I hope that we'll now have the better choice of receive the conjugate.

            MEMBER KARRON:  My second question actually just had to do with a choice of Typhim Vi as the representative traveler's vaccine.  I was wondering what considerations lead you to chose that particular vaccine.

            DR. DECKER:  I can't help but note that we make it.


            DR. DECKER:  And I wonder if that influenced the choice.  But I would have to defer to my colleagues to know more precisely.

            DR. KARRON:  Okay.

            CHAIRMAN OVERTURF:  Dr. Whitley?

            MEMBER WHITLEY:  Rich Whitley, University of Alabama.  This is a simple question.  If I read your data correctly, you only followed those patients 28 days in the prime/boost experiment.  Do you have any later data, six months, one year, two years?  Or the data are not there yet?

            DR. DECKER:  You're referring to immunogenicity data?

            MEMBER WHITLEY:  Yes, yes.

            DR. DECKER:  We have data from the studies that we have conducted in children, age range toddler through ten.  And we anticipate presenting those data to FDA in support of a license extension once Menactra is licensed for the 11 to 55.

            And because the question that you raise is of the most acute interest in that population, it's in those populations that we followed six month antibody levels.  And we could show you those data if you like.

            CHAIRMAN OVERTURF:  Dr. Stephens?

            MEMBER STEPHENS:  Two questions about MTA19.  One has to do with the serogroup C data.  And it looked like in comparison to W135, and in Y, and even A that there was a significant greater fall off of C.  And, in fact, a number of those individuals were at what I would consider borderline SBA titers at three years.

            Can you comment on that particular data?  That's the first.  It's 66, I think, in the slide.

            DR. DECKER:  Slide on please.  I believe this is the slide you're referring to?

            MEMBER STEPHENS:  Right.  I mean just in comparison to the other antibody data, if you look at the other reverse cumulative distribution curves, this is the greater fall off at three years.

            And the question really had to do with some of the, you know, the recent C data in the U.K. that is of some concern.  And just your comments about was this greater than you had anticipated in terms of the fall off in C antibody with Menactra.

            DR. DECKER:  I don't think it was greater than was anticipated because what we've seen from data from other countries that have been previously immunizing with C is that C does tend to fall off.

            What you see here is a uniformity -- let me rephrase that -- the only comparison we have internally here is the comparison, of course, between the Menactra recipients, the Menomune recipients, and the naives.

            And the relative comparisons between those three groups across the four serogroups tells a fairly consistent story.  Now it can be a complicated story because the four serogroups really behave somewhat differently.  A and C co-circulate in the United States at relatively high rates.  And, therefore, what we see, particularly in more modern sera, is that baseline rates tend to be a little bit higher for those.

            I'm sorry, I said A and C.  I mean Y and C co-circulate.  A has cross-reacting antigens in the environment that can raise antibody levels.  And so W is really the only one that's, as far as we know, not stimulated by circulating, cross-reacting antigens.  And isn't stimulated by fairly high levels of circulating organisms.

            And because of this, for many of these pre-titers or post-titers when you look across the four serogroups, you see different patterns.  So we already know that.

            Within that context, what we're seeing here for C was not surprising.  I think it's consistent with the global data.

            MEMBER STEPHENS:  The second question has to do with boosting of A.  Do you really think that you saw boosting of A?

            DR. DECKER:  Are you referring to in MTA19?

            MEMBER STEPHENS:  Yes.

            DR. DECKER:  Could we go back to the core slide for MTA19?  Yes, this is the one.

            Now by the classic definition that I have applied when I showed the first slide, you would say there's no boosting because the naive did equally well.  But I think we have to take --

            MEMBER STEPHENS:  And I guess the polysaccharide alone does about the same?

            DR. DECKER:  No, there's no polysaccharide -- I'm sorry, yes, I misspoke and I apologize.  The polysaccharide alone did about the same.

            But A is unique.  Pre-titers for A are much higher because of the cross-reacting antigens.  Now if you look at the population distribution of existing antibodies in the non-vaccinated for A versus the other serogroups, you see much, much higher levels.

            For example, 60 to 80 percent of the population will have levels that are of 64 or 128.  And so the way we interpret this result that you're looking at is that the naive controls for A are not really naive.  They are essentially pre-primed.  That's our best understanding of what's being seen here.  And so they're getting, in fact, what's an anamnestic response to the polysaccharide.

            Now for the other three serogroups that don't have the cross-reacting antigens such as the E. coli and the bacillus that circulate, we didn't see that.

            CHAIRMAN OVERTURF:  Dr. Self?

            MEMBER SELF:  Yes, I have a few questions just to help connect the dots from the protective effects and the relationship with SBA that were in the Fort Dix study and the measurements that were used in these studies that some actually show the non-inferiority of these two vaccines.

            The piece of data that I don't see here is in a reference which, I admit, I didn't see.  And that is a paper that shows the correlation between the assays using human complement and the baby rabbit complement.

            Do you have that data or could you explain what this one liner is that says that one titer for one assay correlates with a different titer for the other assay?

            DR. DECKER:  There are several lines of evidence that support that.  And if I could see Slide IM68 please?

            Dr. Luis Jodar who wrote on behalf of WHO in this publication summarized the available data which supported WHO's assertion that 1:128 provided a conservative comparison to the 1:4 in humans.  And there were three key points.

            First, that SBA baby rabbit titers less than 1:8 appear to correlate closely with human complement titers less than 1:4.  In other words, that category might be predictive of potential susceptibility.

            SBA baby rabbit titers that were greater than 1:128 correlated well, in fact were even more strongly predictive of protection than human complement titers of greater than 1:4.  And baby rabbit titers that fall between those two measures, between 1:8 and 1:32 were of uncertain predictive value.

            In other words, they couldn't establish a tight correlation either with protection or with non-protection.  So with baby rabbit, there is a gray zone between 8 and 128.  Below 8 seems to correlate with below 1:4 by human.  And above 128 seems even more predictive of protection in 1:4 in humans.

            MEMBER SELF:  So by correlation with the baby rabbit titers greater than 128, does that mean that a baby rabbit titer of over 128 will predict with very high, you know, with what specificity a human titer over 1:4?

            DR. DECKER:  If you'll permit -- let me phrase that just a hair differently and then I can agree.

            A baby rabbit titer of 1:128 or greater is believed to be as highly predictive of protection from invasive meningococcal disease as is a human complement titer of 1:4 or greater.

            MEMBER SELF:  Based on the Fort Dix data?

            DR. DECKER:  No, based on -- well the 1:4 number comes out of Fort Dix and similar studies.

            MEMBER SELF:  Right.

            DR. DECKER:  The 1:128 number comes flows out of two sources, laboratory correlation studies just looking at the assays themselves but more importantly correlations of antibody levels in human populations and the protection of those human populations from disease.

            MEMBER SELF:  In vaccine studies or natural history studies?

            DR. DECKER:  Well, in both.  Data coming out of the U.K. looking at, for example, data -- in the deployment of their vaccination program, the British looked at many of these parameters and they published a number of papers.

            And they looked, for example, at antibody levels in persons who had been immunized and found what levels correlated with protection.

            MEMBER SELF:  Is that data in the package that you submitted?  Because that would seem to be rather key, directly showing that the measurement that you're using in your studies is related at an individual level to risk in human populations.

            DR. DECKER:  I don't know if those references are included in the briefing document or not.  Part of the context for us was that it was -- the use of baby rabbit as the basis for evaluation of both vaccines was predefined with the Agency.  And so we approached from that starting point.

            But recognizing that this is a question of interest, I familiarized myself with the data so I could answer your question.

            MEMBER SELF:  Okay.  So a second part of this question really has to do whether the relationships that are cited here between antibody titers and protection are consistent across the various serogroups that are being identified as potentially being protected against by this vaccine.

            I could see only subtype serogroup C in the references that were given here.

            DR. DECKER:  Most of the modern data relate directly to serogroup C because the vaccines, the conjugate vaccines that are now deployed in population-based programs are C only vaccines.  Menactra will be the world's first multivalent conjugate meningococcal vaccine.

            The use of serogroup A protective vaccines in Africa, of course, happens.  But those are not broad-based population programs such as you see in the U.K. and in the other countries that have adopted the conjugate meningo vaccines.

            Rather they are delimited interventions aimed at aborting epidemics and they don't give rise to the same level of data.

            MEMBER SELF:  So there isn't data comparable say to the Fort Dix data for the other serogroups really?

            DR. DECKER:  There is not the same body of data for the other serogroups.  There are no data that contradict the assumption that what's true for C is true for the others.  But neither is there the same wealth of data for the others that there is for C.

            MEMBER SELF:  And just one last follow up.  Is there, for the other subgroups then, data comparable to the one that's -- Jodar looking at the relationship between the two assays?

            DR. DECKER:  Yes, there are data.  And we have some very limited data in that regard.  If I could go to Slide IM69 please?

            One of the things that the Agency asked us to do was to use a small subset of serum from MTA02 which was the core comparative trial in adolescents.

            Slide on please, I'm sorry.

            I believe this was MTA02.  I could be mistaken it was MTA09.  But that's not an important point.  What this slide compares is two standards, the licensure -- the basis for licensure for Menomune originally, of the conjugate C vaccines in the U.K. and now of Menactra, the primary non-inferior comparison is the proportion achieving a fourfold rise.

