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:
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:
CARL FRASCH, Ph.D.
LUCIA H. LEE, M.D.
KAREN MIDTHUN, M.D.
SPONSOR REPRESENTATIVES:
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
PAGE
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 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 100th
VRBPAC Meeting, and as such, I'd just like to take a few moments to thank all
of our members of the Advisory Committee, the public and all of the staff who
have helped make this be a really good meeting time after time. And because of this, we actually have a cake
that we ordered for this occasion, and at the break, please help yourself to a
piece. So without further ado, back to
serious business.
DR.
OVERTURF: Next on the agenda is the open public hearing.
MS.
WALSH: As part of the FDA Advisory Committee meeting procedure, we
are required to hold an open public hearing for those members of the public who
are not on the agenda and would like to make a statement concerning matters
pending before the committee. Dr.
Overturf.
DR.
OVERTURF: I'm required to read into the record a statement regarding
open public hearing announcements. Both
the Food and Drug Administration and the public believe in the transparent
process for information-gathering and decision making. To assure such transparency, the Open Public
Hearing Session of the Advisory Committee Meeting, FDA believes that it's
important to understand the context of an individual's presentation. For this reason, the FDA encourages you, the
open public hearing speaker at the beginning of your written or oral statement
to advise the committee of any financial relationships you may have with the
sponsor, his products, and if known, its direct competitors.
For
example, this financial information may include the sponsor's payment of your
travel, lodging, or other expenses in connection with your attendance at the
meeting. Likewise, FDA encourages you
at the beginning of your statement to advise the committee if you do not have
any other such financial relationships.
If you choose not to address this issue of financial relationship at the
beginning of your statement, it will not preclude you from speaking.
Our
first speaker is Dr. David King, who is speaking as a New Jersey representative
for the Coalition for Mercury-Free Drugs.
DR.
KING: First of all, my name is Dr. Paul G. King. I don't know who this other guy is, but
that's who I am. And I'm speaking today
on behalf of the American public and CoMeD.
I have prepared a set of notes which I will diverge from fairly
drastically, not because I wanted to, but because different information was
revealed here than was in the packet that they provided, that the applicant
provided.
I
am neither affiliated with the government, nor any pharmaceutical
manufacturer. My background is the area
of CGMP regulatory compliance and sound science. I am a Ph.D. chemist with a Master's Degree in inorganic
chemistry, and I am definitely not a vaccinologist. If you're interested in finding out about my credentials, my
website is in the handout.
In
general, my oral presentation will discuss Aventis proposed new vaccine from
the viewpoint of a vaccine, and also the risk of reducing Mercury
poisoning. Now one of the things I
found out was that they did the study.
They didn't compare it to their vaccine they got approved, the approved
Menomune vaccine, is a preserved vaccine, but they did it against their single
dose vaccine, which is a low trace level Mercury vaccine, I believe. I guess I understand why. It might have got a lot more adverse
reactions if you compared it against that one, so somebody is making a leap
over a couple of hurdles that wasn't presented to this committee, because they
presented this as if they were comparing this to their approved Menomune
vaccine which they did by clinicals, and they're not doing that, which I find
reprehensible. If somebody is going to
do that, they should clearly have said that.
We put this intermediate step in, and here is why.
By
the way, I support doing that. I
wouldn't have ?? I would
hate to have given any 18 to 55 year old or child a Mercury-containing vaccine
at levels well above the toxic level, which according to Leong's work is on the
order of oh, let's see - if you do the math, comes out to something like 4
times 10 to the minus 11 grams were applied to 2ML preparations of growing
nurides, and 77 percent of them died.
And he tried Aluminum, Lead, Cadmium, and Manganese, and they didn't
cause any deaths to speak of at all.
Now
returning briefly to my remarks, the data on Menactra shows it's not worse than
the Menomune single dose vaccine, and it does boost immunity, which the
previous vaccine wouldn't do. So on
that basis, I would probably support it as a vaccine for being approved. However, I have a very big caveat emptor.
With
this vaccine, the sub titer varying shortly after vaccination less than 70
percent are protected, is this vaccine a preventive or is more indicator or
discriminator? Does it simply ID those
whose immune system can innately cope with this disease and blown its adverse
effect to the mild or silent ones? Does
it simply protect those who are not susceptible to the disease's severe
effects? Perhaps these questions should
be answered, because again, I would support it only to use just blunt
outbreaks, or when you have populations of diverse people coming together, like
in militaries or going to school where kids don't practice very good hygiene. I certainly didn't my first year in school,
and my university required me to live on campus.
