UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

VACCINES AND RELATED BIOLOGICAL PRODUCTS

ADVISORY COMMITTEE

100th MEETING

WEDNESDAY,

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.

[PRESENT:]{.underline}

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

DAVID M. MARKOVITZ, M.D. Member

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

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

Representative

CINDY LYN PROVINCE, R.N., M.S.N.

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.

[FDA REPRESENTATIVES:]{.underline}

CARL FRASCH, Ph.D.

LUCIA H. LEE, M.D.

KAREN MIDTHUN, M.D.

[SPONSOR REPRESENTATIVES:]{.underline}

GARY CHIKAMI, M.D.

MICHAEL D. DECKER, M.D.

GREG GILMET, M.D., M.P.H.

LUC KUYKENS, M.D., M.P.H.

[C O N T E N T S]{.underline}

[PAGE]{.underline}

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

P-R-O-C-E-E-D-I-N-G-S

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]{.underline} 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.

(Laughter.)

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 100^th^ 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 4^th^, 2000 - it\'s now been four years -
it seems like yesterday, and he was dead on March 5^th^.

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.)