            The standard of comparison that was established 35 years ago by Goldschneider and colleagues was a 1:4 by human complement.  So a reasonable question is to what extent is the population characterized equivalently by those two measures?

            So these data show you for about 75 people who received either Menomune or Menactra, 75 in each group, how the fourfold rise rates compare to the 1:4 human complement rates.  Those achieving a fourfold rise by baby rabbit are in green.  Those achieving a 1:4 by human complement are in the pale yellow.

            This is serogroup C.  What you see here is that the results are very comparable.

            If I can have the next slide please?

            MEMBER SELF:  Just to interject.  That is group means rather than the association between those two assays.  So what would be really interesting, I think, would be to look at the scatter plot of the titers, one assay versus the other for subgroup C.  And if the data were available for the other relevant subtypes.

            DR. DECKER:  The analysis you are requesting was conducted by the FDA statistical analyst and is present in the FDA's briefing document.  But I'd respectfully suggest that that's not the most important question for this use of the assay because we're not seeking to validate the baby rabbit assay as a diagnostic tool for individual patients.

            And we actually have no interest in whether or not it produces the same result for an individual as does the human complement.  Rather we're using this as a probe to test a population to see if it gives us the same predictive ability in a population as does the human complement.

            And, therefore, the scatter plot, which frankly doesn't look very good, would be misleading because it's only on the population level that these two perform very, very similarly.  So that's why I'm showing you population data.

            MEMBER SELF:  Yes.  I guess what you could find from that scatter plot would be you could identify the range of the baby rabbit assay titers that is induced by the vaccine.  And then look up to see that essentially all or, you know, what fraction of those meets the 1:4 criterion for the human complement assay that then has the connection to the risk data.

            DR. DECKER:  Yes, and that would be entirely appropriate if the goal was to validate that assay's sensitivity and specificity as applied to individuals.  But --

            MEMBER SELF:  I guess we'll disagree.

            CHAIRMAN OVERTURF:  Dr. Markovitz?

            MEMBER MARKOVITZ:  Yes.  David Markovitz.  I had another -- one comment and one question.

            First of all, the comment is when you look at the racial makeup of your subjects, it doesn't really reflect very well the makeup of the United States on a percentage basis.  And I guess on a gut level, I doubt that's going to matter in terms of the results.

            But I would like to suggest that future studies try to have a little closer approximation because that will give us -- get more faith that the data reflect what will happen to the United States population.

            My second question, which is not certainly essential to the process here but I'm very curious why it is that we don't have, you know, serogroup B included in any of these vaccines.  Can you give me some background on what's going on with that?  And what are people trying to do to rectify that problem?

            DR. DECKER:  Let me respond to both of your comments.

            With respect to the racial/ethnic distribution of the participants in the studies, there were 14 percent who were not white, non-Hispanic, which is less than the distribution of the U.S. population but more than historically we've been able to achieve in studies.  And I think what you've seen, as candidates come forward here over the years, is that number is creeping up.

            Everybody is trying to bring that up in alignment.  But it's a lot harder to get participation in inner cities and so on in study recruitment.  And so it's a difficult process.  And all I can say is it's improving.

            I can also tell you that subgroup analyses by race showed no worrisome deviations in the response rates.  In fact, the Blacks and the Hispanics and so on tended to have higher immune response rates than the white.  And so we find no evidence to suggest that there is a concern there.

            With respect to the second and really compelling question why not B, the fact is that one cannot have a polysaccharide-based vaccine for B because the polysaccharide of B is the same polysaccharide that's involved in neural coding in the human nervous system.

            And so if a vaccine of B worked, it would be an effective vaccine against your own nervous system.  But it won't work because you are tolerant to that.

            Now that means the pathway for a vaccine to B has to lie through protein types but there are nearly 100 protein types for B.  So in the world right now, there are only a couple of vaccines against B.  And they're only known to work on isolated island situations where they -- they don't work on continental masses because on an island, you can a single dominant protein type.

            So the Cuban vaccine probably does work in Cuba.  And the recently-developed vaccine for New Zealand is specifically targeted to the protein type that's dominant in New Zealand.

            And in these isolated island populations, they'll probably work.  But we yet have no real answer for continental populations.

            MEMBER MARKOVITZ:  Are there problems with side effects also if it's so close to neural proteins?

            DR. DECKER:  Well, one simply doesn't do it.  There are no polysaccharide-based vaccines for B because of this.

            CHAIRMAN OVERTURF:  Dr. Stephens?

            MEMBER STEPHENS:  As you suggest, one strategy may be to give this vaccine to 11 or early adolescents with Td.  And I was interested that there looked like there was some significant difference between the immune response with concomitant Td and Menactra.

            Can you comment on those data?

            DR. DECKER:  Different response in what way?

            MEMBER STEPHENS:  It was an enhanced immune response.  When you gave Td with Menactra, the geometric mean titers were significantly or at least appeared to be significantly elevated as opposed to Menactra without Td.

            And it looked like you were getting some additional booster effect of Td in that kind of setting.

            DR. DECKER:  Well, remember Menactra is a diphtheria conjugate vaccine so when one administers Td, in essence one is administering an additional dose of the carrier in the other arm.  And I think what we're seeing is carrier enhancement here.  And, therefore, an increased antibody response.

            And it goes both ways.  The concomitant administration probably augments the antibody response to each vaccine.

            DR. OVERTURF:  We'd like the members of the committee to have their seats again so that we can resume, please.  At this time I'd like to invite Dr. Lee to the podium to begin the review of the Clinical Safety and Efficacy for the FDA.

            DR. LEE:  Good morning.  I'll be presenting FDA's Clinical Review of Aventis Pasteuris tetravalent meningococcal conjugate vaccine.  I will first present the proposed basis for licensure in ages 11 to 55 years old.  Next, I will focus on four studies presented earlier today, MT02, MT09, MT04, and 12, and the primary data submitted in support of efficacy, safety, and concomitant vaccine administration with Td.  I will then present the questions and the discussion points for the committee.

            The approach to licensure of Menactra was based on the demonstration of immunogenicity and safety through non-inferiority comparisons to Menomune, a U.S. licensed meningococcal polysaccharide vaccine.  These non-inferiority comparisons were a means of demonstrating immunologic and safety equivalents to Menomune.  Licensure was also based on the demonstration of lot consistency.

            Efficacy was inferred from an immune correlate rather than directly measured from a clinical disease end-point.  As reviewed by Dr. Frasch, induction of bactericidal antibody following meningococcal vaccination has been shown to be protective, and thus this immune measure is considered a useful predictor of vaccine effectiveness. 

            Clinical efficacy of meningococcal A and C monovalent and AC combined polysaccharide vaccines have been confirmed in large scale field trials.  In studies MT02 and MT09, bactericidal antibody response was measured with an assay using baby rabbit complement.  Group C meningococcal antibody titers, however, reported from recent studies in the United Kingdom were found to be elevated when baby rabbit complement was used in the bactericidal assay relative to results using human complement.

            Historically, bactericidal antibody results generated with an assay using human complement are most closely linked to individual susceptibility to meningococcal disease, but large volumes of human sera that are a suitable source of exogenous complement are not readily available today.

            The sponsor was thus asked to test sera in a subset of study participants to determine the similarity of Menactra bactericidal antibody responses compared to Menomune when each of the complement sources was used in the assay.  A similar immunogenicity profile with the two vaccines would provide reassurance that efficacy estimates would also be similar. 

            In MT02, pre and post vaccination sera was obtained from 84 Menactra participants, and 81 Menomune participants.  Sera was also obtained in MT09 from 50 participants in each group.  Data generated from each assay was provided for sera groups C, Y, and W135 from MT02 participants from whom sufficient sera was available.  And likewise, for W135 and Y in study MT09.  Sera from a separate subset of 102 MT02 participants was used for Sera Group A analysis. 

            The antibody response was assessed by reverse cumulative distribution curves, seroresponse, and seroconversion rates.  These reverse cumulative distribution curves represent post vaccination antibody results from a subset of Menactra and Menomume participants 11 to 18 years old with the serum bactericidal assay using baby rabbit complement.

            For Serum Group C, 100 percent of Menactra participants achieved a titer of at least 1 to 8, and 92 percent achieved a titer of at least 256, compared with 100 percent and 95 percent respectively in the Menomune group.  Likewise, for Sera Groups A, Y and W135 the reverse cumulative distribution curves for the two vaccines were overlapping. 

            When the same sera was tested using human complement in the assay, the reverse cumulative distribution curves for each sera group were again overlapping.  The sera response rate using baby rabbit complement was defined as four-fold or greater increase in antibody titer post vaccination compared with baseline.  The proportion of sera responders was the primary endpoint in the two main immunogenicity studies.  Here the sera response rate in the Menactra subset showed general agreement for each sera group except for Sera Group Y.  For Sera Group Y, the 95 percent confidence interval for the difference in the two proportions do not include zero.  However, the sample size was not large enough to draw definite conclusions. 

            The sera response rate using human complement also showed general agreement for the Menactra and Menomune groups.  For each subgroup, the rate was 90 percent or greater in both vaccine groups, except for Sera Group C in the Menomune group, which was 86 percent.

            The seraconversion rates in adolescents using a baby rabbit or human complement source was also similar.  And likewise, the immune response in adults using the same immunogenicity parameters was also similar. 