The
third thing I have a problem with is when we talk about going to extend this to
doing it to children. Since the B
subtype is not protected at all in the vaccine, I don't understand why you're
going to give a vaccine that will, at best, initially protect less than, as I
count it, 40 percent of the children
inoculated, and after a year less than 20 percent. That's at best, and probably may not protect
even that many. The cost of it doesn't
seem to be beneficial.
The
other thing I would point out is if you look at the history, Menomune has been
around for a long time, and yet I don't see any drop in the outbreak rate, nor
any real decrease in the death rate. So
maybe again, it's like I said, it's only a vaccine. It's a good indicator of those people who are ?? you give it to people and they don't get very
sick with it, they are being who couldn't get sick with the disease very
much. That's what I would say about ?? that's what all I have to say about that, I
would think.
Now
the other thing which I worry about is that you say the strains vary and
whatever, but as I read all the things I could get my hands on, which aren't
very many, it seems that the vaccine has shifted the population of
strains. And that may not be in the
long term a good thing to do either, and that's another reason I'd recommend
this be only approved for outbreaks or in situations where the potential of
outbreaks is large, and not as a general vaccine to the general population.
Also,
I noticed that these people failed to provide a risk benefit analysis, and I
find that particularly reprehensible because the FDA says now everything is
supposed to be based on risk benefit.
In other words, here's what the cost is to the population, the risk -
you know, the total risk, health effects, could of the medicine and
whatever. Here's what the people who
are going to get this, going to get as a benefit. If it really doesn't protect anybody but the people who would be
protected anyway, maybe if it blunts the more ?? it might be worth it in an outbreak sense, but at $80 a dose for 300
million people every three years, I think I'd have a hard time justifying that
as being cost-effective healthcare. We
could do much more better things just to get the kids to wash up better,
practice better hygiene, clean their rooms and stuff better, and that would
reduce the risk of anyone getting the disease in the first place.
As
I've said before, nonetheless on balance, being forced to consider it less ?? I would still support this vaccine being
approved, provided the following actions are taken. There should be at least a five-year Phase Four trial where all
the data is collected on all the people given it for five years afterwards,
especially since you're going to be giving a booster dose after three
years. It looks like you're going to
give this as a vaccine in the normal sense of that word.
Also,
I think if you're going to approve Menactra, you should certainly revoke the
license for the Mercury laced or the preservative Menomune, if not both of
those vaccines, because they're obviously inferior in that they do have an
adverse effect if you ever try to get re-vaccinated with the Menomune, even the
low dose one.
Third,
again I will re-emphasize, only approve for vaccinations of most seriously
at-risk sub-populations; for example, incoming college freshmen who reside in
dormitory settings, military conscript, volunteers in service, orphanage
residents, nursing home or residential communities for the elderly. And for a similar reason, vaccination should
be restricted to initial dosing and one booster dose at three years subject to
review after five years experience under the Post Approval Surveillance
Program.
And
C, to prolong a rabies acquired internal immunity, DHHS should strongly promote
breast feeding for not less than two years because in Mother Nature, that's
what happens.
In
closing, let me assure this panel that failure to truly consider these simple
science-based requests and acting appropriately may further undermine the
public's willingness to subject themselves and their children to vaccines that
have real cost and real risk to them for the sake of the purported benefits to
the population as a whole. Because
again with the babies' case, if you believe herd immunity requires 80 percent
immunization, then there's no way you're going to get it by giving babies a
Non-B vaccine when that's the majority sub titer.
Remember
rather than trying to continue to increase the number of vaccines, the number
of doses given to the point that bad vaccines - my favorite examples are Lyme
disease vaccines and the Smallpox vaccine, in worst practices are incorporated
into the vaccine schedule, the money would be better spent re-emphasizing the
importance of personal hygiene and providing clean housing for the poor and the
homeless.
For
example, since bed bugs and not direct contact with a vector that transmits
Smallpox, and with supportive medicines which we have, the death rate is under
10 percent, DHHS would be better off spending money on providing clean
insect-free housing for the poor and homeless, and promoting the washing of bed
clothes with very hot water and bleach, instead of trying to vaccinate the
public and cause thousands of unnecessary Cowpox reactions, and hundreds of
unnecessary Cowpox deaths.