            Menatra and Menomune bactericidal antibody response with each complement source supported the same conclusion.  The reverse cumulative distribution curves representing post vaccination titers in the two vaccine groups overlapped when either baby rabbit or human complement was used.  Sera response and seraconversion rates were also similar, as well as the immunogenicity profile in adults.

            Similarity of the immune response for the two vaccines with each source of complement, thus supported analyses of antibody response by baby rabbit complement in the larger immunogenicity cohort. 

            I will now discuss the two immunogenicity studies in greater detail.  Studies MT02 and MT09 were designed as randomized modified double blinds due to the different routes of administrations, multi-centered active controlled trials.  Enrollment in MT02 included participants 11 to 18 years old, and in MT09, 18 to 55 years old.  A single dose of Menactra or Menomune was given and serum samples were obtained at baseline and 28 days after vaccination. 

            The primary end point was the proportion of sera responders defined as participants with a four-fold or greater increase in bactericidal antibody titer 28 days after vaccination compared with baseline for each sera group.  Other measures of immune response included bactericidal geometric mean titer, seraconversion rate, and group-specific igG and igM measured by ELISA. 

            The primary hypothesis was to demonstrate that 28 days after vaccination Menacta was non-inferior to Menomune.  In MT02, the hypothesis would be supported if the upper limit of the one-sided 95 percent confidence interval of the difference in the proportion of sera responders was less than .1, which was equivalent to a 10 percent difference. 

            Subsequent to the conduct of study MT02, CBER preferences for using a two-sided 95 percent confidence interval in non-inferiority hypothesis testing evolved to be consistent with the FDA's Center for Drugs and the European Union.  This change was reflected in the primary hypothesis for study MTO9.

            The results of the primary immunogenicity analysis for MT02 are shown here.  For Sera Group Y, the sera response rate in participants 11 to 18 years old was greater than 80 percent in both vaccine groups.  And the rate was greater than 88 percent for C, A, and W135.  For the difference in the two proportions, a negative value indicated that the sera response rate was higher in the Menactra participants than in Menomune participants for any of the four Sera Groups.  The upper limit of the one-sided 95 percent confidence interval for the difference in the two proportions was less than .1, which was equivalent to less than a 10 percent difference for each Sera Group.  Likewise, the upper limit of the two-sided 95 percent confidence interval was also less than .1.  The primary immunogenicity hypothesis was thus achieved even by the more stringent of the two statistical criteria. 

            In study MTA09, the prevalence of baseline antibody titer increased gradually with age.  For Sera Group Y, the response rate in participants 18 to 55 years old was greater than 74 percent in both vaccine groups, and the rate was greater than 85 percent for the remaining Sera Groups. 

            The proportion of sera responders was higher after Menomune vaccination than after Menactra vaccination, resulting in positive values for the difference in the two proportions.  The primary immunogenicity hypothesis was still achieved since the upper limit of the two-sided 95 percent confidence interval for the difference in the two proportions was less than .1 for each Sera Group. 

            I will now move on to the studies evaluating safety of Menactra.  Safety information from six main studies and one supporting study were submitted in the license application.  In total, these studies were comprised of over 7,000 Menactra participants, and over 3,000 Menomune participants.  Characterization of the safety profile in ages 15 to 25 years old was felt to be important since the epidemiology of meningococcal disease in the U.S. and current ACIP recommendations for the prevention of meningococcal disease in college freshmen projected frequent use of this vaccine in adolescents and young adults. 

            For all Menactra and Menomune participants, detailed safety information was obtained which consisted of local and systemic adverse events and unsolicited adverse events within 28 days following immunization.  Planned safety assessment after vaccination was included for four studies.  At this evaluation, the participant was asked about visits to an emergency room, unexpected visits to an office physician, and the occurrence of serious adverse events.  Ninety-six percent of participants from the four studies combined completed the follow-up evaluation. 

            In studies MT04 and MT09, these were studies that included a primary safety hypothesis.  Both studies were randomized, blinded, multi-centered, active controlled trials.  In MT04, 75 percent of enrolled participants in each group were 15 to 18 years old, and 60 percent of MT09 participants enrolled in each group were 18 to 25 years old.  Enrollment was stratified by age group to ensure adequate representation of adolescents and young adults. 

            The primary objective was to compare the relative frequency of a solicited severe systemic reaction among Menactra and Menomune recipients.  Menactra was given intramuscularly, and Menomune subcutaneously.  Since the routes of administration differed, study personnel administering the vaccine differed from personnel collecting the safety data. 

            Local and systemic adverse reactions were assessed daily for seven days following the vaccination, and the information was obtained by diary card and periodic telephone interview.  The primary hypothesis was to demonstrate that Menactra was not inferior to Menomune in the proportion of participants with at least one severe systemic reaction during the seven-day period following vaccination.

            The sample size supported the hypothesis if the upper limit of the two-sided 90 percent confidence interval for the ratio of the two proportions was less than 3.  The sponsor also included an analysis according to current CBER recommendations, which is based on the upper limit of the two-sided 95 percent confidence interval. 

            Hypothesis testing was based on the assumption that the expected proportion of Menomune participants with at least one severe systemic reaction was .01, meaning 1 percent. 

            The criteria that constituted a severe systemic reaction is shown here.  Of note, headache, fatigue, chills, and arthralgia were considered to be severe if the participant felt that the symptom was disabling, required bed rest or analgesics.  Any seizure was considered as severe, as was any rash occurring during the seven-day post-vaccination period.  Rashes of interest in this category were lesions such as hives, purpura, or petechiae, since these rashes would be clinically significant, and rash had been included in post marketing surveillance reports for other meningococcal vaccines. 

            Since these rash descriptions were difficult to characterize for the vaccine recipient, all rashes were designated as severe in an effort by the sponsor to prompt the investigator for additional details regarding the rash, such as color, blanching or non-blanching, presence or absence of pruritus, and duration of symptoms. 

            The intent-to-treat population for safety included randomized participants who received one dose of vaccine, for whom safety information was available, and analyses were performed according to the vaccine received. 

            In MTO4 participants 11 to 18 years old, the frequency of pain and duration, redness and swelling was reported two to three times more frequently in the Menactra group compared with the Menomune group.  The 95 percent confidence intervals between the two vaccine groups for each of these adverse events were not overlapping.  Moderate reactions, including moderate pain, was also more common among individuals receiving Menactra.  The rate of each severe local reaction, although more frequent in the Menactra group, were all less than 1 percent.

            In both groups, headache and fatigue were reported most often, and the rates were somewhat similar.  Chills and arthralgia, however, were reported more frequently by Menactra participants.  And for these two adverse events, the 95 percent confidence intervals between the two vaccine groups were not overlapping. 

            Fever defined as an oral temperature, 39.5 degrees Celsius or higher, was not a prominent feature in either group.  And also, no seizures occurred in either group.  Rash occurring during the seven-day post-vaccination period was reported by 51 participants.  Fourteen participants reported localized rash either at or near the injection site, and 34 participants described the rash as non-specific, located on the extremities more often than the trunk, neck, or face.  These rashes lasted a median of two days.  Three participants reported generalized rash.  One participant in each group described the rash as itchy, blanching, and which responded to Benadryl.  A third participant received Menactra and reported a generalized non-blanching red, raised rash that occurred two days post-vaccination and lasted four days.

            In the primary analysis for MT04,all rashes were counted as severe, and for each reaction each participant was counted no more than once.  The rate of severe systemic reactions in the Menactra group was .043, which was equivalent to 4.3 percent, and in the Menactra group and in the Menomune group the rate was .026 or 2.6 percent.  The ratio of the two proportions was 1.7. 

            The primary safety hypothesis was achieved by the proposed criteria, which was the upper limit of the two-sided 90 percent confidence interval, and was achieved since the ratio was less than 3.  The hypothesis was also achieved by current CBER criteria since the upper limit using the two-sided 95 percent confidence interval was also less than 3. 

            When rashes were excluded from the analysis, the percentage of participants with at least one severe systemic reaction was 2.7 percent in the Menactra group, and 1.2 percent in the Menomune group.  The ratio of the two proportions was 2.2.  Of the study population which excluded rash, 1.1 percent of Menactra participants and .3 percent of Menomune participants reported two or more severe systemic reactions. 

            In both groups severe headache, malaise were most frequent.  Although a higher percentage of Menactra participants had multiple severe systemic reactions, the difference was not statistically significant. 

            In MT09 participants 18 to 55 years old, the rate of pain in the study was similar in the two vaccine groups due to increased frequency of reported pain in the Menomune group,  and duration and swelling were reported 1.5 times and 1.7 times more frequently in the Menactra group compared with the Menomune group respectively.  The differences in these rates were statistically significant.

            The rate of each severe local reaction, although more frequent in the Menactra group, were all less than or equal to 1.1 percent.  Moderate pain was about three times more common among individuals receiving Menactra when the study population was considered as a whole. 

            When the study population was divided into two age groups, pain was more discordant in the younger age group.  Within the 18 to 25 year old cohort, moderate pain was reported four times as often in the Menactra group than in the Menomune group.  And in participants 26 years and older, moderate pain was reported twice as often in the Menactra group.  The rate of severe systemic reactions overall in participants 18 to 55 years old is more similar in the two vaccine groups compared with MT04.  The rate of severe systemic reactions in the Menactra group was .038, and in the Menomune the rate was .026.  The ratio of the two proportions was 1.5.

            The primary safety hypothesis by the upper limit of the two-sided 90 percent and 95 percent confidence intervals for the ratio were again achieved by both statistical criteria.  The percentage of participants with at least one severe systemic reaction when rash was excluded from the analysis was 2.6 percent in the Menactra group, and 1.9 percent in the Menomune group.  The ratio of the two proportions was 1.3. 

            Similar to MTO4 results, the percentage of participants with two or more severe systemic reactions was higher in the Menactra group than in the Menomune group, but the difference in the two groups was not statistically significant. 

            For the seven studies combined submitted in the license application combined, the overall rate of serious adverse events was 1 percent in the Menactra group, and 1.3 percent in the Menomune group.  Pertinent events included two deaths, one death was reported in a 25-year old woman in a motor vehicle accident after Menactra vaccination, and the other in a 35-year old man who experienced cardiopulmonary arrest following drug overdose after Menomune vaccination.  One event was reported by the investigator as possibly related to vaccination.  This was a 17-year old Menactra participant with severe esophagitis who was hospitalized six days after vaccination.  A plausible cause for the event, however, included a history of a sports-related back injury four weeks prior to enrollment, and extensive and safe use thereafter. 

            Reports of anaphylactic and allergic reactions were uncommon.  One Menactra participant had a prior history of a peanut allergy, and the other had a prior reaction to an antibiotic.  Both participants reported symptoms after exposure to the same participants.  The third Menactra participant an anaphylactic reaction after multiple bee stings.  The recovery of all three individuals was uneventful.  Reports of meningitis and  pneumonia were also rare.

            I will now move on to the study evaluating the concomitant vaccine administration of Menactra with Td.  Study MTA12 included two groups, Study Group A received Menactra and Td concomitantly, then a saline placebo 28 days later.  Study Group B received Td first, then Menactra.  Enrollment included participants 11 to 17 years old.  Antibody response to the meningococcal components was evaluated by the proportion of sera responders to each sera group. 

            The proportion of sera responders are shown in this slide as a percentage.  In Study Group A, when Menactra was given concomitantly with Td, the percentage of sera responders was greater than 85 percent for Sera Group Y, greater than 90 percent for C, and greater than 95 percent for W135.  In Study Group B, however, when Td was given 28 days prior to Menactra, the percentage of sera responders for each of these sera groups was lower.  The difference in the two proportions was 8.8, 20.7, and 8.7 percent respectively. 

            Similar to the percentage of sera responders, the meningococcal geometric mean titer 28 days after Menactra vaccination also showed differences in antibody response for Sera Groups C, Y, and W135.  When an analysis was done to adjust for disparities in baseline titers, the difference in antibody response in the two vaccine groups was still noted.  The effect of vaccine regime on antibody response was not easily interpretable without a direct comparison of each study group of adolescents to a group of adolescents receiving Menactra alone.

            In the absence of this control group in Study MTA12, without making cross-study comparisons and acknowledging the differences in study characteristics across studies could be different, definite conclusions could not be drawn about whether increased  meningococcal antibody responses alone occurred when the two vaccines were given together, or if suppressed antibody responses also occurred in the group given Td prior to Menactra. 

            In the context of Menactra and Td vaccination, the safety of this vaccine regime was assessed from the perspectives of local pain rates, and any relationship between the frequency of adverse events to pre-existing antibody levels to diphtheria.  The frequency of local pain at the Menactra and Td injection sites during the seven days following concomitant vaccine administration is shown here.  Pain at the Menactra injection site was reported by 52.9 percent of participants, whereas pain at the Td injection site was reported by 70.9 of the same participants.  Redness, swelling, and duration and pain was noted to be similar whether Menactra was given concomitantly, or in a sequential fashion. 

            From an alternative viewpoint, the frequency of Menactra adverse events appeared unchanged by diphtheria antibody levels when Td was given with or prior to Menactra. 

            In both groups, the diphtheria GMT pre-vaccination was the same.  However, 28 days after Td vaccination, the diphtheria GMT was 20.9 international unit per mil with the concomitant vaccine group, and 8.4 international units per mil when Td was given prior to Menactra.  The diphtheria antibody level in the sequential vaccine group was consistent with diphtheria levels following routine TD vaccination in adolescents. 

            Hence, similar Menactra adverse event profiles, whether Td was given with or 28 days prior to Menactra, suggests that the frequency of adverse reactions are more related to the amount of diphtheria contained in Menactra than to the level of pre-existing diphtheria antibody. 

            In summary, the primary immunogenicity hypothesis to demonstrate non-inferiority of Menactra compared to Menomune were achieved for each sera group.  The proportion of sera responders with a four-fold or greater increase in bactericidal antibody titer 28 days after vaccination compared with baseline. 

            In MTA12, a difference in the antibody response to meningococcal components was noted in the group receiving Td prior to Menactra, and the group receiving Menactra and Td concomitantly.  In the absence of a group receiving Menactra alone, these results were less easily interpretable. 

            Increased frequency of local and systemic reactions were observed in Menactra participants compared to Menomune.  Although the percentage of Menactra participants with two or more severe systemic reactions was higher, the difference was not statistically significant, and the safety hypothesis to demonstrate non-inferiority of Menactra to Menomune were achieved. 

            I will now present the questions and discussion points to the committee.  Question one - are the available data adequate to support the efficacy of Menactra, i.e., non-inferiority of the antibody response to Menactra compared to the licensed  polysaccharide vaccine Menomune when administered to individuals 11 to 55 years of age?  If not, what additional data are necessary.

            Question two - are the available data adequate to support the safety of Menactra when administered to individuals 11 to 55 years of age?  If not, what additional data are necessary.

            Discussion Point One - please discuss the adequacy of the data regarding the use of Menactra and other vaccines likely to be concurrently administered, e.g., Td.   Discussion Point Two - please identify any issues that should be addressed in post licensure studies.  Thank you.

            DR. OVERTURF:  Thank you, Dr. Lee.  We will address the questions this afternoon, but at this time if there are questions of the committee for Dr. Lee on clarification of the data that she presented, I'll entertain them now.  If there are no questions now ??

            DR. FARLEY:  Monica Farley.  You didn't mention, I don't believe, the lot-to-lot variation study, and I wonder if you ?? there apparently was a review of that, and do you have any comments on the ?? did they achieve the goals there?

            DR. LEE:  As the sponsor mentioned this morning, there were ?? the primary endpoint for a few of the sera groups was not achieved, and although the endpoint was not achieved, all the ratios of the GMT of the bactericidal GMT were all less than a ratio of 2.  And so that the differences, while they were apparent, were thought to be less clinically significant.

            DR. OVERTURF:  Other questions?  I think if there are no other questions, we will adjourn now, and plan to reconvene at 2:00 following lunch.  Thank you very much.

            (Whereupon, the proceedings in the above-entitled matter went off the record at 12:58:04 p.m. and went back on the record at 2:03:08 p.m.)

            DR. OVERTURF:  The afternoon session is beginning.  Thank you.  Before we begin the afternoon session, I'd like to introduce Dr. Karen Midthun who has an announcement she'd like to make for the FDA.

            DR. MIDTHUN:  Hello and good afternoon.  I just wanted to say that, as was mentioned earlier, this is the 100th VRBPAC Meeting, and as such, I'd just like to take a few moments to thank all of our members of the Advisory Committee, the public and all of the staff who have helped make this be a really good meeting time after time.  And because of this, we actually have a cake that we ordered for this occasion, and at the break, please help yourself to a piece.  So without further ado, back to serious business.

            DR. OVERTURF:  Next on the agenda is the open public hearing. 

            MS. WALSH:  As part of the FDA Advisory Committee meeting procedure, we are required to hold an open public hearing for those members of the public who are not on the agenda and would like to make a statement concerning matters pending before the committee.  Dr. Overturf.

            DR. OVERTURF:  I'm required to read into the record a statement regarding open public hearing announcements.  Both the Food and Drug Administration and the public believe in the transparent process for information-gathering and decision making.  To assure such transparency, the Open Public Hearing Session of the Advisory Committee Meeting, FDA believes that it's important to understand the context of an individual's presentation.  For this reason, the FDA encourages you, the open public hearing speaker at the beginning of your written or oral statement to advise the committee of any financial relationships you may have with the sponsor, his products, and if known, its direct competitors. 

            For example, this financial information may include the sponsor's payment of your travel, lodging, or other expenses in connection with your attendance at the meeting.  Likewise, FDA encourages you at the beginning of your statement to advise the committee if you do not have any other such financial relationships.  If you choose not to address this issue of financial relationship at the beginning of your statement, it will not preclude you from speaking.

            Our first speaker is Dr. David King, who is speaking as a New Jersey representative for the Coalition for Mercury-Free Drugs. 

            DR. KING:  First of all, my name is Dr. Paul G. King.  I don't know who this other guy is, but that's who I am.  And I'm speaking today on behalf of the American public and CoMeD.  I have prepared a set of notes which I will diverge from fairly drastically, not because I wanted to, but because different information was revealed here than was in the packet that they provided, that the applicant provided.

            I am neither affiliated with the government, nor any pharmaceutical manufacturer.  My background is the area of CGMP regulatory compliance and sound science.  I am a Ph.D. chemist with a Master's Degree in inorganic chemistry, and I am definitely not a vaccinologist.  If you're interested in finding out about my credentials, my website is in the handout.

            In general, my oral presentation will discuss Aventis proposed new vaccine from the viewpoint of a vaccine, and also the risk of reducing Mercury poisoning.  Now one of the things I found out was that they did the study.  They didn't compare it to their vaccine they got approved, the approved Menomune vaccine, is a preserved vaccine, but they did it against their single dose vaccine, which is a low trace level Mercury vaccine, I believe.  I guess I understand why.  It might have got a lot more adverse reactions if you compared it against that one, so somebody is making a leap over a couple of hurdles that wasn't presented to this committee, because they presented this as if they were comparing this to their approved Menomune vaccine which they did by clinicals, and they're not doing that, which I find reprehensible.  If somebody is going to do that, they should clearly have said that.  We put this intermediate step in, and here is why. 

            By the way, I support doing that.  I wouldn't have ?? I would hate to have given any 18 to 55 year old or child a Mercury-containing vaccine at levels well above the toxic level, which according to Leong's work is on the order of oh, let's see - if you do the math, comes out to something like 4 times 10 to the minus 11 grams were applied to 2ML preparations of growing nurides, and 77 percent of them died.  And he tried Aluminum, Lead, Cadmium, and Manganese, and they didn't cause any deaths to speak of at all.

            Now returning briefly to my remarks, the data on Menactra shows it's not worse than the Menomune single dose vaccine, and it does boost immunity, which the previous vaccine wouldn't do.  So on that basis, I would probably support it as a vaccine for being approved.  However, I have a very big caveat emptor.

            With this vaccine, the sub titer varying shortly after vaccination less than 70 percent are protected, is this vaccine a preventive or is more indicator or discriminator?  Does it simply ID those whose immune system can innately cope with this disease and blown its adverse effect to the mild or silent ones?  Does it simply protect those who are not susceptible to the disease's severe effects?  Perhaps these questions should be answered, because again, I would support it only to use just blunt outbreaks, or when you have populations of diverse people coming together, like in militaries or going to school where kids don't practice very good hygiene.  I certainly didn't my first year in school, and my university required me to live on campus. 

            The third thing I have a problem with is when we talk about going to extend this to doing it to children.  Since the B subtype is not protected at all in the vaccine, I don't understand why you're going to give a vaccine that will, at best, initially protect less than, as I count it, 40 percent of the children  inoculated, and after a year less than 20 percent.  That's at best, and probably may not protect even that many.  The cost of it doesn't seem to be beneficial.

            The other thing I would point out is if you look at the history, Menomune has been around for a long time, and yet I don't see any drop in the outbreak rate, nor any real decrease in the death rate.  So maybe again, it's like I said, it's only a vaccine.  It's a good indicator of those people who are ?? you give it to people and they don't get very sick with it, they are being who couldn't get sick with the disease very much.  That's what I would say about ?? that's what all I have to say about that, I would think.

            Now the other thing which I worry about is that you say the strains vary and whatever, but as I read all the things I could get my hands on, which aren't very many, it seems that the vaccine has shifted the population of strains.  And that may not be in the long term a good thing to do either, and that's another reason I'd recommend this be only approved for outbreaks or in situations where the potential of outbreaks is large, and not as a general vaccine to the general population.

            Also, I noticed that these people failed to provide a risk benefit analysis, and I find that particularly reprehensible because the FDA says now everything is supposed to be based on risk benefit.  In other words, here's what the cost is to the population, the risk - you know, the total risk, health effects, could of the medicine and whatever.  Here's what the people who are going to get this, going to get as a benefit.  If it really doesn't protect anybody but the people who would be protected anyway, maybe if it blunts the more ?? it might be worth it in an outbreak sense, but at $80 a dose for 300 million people every three years, I think I'd have a hard time justifying that as being cost-effective healthcare.  We could do much more better things just to get the kids to wash up better, practice better hygiene, clean their rooms and stuff better, and that would reduce the risk of anyone getting the disease in the first place.

            As I've said before, nonetheless on balance, being forced to consider it less ?? I would still support this vaccine being approved, provided the following actions are taken.  There should be at least a five-year Phase Four trial where all the data is collected on all the people given it for five years afterwards, especially since you're going to be giving a booster dose after three years.  It looks like you're going to give this as a vaccine in the normal sense of that word.

            Also, I think if you're going to approve Menactra, you should certainly revoke the license for the Mercury laced or the preservative Menomune, if not both of those vaccines, because they're obviously inferior in that they do have an adverse effect if you ever try to get re-vaccinated with the Menomune, even the low dose one. 

            Third, again I will re-emphasize, only approve for vaccinations of most seriously at-risk sub-populations; for example, incoming college freshmen who reside in dormitory settings, military conscript, volunteers in service, orphanage residents, nursing home or residential communities for the elderly.  And for a similar reason, vaccination should be restricted to initial dosing and one booster dose at three years subject to review after five years experience under the Post Approval Surveillance Program. 

            And C, to prolong a rabies acquired internal immunity, DHHS should strongly promote breast feeding for not less than two years because in Mother Nature, that's what happens. 

            In closing, let me assure this panel that failure to truly consider these simple science-based requests and acting appropriately may further undermine the public's willingness to subject themselves and their children to vaccines that have real cost and real risk to them for the sake of the purported benefits to the population as a whole.  Because again with the babies' case, if you believe herd immunity requires 80 percent immunization, then there's no way you're going to get it by giving babies a Non-B vaccine when that's the majority sub titer.

            Remember rather than trying to continue to increase the number of vaccines, the number of doses given to the point that bad vaccines - my favorite examples are Lyme disease vaccines and the Smallpox vaccine, in worst practices are incorporated into the vaccine schedule, the money would be better spent re-emphasizing the importance of personal hygiene and providing clean housing for the poor and the homeless.

            For example, since bed bugs and not direct contact with a vector that transmits Smallpox, and with supportive medicines which we have, the death rate is under 10 percent, DHHS would be better off spending money on providing clean insect-free housing for the poor and homeless, and promoting the washing of bed clothes with very hot water and bleach, instead of trying to vaccinate the public and cause thousands of unnecessary Cowpox reactions, and hundreds of unnecessary Cowpox deaths. 

            Finally, does the cost of one dose outweigh the potential maximum benefits per year?  I don't think so.  Thank you.  Any questions, I'll try to answer them.

            DR. OVERTURF:  Thank you, Dr. King.  Are there any questions for Dr. King?  Thank you very much.  Our next speaker is, I hope I have this right, Mike Kepferle from the National Meningitis Association. 

            MR. KEPFERLE:  Thank you.  My name is Mike Kepferle, and I'm one of the founding directors of the National Meningitis Association.  We're at a non-profit health education foundation that tries to educate families, medical professionals, and just the general public about meningococcal meningitis, meningococcal disease, in particular, and the ways that you can help prevent it; which obviously include both immunization and good hygiene. 

            I want to say that we have been waiting.  I'm a parent, and I represent a lot of parents that have been impacted by meningococcal disease, and we have been waiting for something to change.  Now we haven't been waiting passively.  We've been trying to make things happen, but we look forward to this new conjugate meningococcal vaccine, if it's approved, because of what we hope that it will do to protect the children. 

            We're also waiting for a serogroup B vaccine, and I hope there's some discussion with the folks down in New Zealand about what's going on there, and the potential for a vaccine here in the U.S. 

            One Saturday I took my son, Patrick, who was 18 years old and dropped him off at college.  Sunday he was dead.  I couldn't even pronounce meningococcal, and I'd heard about Meningitis.  In fact, we had received some information in 1999 in our college application that recommended he be vaccinated with a  Menomune vaccine.  But the wording of the recommendation was kind of hard to follow.  It didn't matter.  We're very pro vaccine.  He had his Hepatitis vaccines, but we took him to a Navy clinic, which is where we were getting our medical help, and ironically at a military base we couldn't get the Menomune vaccine for him.  But we weren't worried.

            We didn't know much about Meningitis, but we figured he'd just get a shot when he went to school, and we encouraged Patrick to do that.  Well, he didn't do it the first semester, and so I remember distinctly besides telling him to get his grades up, that he needed to go to the health center and get the shot, and I'd pay for it.  Well, in March he came home to watch his high school team play in the regional playoffs, and then went back that March 4th, 2000 - it's now been four years - it seems like yesterday, and he was dead on March 5th. 

            After that happened, I reached out to other parents who I know lost children.  I found about it, and I learned a lot, and we started the National Meningitis Association.  And if I could have every one of those parents sitting in this room, because there are more parents than would fit in this room, and I have to represent them because I'm the only one that could make it here, but if I could have them sitting here, they'd say please, please get us another vaccine, and help protect our kids. 

            Now my son was in that classic college 18-year old freshman living in a dorm situation, but believe me, I've talked to a lot of parents that have lost kids that are 11, 14, 12.  Last week, David Pasick, Wall, New Jersey died at 13 years old.  I met with a family up in Washington State whose 12-year old son, Carl, had both of his legs amputated.  And I don't think I need to tell most of the medical folks here what this disease can do, but I do want you to know that we parents that didn't know what this disease could do, and all of the parents out there that still don't know, no matter how much we try to educate them, need to be given a vaccine that is going to protect not just the college kids, but also the ones that are younger.  And every child in this country that is eligible for a vaccine and can be protected by the vaccine should be given that vaccine.

            All the families that are involved with NMA want you to know that we know that immunization and education are the only combination that are going to save our children's lives.  And I don't want next year to tell a parent of a 12-year old who lost their child because they didn't have a vaccine that could have saved their lives, that well, we're another year later, and I'm sorry.  Because that's what I'm telling them right now, and I don't like it.  So please, please get us the vaccine that we need, work with us to educate the public so that they know what the vaccine can do for it, and thank you.    Do you have any questions?

            DR. OVERTURF:  Are there any questions for Mr. Kepferle?  Thank you very much.  Is there anyone else who would like to make a presentation during the open public hearing?  If not, I will ask Dr. Carl Frasch to come forward and we'll begin addressing the questions for the afternoon. 

            DR. FRASCH:  Okay.  What I'm going to do is I'm going to go through two questions and two discussion points, and then be sure that there's a clear understanding of exactly what the committee is being asked.  Then we'll go back to question one, and  Dr. Overturf's open the questions for discussion.

            So the first question is, are the available data adequate to support the efficacy of Menactra, in this case as defined by non-inferiority of the antibody response to Menactra compared to the licensed polysaccharide vaccine Menomune, when administered to individuals 11 to 15 years of age.  If not, what additional data are needed.

            The second question and the last question for which the committee will vote is, are the available data adequate to support the safety of Menactra when administered to individuals 11 to 15 years of age?  If not, what additional data are necessary.

            Now the next two are discussion points.  First discussion item is, please discuss the adequacy of the data regarding the use of Menactra with other vaccines likely to be used concurrently, administered concurrently.  For example, Td.  And the last discussion item - please identify any issues that should be addressed in post licensure studies.

            So I would open the ?? see if there's any discussion regarding the meaning of any of the questions.  If the meaning of the questions are clear, then I'll be finished.  Okay. 

            DR. OVERTURF:  If not, we'll go ahead and proceed with a discussion of the first question.  The first question is, are the available data adequate to support the efficacy of Menactra, i.e., non-inferiority of the antibody response to Menactra compared to the licensed polysaccharide Menomune when administered to individuals 11 to 55 years of age.  If not, what additional data are necessary?  Are there discussions or questions?  This is a question we will vote on, and what we will do at the time of the vote is to proceed around the room.  If you have additional data that you think is necessary, regardless of what your vote is in that regard, you should state it at that time into the record.  Did you have a question, David?  No.  Any other discussion regarding this question?  This is a very quiet committee today. 

            This time I think we'll start with Dr. Karron, and ask her for a yes or no vote, and any questions regarding additional data that she feels is necessary.

            DR. KARRON:  Yes, I believe that the data are adequate to support the efficacy of Menactra; that is non-inferiority of the response to Menactra compared to Menomune. 

            DR. OVERTURF:  Dr. Self.

            DR. SELF:  Well, at risk of contradicting myself I will vote yes, I think the data are adequate.  But I'll also say that I would like to see some more data, and that would have to do with the relationship between the antibody response and risk for other serogroups. 

            DR. OVERTURF:  Dr. Densen.

            DR. DENSEN:  I believe the data are adequate to support the non-inferiority of the candidate vaccine to the current vaccine. 

            DR. OVERTURF:  Dr.  Whitley.

            DR. WHITLEY:  According to the standards specified by the Food and Drug Administration and Aventis, I believe that Menactra should be approved for efficacy.

            DR. OVERTURF:  Dr. Word.

            DR. WORD:  I would agree that there is adequate data to support the efficacy of Menactra.

            DR. OVERTURF:  Dr. Petteway, I believe you're a non-voting member for this.  Do you have any comments that you want to make?

            DR. PETTEWAY:  Well, the only comment is I think it's clear, I think that the data does support non-inferiority.

            DR. OVERTURF:  Yes, Dr. Stephens.

            DR. STEPHENS:  I also agree the data are supportive that this vaccine is non-inferior.

            DR. OVERTURF:  Dr. Gellin.

            DR. GELLIN:  Also in agreement that the data as presented are in agreement with the ?? supporting Menactra based on non-inferiority for efficacy.

            DR. OVERTURF:  Cindy Province.

            MS. PROVINCE:  Yes, I do believe that the available data are adequate to support the efficacy of Menactra according to the conditions that have been given.

            DR. OVERTURF:  Dr. McInnes.

            DR. McINNES:  I believe that the available data are adequate with regard to efficacy for Menactra.  I would like to see additional data on persistence of antibody so that one might better understand the possible priming, boosting.  And I think data on the kinetics of the antibody response would be of great interest also in further understanding the biology of what is happening.

            DR. OVERTURF:  Dr. Farley.

            DR. FARLEY:  Yes, I think that the data do support the non-inferiority of the product.  I agree that having more information on the subsequent dosing  and boosting would be of great interest.

            DR. ROYAL:  I agree that the data demonstrate that Menactra is not inferior to Menomune.

            DR. OVERTURF:  I'm sorry.  I didn't call Dr. Royal's name.  That was Dr. Royal's vote.  Dr. Markovitz. 

            DR. MARKOVITZ:  Yes, I'd like to vote yes, that this has been demonstrated and strongly echo the comments of Dr. McInnes and Dr. Farley, that it's going to be very important to see that follow-up about boosting and antibody persistence, because I think that's what will ultimately make this a vaccine that people will really want to use. 

            DR. OVERTURF:  I also would vote affirmatively for this, but I think the data strongly support this.  I think there is going to be needed data regarding persistence of antibody, and particularly persistence of protected antibody, and also when boosting will be required.

            I also would hope very much that there would be ?? that the data for children will be coming along very, very shortly, because I think that's going to be an important long-term component, probably controlling  meningococcal disease, as well. 

            The second question is, are the available data adequate to support the safety of Menactra when administered to individuals 11 to 55 years of age?  If not, what additional data are necessary?  So this question is now open for discussion from any member of the committee.  Are there questions regarding this?  So a slightly different standard here because it's not truly a comparable vaccine.  It has actually more antigenic components and, therefore, the non-inferiority is a little bit more difficult to apply, because of the fact that you going to expect more reactions, which I think the sponsor addressed.  Ye, Dr. Whitley.

            DR. WHITLEY:  I just think to reiterate that point, don't forget the two vaccines are given by different routes.  One is given subcutaneously, and the other is given intramuscularly, and that does introduce a variable that needs to be considered. 

            DR. OVERTURF:  Are there any further comments or questions, discussion?  Well, this time we'll start with you, Dr. Markovitz, if you could address that question. 

            DR. MARKOVITZ:  Yes.  I mean, I think similar to what might be expected by the comments that Drs. Overturf and Whitley have made, this is slightly more reactogenic vaccine than is the currently licensed version.  But nonetheless, I think it's safe.  I'm convinced that the safety data are good.  Because it's more reactogenic, I'd certainly want to see very close follow-up once people are vaccinated in larger numbers, so I would vote yes, for the safety issue.

            DR. OVERTURF:  Dr.  Royal.

            DR. ROYAL:  Thank you.  I would vote that the data do demonstrate that the vaccine is safe.

            DR. OVERTURF:  Dr. Farley.

            DR. FARLEY:  I would say yes, the data are adequate to support the safety of the new vaccine.

            DR. OVERTURF:  Dr. McInnes.

            DR. McINNES:  Yes, I found the data to be adequate to support the safety of Menactra.

            DR. OVERTURF:  Yes, Ms. Province.

            MS. PROVINCE:  I do agree that the data are adequate to support the safety of Menactra.  And I just want to make a general comment for the record about the importance of post-licensure surveillance.  That may be more appropriately addressed under the discussion points, but I think it will be very important to look at the safety data as it continues to come in, both for the adverse events that have been detected so far, and is of extreme importance, and continue to monitor this vaccine for even the possibility of rare adverse events that might not have been adequately detected pre-licensure. I think that that's just a growing issue involving public confidence in vaccines.

            DR. OVERTURF:  Thank you.  Dr. Gellin.

            DR. GELLIN:  Given the caveat stated about the differences in antigen content and the route of administration, I also believe that the safety data as presented are adequate to license this vaccine based on safety.  And agree with Cindy that there's a need to have ongoing safety studies, particularly - and we'll get into this with the next question - with concomitant administration, and if this is a vaccine  that is then given to children, where there are more vaccines administered.

            DR. OVERTURF:  Dr. Stephens.

            DR. STEPHENS:  I would agree this is, as the data suggests, this is a safe vaccine.  I would also agree with the comment just made about concomitant vaccines, in particular Td concomitant administration where I think the reactogenicity issues may be even more pronounced.  And other vaccines concomitantly given is of concern.

            DR. OVERTURF:  Dr. Petteway, do you have any comments?

            DR. PETTEWAY:  It's clear that the data supports safety.

            DR. OVERTURF:  Dr. Word.

            DR. WORD:  I think it does support the safety of Menactra.

            DR. OVERTURF:  Dr. Whitley.

            DR. WHITLEY:  I believe the vaccine's data support safety, but I want to contribute to the caveat that was made earlier; and that is, I think surveillance studies need to be in place when this vaccine is licensed recognizing that the total number of people who participated in the clinical trials were only 7,500.  And by my standards, that's a bit slim in terms of understanding the safety profile.

            Furthermore, we all know that once we go beyond clinical trials, what happens in the real world is very different.  And so being able to monitor that, and reinforce public confidence is essential.

            DR. DENSEN:  I agree with my colleagues that  the vaccine is safe, and I echo the comments of Dr. Whitley.

            DR. OVERTURF:  Dr. Self.

            DR. SELF:  I agree the data are adequate to support the safety of Menactra, and concur with Whitley and others about surveillance post-licensure.

            DR. OVERTURF:  Dr. Karron.

            DR. KARRON:  I agree that the data are adequate to support the safety of Menactra, and agree with others' comments about the need for post-licensure surveillance.

            DR. OVERTURF:  I also will vote affirmatively for the confidence in the data on the safety of Menactra.  I also feel that with recent history as the test, that 7,500 patients sounds like a lot but it turns out to be a fairly slim number, particularly for  those very rare adverse events, so post-marketing surveillance will be a critical part of this vaccine's future.

            Now at this point, we're going to open up the discussion to the adequacy of the data regarding use of Menactra with other vaccines likely to be concurrently administered, such as Td.  And we've already commented on Td.  When and if we begin to extend this vaccine to much younger children ?? yes, I'm sorry. Dr. Frasch.

            DR. FRASCH:  I just want to clarify that concurrent doesn't only mean given at the same time as, but within reasonable proximity of, like a week or so on either side.

            DR. OVERTURF:  My comment would be that there are vaccines which are given in college health services, and are recommended.  Often college students do not get the second dose of MMR until college.  The other vaccine, which is a live vaccine, they also may not get vaccinated for Hepatitis A and Hepatitis B prior to college, and some of those are recommended, as well.  So there will be a need for at least some additional data for safety and the effects on immunogenicity of this vaccine.  So at this point, I'll open the question up for discussion, and see if there are additional comments by the committee members.  Any additional comments?  Dr. Word.

            DR. WORD:  I think you've mentioned a number of other vaccines that need to be addressed when you administer this, but it's not just that we're just talking about the adolescent population.  You're extending it out, and besides just routine healthy immunizations, you have to think about people who do participate in international travel.  And there are a number of other vaccines that may be administered at those time periods, like Yellow Fever, Japanese Encephalitis.  I mean, you're not going to need a lot, but when you're dealing with some of these adolescents particularly go out of the country, they go to missions.  And also, I think Dr. Karron brought up the question about oral Typhoid, even though many of us don't use it as much, we use the injectable because of the conflicts occasionally with Malaria prophylaxis.  There are some people who still use oral Typhoid. 

            DR. OVERTURF:  Are there any other questions?  There's actually a number of those travel vaccines, including for people going on extended stays in rural countries, Rabies vaccine, pre-exposure prophylaxis is recommended.  Others receive dosing of things like Yellow Fever vaccine for certain kinds of settings, as well.  So in addition to Typhoid and also the Hepatitis A vaccine that I mentioned, so I think there will be a number of the travel vaccines that will have to be looked at.

            DR. WHITLEY:  Procedurally, Gary, what do we have to do?  Do we have to make a formal statement for the agency on discussion items, since this is a non-voting item, or what do you want from the committee?

            DR. OVERTURF:  We do not have to have a vote.  What's required here is a discussion for the sponsor and for the FDA to help direct them into studies that need to be done further for concurrently given vaccines.

            DR. WHITLEY:  Then I think we should make a definitive statement that the data regarding the use of Menactra plus Td, versus administration of Td followed a month later by Menactra need to be clarified so that the immune response, persistence of immunity, and kinetics of immune response are all identified under those circumstances. 

            DR. OVERTURF:  I agree.  I think also safety needs to be addressed in that regard.  When the vaccine is given with some of these other vaccines, that's going to be necessary.  Actually, the data that's presented today I think we all would agree is very limited and only begins to scratch the surface with what's needed. Dr. Stephens.

            DR. STEPHENS:  I think there also needs to be some additional data about the use of this vaccine in individuals that have previously received the polysaccharide vaccine.  We heard some data today and it hadn't been, as I understand it, reviewed by the FDA, but there was data presented, a little bit of data in that regard.  But I think this is an important group, because a number of college kids, obviously, a number of the population have already been vaccinated with a polysaccharide, and we need to have some understanding, a better understanding of how this vaccine would be used in those groups, laboratorians, for example.

            It's also true that there needs to be a better understanding of what happens when the polysaccharide is used after this vaccine.  We didn't hear any data from my perspective, or I didn't hear any data about that today; although, I think that data does exist, and I think it may be an effective booster.  But some more data about the concurrent use or the previous use of polysaccharide vaccine in conjunction with this vaccine needs to be obtained. 

            DR. OVERTURF:  Yes.

            DR. WHITLEY:  Can I just amplify on what Dave said for one minute.  And I think it goes back to the question that I posed earlier; and that is, the day-28 data need to be extended far out.  And I understand that data will be forthcoming in children, and you have it, but it should be also available in other populations, as well, because that will be crucial in terms of the people who just get Menactra, versus those who have the polysaccharide vaccine followed by Menactra. 

            DR. OVERTURF:  All right.  I think we'll probably ?? the likelihood is that we'll be exposing a fairly sizeable large population immediately to this vaccine, particularly in the adolescent age group.  And we don't know much past a few months, so I think that's where the critical early information needs to come from.  Yes, Dr. Farley.

            DR. FARLEY:  I agree.  I'm concerned if we have a successful vaccine campaign of 11 year olds ,we will be uncertain what to be advising them to do when they're going to be college freshmen in dormitories, so I think we have a lot to learn for that very high risk population. 

            DR. OVERTURF:  Is it fair to ask the sponsor if any of those kinds of studies are planned, with some of the initial populations that were immunized at 11 to 12 or 15 years of age.  Are any of those planned for long-term booster studies?  Just introduce yourself again.

            DR. DECKER:  I'm Dr.  Michael Decker.  I heard several issues raised that are closely related.  We showed you the data from MTA19, which are being submitted or may have just been submitted to FDA for their formal review.  And that involves a three-year follow-up with the cohort from the MTA02 participants.  We're continuing to follow these children.  One reason why it was a subgroup that was reimmunized there was to leave some children behind who could be evaluated, and potentially reimmunized at five years, or at successive time points.  So it's our intention to follow this MTA02 cohort on out.  And remember now, they're a full four years ahead of the public that has not received the vaccine at all yet.  So we recognize precisely the question was raised.  In fact, to me that's one of the most compelling questions, is if we immunize a cohort of 11 year olds as I hear that ACIP is considering, the question will be raised when they approach colleges are they covered, do they need a booster?  And so we have this cohort who were immunized at 11 years old already in the study, and the adolescents limit 18, but it includes ?? it will provide data that will address this question.  And you saw what it looked like three years out.  We're waiting to see in about year, we're going to see what it looks like five years out, and so on.  And so we have that going.

            I don't want to talk much at all about the data for persons younger than 11, because that's not the subject of today's meeting, but I know it's of great interest to people.  And we have done similar work in that group, and are following them on out.  So I believe that we will have data that will directly address the things that we all need to know. 

            DR. OVERTURF:  Dr. Royal.

            DR. ROYAL:  I'd like to put in a plug for studies being pursued that might increase our understanding of the mechanisms that might be associated with any increased efficacy that might be seen going back to the comment about not only were the formulations different, but also the routes of administration were different, which makes it a bit difficult to understand whether it's the formulation or the intramuscular injection that's really responsible for the increased immunogenicity.  So such studies may not necessarily involve humans, and it may be difficult to do in humans, but I would be very much in favor of them being done.

            DR. OVERTURF:  Another issue in mechanism might be also to look more closely at those sub-populations which actually have complement deficiency.  That will be a difficult study, although at least in many populations, the estimated number of individuals who are deficient have those complement deficiencies vary from a 5 or 10 percent number, all the way up to as much as 30 percent, depending which population you're looking at.  It will be interesting to see what the immunology is in those patients who received those vaccines in that particular population, particular group.

            DR. DENSEN:  I have two comments, one just related to your last comment.  I think the variation, the number of complement deficient patients in different populations depends on the incidence of meningococcal disease and the population in general.  But in an endemic population, it runs pretty consistently about 10 percent.

            I would like to encourage the FDA to organize studies that would look at the principles that might emerge when you give mixed vaccines, so you give this vaccine with another vaccine, so that we could understand whether or not there are general immunologic principles about combining vaccines that could be derived, or whether these combined administrations always represent unique events related to the vaccine properties itself.  So that as we move forward, we would have a handle on some of the very real questions that have been raised here, and we wouldn't have to solve that problem each time, if there are emerging concepts. 

            DR. OVERTURF:  Dr. Word.

            DR. WORD:  Just a question - I guess I thought of it when you started talking about some of the people who have some complement deficiencies, but  people routinely are recommended to receive meningococcal vaccine because of underlying health problems.  Where will they fit in, because the wording here is just for individuals 11 to 55, and so many of them would be of the age where they're getting a booster, or if there splenectomized.  I'm not quite sure how ?? is it only going to be for healthy people?  I mean, the way it's worded, it seems like it's for anyone between 11 and 55. 

            DR. OVERTURF:  Well, I think the populations that were studied were healthy populations, so whether ?? that actually is not really technically an issue for this committee.

            DR. WORD:  Okay.

            DR. OVERTURF:  How the vaccine is used, and how it's recommended to be used once it's approved is for other agencies.  And the point I was trying to make is that there does need to be additional studies of those populations specifically.  Whether it will be used or not immediately is up to other groups.  Dr. Stephens.

            DR. STEPHENS:  The real question is whether this is a better vaccine than the polysaccharide, and I think the data - we'll get to that probably in question four, but the real data is not there, in my view, that this is a better vaccine.  We have a lot of promises.  We have the experience in the U.K. with different vaccines.  One of the hopes is that this vaccine will induce a herd immunity response, a significant herd immunity response.  We don't have any data about that with this particular vaccine.  I think very clearly we would like to - I would certainly like to see some data looking at mucosal antibody, looking at potential of herd immunity for this particular vaccine. 

            Sixty percent of the preventive cases in the U.K. were due to herd immunity, a very powerful correlate, immune correlate of conjugate vaccine, certainly see with the pneumococcal conjugate, as well as the Hib conjugate.  There is hope that this conjugate will do similar kinds of herd immunity effects, but we don't have any information, other than the promise that there may be a herd immunity effect. So that's one issue that I think we need to make sure that's at least raised with the manufacturers as this vaccine moves forward.

            Second issue is memory - does memory protect?  I don't whether memory protects or not.  That's a big question in the meningococcal world about whether memory is going to protect, whether it's simply ??  waning of antibody, as Dr. Farley points out, is going to be a real issue.  And whether memory response, whether it may be a laboratory phenomena, but is that memory response going to protect for meningococcal disease? 

            There is some data, as we've mentioned this morning in the U.K. suggesting that at least in toddlers who were getting a different immunization schedule, that even though they generate these memory responses, they don't protect after one year, so that's of concern with these conjugate vaccines.  So I think the whole issue of memory and whether it's going to be protective or not, and whether a boosting response is going to protect is another important area for this particular vaccine.  Is it going to be better than the currently available polysaccharide, and those are important questions from a public health standpoint, anyway, that need to be considered as this vaccine moves forward.

            DR. OVERTURF:  Dr. Royal.

            DR. ROYAL:  I concur with all of the points made by Dr. Stephens, and I'd like to sort of just get something out of my head and ask whether one might have expected to see some change in the response to Menomune merely by instead of administering subcutaneously, to give it IM.

            DR. OVERTURF:  Does the sponsor want to address that question?  Dr. Frasch.

            DR. FRASCH:  If you look at the very early trials in the early 1970s, which Dr. Gotschlich and colleagues were involved with, and at that time they did not know whether they were going to give the vaccine subcu or IM. And limited studies were done at that time, and there was no difference in the immune response to the vaccine given IM versus subcu.  The only difference was some differences in adverse reactions, but not immunogenicity.

            DR. OVERTURF:  Are there any other comments on discussion Point Three?  Dr. Gellin.

            DR. GELLIN:  I mean, just to round it out, given that the age range is 11 to 55, we have identified a number of populations that would have different vaccines given concomitantly, adolescents, laboratorians potentially, international travelers.  I would throw the military on that list, as well, and I don't know if there's any here can speak to that, but knowing it's a vaccine that's probably of interest to them, that's probably another set of studies given the databases they have that looks at vaccine safety.

            DR. OVERTURF:  Dr. Karron.

            DR. KARRON:  And just to amplify on Dr. Gellin's comment, we actually saw data in the aggregate presented from age 11 to 55.  I think as there are post-licensure studies done, it would be interesting to see some breakdown by age regardless of the issue of concomitant vaccines administered to see if responses are equivalent across the age range.

            DR. OVERTURF:  Are there other comments?  I'd like to then go ahead and proceed to question number four; which is, please identify any issues - I think we've partly begun to address this - that should be addressed in post-licensure studies.  Are there any additional issues that haven't been addressed?  I think in addition to breaking things down by - we've already mentioned host, and age, probably racial and ethnic backgrounds need to be looked at more closely also.  Dr. Whitley.

            DR. WHITLEY:  I think the qualifier on that, and Barbara and I were just talking about it a minute ago, is that not only under-represented minorities, but the populations that may not best be served by current nutritional balances in the United States, where you would you expect a less advantageous an immune response, and I wouldn't make that comment just for this vaccine, but for vaccine development in general.

            DR. OVERTURF:  Yes, Dr. Farley.

            DR. FARLEY:  I think that obviously the post-marketing surveillance is important, but I think general surveillance for meningococcal disease and the distribution, ongoing activities of surveillance where we look for so-called replacement, or shifting towards predominance of B disease, for instance, serogroup B disease because it's not in the vaccine, obviously following that.  I think it would be very interesting to look at carriage studies, depending on what the recommendations actually are, whether it's going to be a solid block of the population that it will be recommended for, and whether you can look at that age group for reduction in carriage of the vaccine serogroups. 

            DR. OVERTURF:  Yes, Dr. Stephens.

            DR. STEPHENS:  Just to echo what Dr. Farley was saying, I think the U.K. really had a very aggressive program as they went forward with their conjugate vaccine to look at issues of carriage, and to look at issues of serotype or serogroup replacement.  And those studies are still ongoing, and still very helpful.  And I think similar kinds of studies really need to be done in this country to look at the effects of this conjugate.  Again, it depends to some degree on how it's introduced, and how it's used, but those were very important studies in understanding how that vaccine in that country was and is working.

            DR. OVERTURF:  Just to echo some of the previous comments, actually those of Dr. Stephens, I think the issue about how ?? whether this is a better vaccine really is going to be a very early critical issue, because many assumptions are being made about this vaccine, and I'm not sure that the data yet is completely adequate to suggest that.  I think it's going to be difficult for practitioners and providers to make a decision a little bit about which one of these vaccines they want to use.  So I think that will be an early immediate issue, mostly because many of the issues that we've talked about which leave big blank spaces in the knowledge about this vaccine.  Dr. Self.

            DR. SELF:  So if that distinction hinges, at least in part, on herd immunity or secondary transmission, I guess I would make a plug for considering study designs to directly measure the differences in secondary transmission rather than relying on some of the presumed surrogates that I've heard thrown out since I think probably none of those are validated in any reasonable way for rates of secondary transmission.

            DR. OVERTURF:  Dr. Markovitz.

            DR. MARKOVITZ:  Yes.  I'd like to echo what Dr. Farley said, because this idea of the serogroup changing to stay one step ahead of the vaccine has actually been noted in the very earliest studies.  If you look at the oft quoted studies of Artenstein, and then they were re-analyzed actually by Lee Sabbath about 30 years ago, where they actually looked at the numbers and they found that, indeed, there was this shift from the serotype you were protected against, and now there was more of a different serotype, so this is actually a very real thing that's been known about for quite a long time, and would be well worth looking at in the post-marketing surveillance.

            DR. OVERTURF:  Dr. Karron.

            DR. KARRON:  This is really a question for the FDA, and it has to do with issues of lot variability.  And my question is really what will routinely be done to look at issues of lot variability.  The data that we saw today, there were some values that fell outside of the bounds.  They were not considered to be biologically significant, but I'd like to know what is routinely done.

            DR. FRASCH:  Well, this is addressed actually in two aspects.  One, we do routine lot release of every batch that the company makes.  And two, we do yearly inspection of the company, and checking the batch records for the vaccine.  And we also periodically go over the company, their specifications for the vaccine, not only does it meet the specification, but is there any drift within the specifications.  And so we try to keep up with the company, and with our own records to see if there's any change in the physical/chemical characteristics of the product. 

            We have the problems of looking at the vaccine physical chemically, but then at the same time we know that there's a lot of variation in different populations, so a single studies is sometimes somewhat difficult to know if that's really a variability in the vaccine, or a variability across the population.  But the important point is that we do do routine lot release of every batch of the vaccine, and we follow the specifications. 

            DR. KARRON:  So that lot release testing is both physical chemical characterization and immunologic characterization?

            DR. FRASCH:  No, no.  It's only physical chemical characterization.  No, there's no requirement for a vaccine to be tested - I would guess you mean in the clinic.  No, there's no requirement like that.  That's for any vaccine.

            DR. OVERTURF:  Dr. Stephens.

            DR. STEPHENS:  This is another comment concerning one component of this vaccine, and that's the A component.  We don't A disease to any great degree in this country, but this is the first A conjugate really to come to approval, and in some parts of the world, sub-Sharan Africa, for example, the A conjugate could make a huge difference in terms of burden of disease.  I would like to encourage them to - and I think they are - to think about that particular issue in terms of the use of this vaccine  in populations where A disease is much more prevalent.  And to get more information about the A component of this vaccine for that particular purpose.

            DR. OVERTURF:  Are there other comments?

            DR. DENSEN:  In addition to Dr. Farley's comments, I'd like to add what may be an obvious comment; which is, that I think it would be very important to do the surveillance for vaccine failures, particularly in some of the subgroups such as the complement-deficient patients or splenectomized patients, because I think the possibility is there that there will be a potentially higher failure rate in those populations - that would be number one.

            And I guess I feel, David Stephens and others, that while I agree very strongly with the comments about serogroup analysis and carriage rates and whatnot, and that the efficacy of the vaccine has not been demonstrated per se, I think on the other hand there are no data to suggest that the opposite is true.  And I think I would not personally like to come away from this session with the idea that I'm feeling negative about the opportunity, the potential, because I think the potential is very great based on the other conjugate vaccines that have been used. 

            DR. OVERTURF:  Any other questions, discussion?  We were supposed to take a break at 3:30, but I'm going to ask the members of the FDA if there's any other issues that we have not addressed for today's session before I call for an adjournment.  Then I think the meeting for the day is adjourned.  We re-adjourn at 9 a.m. tomorrow morning.

            (Whereupon, the proceedings in the above-entitled matter went off the record at 3:05 p.m.)