Finally,
does the cost of one dose outweigh the potential maximum benefits per
year? I don't think so. Thank you.
Any questions, I'll try to answer them.
DR.
OVERTURF: Thank you, Dr. King.
Are there any questions for Dr. King?
Thank you very much. Our next
speaker is, I hope I have this right, Mike Kepferle from the National
Meningitis Association.
MR.
KEPFERLE: Thank you. My name
is Mike Kepferle, and I'm one of the founding directors of the National
Meningitis Association. We're at a
non-profit health education foundation that tries to educate families, medical
professionals, and just the general public about meningococcal meningitis,
meningococcal disease, in particular, and the ways that you can help prevent
it; which obviously include both immunization and good hygiene.
I
want to say that we have been waiting.
I'm a parent, and I represent a lot of parents that have been impacted
by meningococcal disease, and we have been waiting for something to change. Now we haven't been waiting passively. We've been trying to make things happen, but
we look forward to this new conjugate meningococcal vaccine, if it's approved,
because of what we hope that it will do to protect the children.
We're
also waiting for a serogroup B vaccine, and I hope there's some discussion with
the folks down in New Zealand about what's going on there, and the potential
for a vaccine here in the U.S.
One
Saturday I took my son, Patrick, who was 18 years old and dropped him off at
college. Sunday he was dead. I couldn't even pronounce meningococcal, and
I'd heard about Meningitis. In fact, we
had received some information in 1999 in our college application that
recommended he be vaccinated with a
Menomune vaccine. But the
wording of the recommendation was kind of hard to follow. It didn't matter. We're very pro vaccine.
He had his Hepatitis vaccines, but we took him to a Navy clinic, which
is where we were getting our medical help, and ironically at a military base we
couldn't get the Menomune vaccine for him.
But we weren't worried.
We
didn't know much about Meningitis, but we figured he'd just get a shot when he
went to school, and we encouraged Patrick to do that. Well, he didn't do it the first semester, and so I remember
distinctly besides telling him to get his grades up, that he needed to go to
the health center and get the shot, and I'd pay for it. Well, in March he came home to watch his
high school team play in the regional playoffs, and then went back that March 4th,
2000 - it's now been four years - it seems like yesterday, and he was dead on
March 5th.
After
that happened, I reached out to other parents who I know lost children. I found about it, and I learned a lot, and
we started the National Meningitis Association. And if I could have every one of those parents sitting in this
room, because there are more parents than would fit in this room, and I have to
represent them because I'm the only one that could make it here, but if I could
have them sitting here, they'd say please, please get us another vaccine, and
help protect our kids.
Now
my son was in that classic college 18-year old freshman living in a dorm
situation, but believe me, I've talked to a lot of parents that have lost kids
that are 11, 14, 12. Last week, David
Pasick, Wall, New Jersey died at 13 years old.
I met with a family up in Washington State whose 12-year old son, Carl,
had both of his legs amputated. And I
don't think I need to tell most of the medical folks here what this disease can
do, but I do want you to know that we parents that didn't know what this
disease could do, and all of the parents out there that still don't know, no
matter how much we try to educate them, need to be given a vaccine that is
going to protect not just the college kids, but also the ones that are
younger. And every child in this
country that is eligible for a vaccine and can be protected by the vaccine
should be given that vaccine.
All
the families that are involved with NMA want you to know that we know that
immunization and education are the only combination that are going to save our
children's lives. And I don't want next
year to tell a parent of a 12-year old who lost their child because they didn't
have a vaccine that could have saved their lives, that well, we're another year
later, and I'm sorry. Because that's
what I'm telling them right now, and I don't like it. So please, please get us the vaccine that we need, work with us
to educate the public so that they know what the vaccine can do for it, and
thank you. Do you have any questions?
DR.
OVERTURF: Are there any questions for Mr. Kepferle? Thank you very much. Is there anyone else who would like to make
a presentation during the open public hearing?
If not, I will ask Dr. Carl Frasch to come forward and we'll begin
addressing the questions for the afternoon.
DR.
FRASCH: Okay. What I'm going
to do is I'm going to go through two questions and two discussion points, and
then be sure that there's a clear understanding of exactly what the committee
is being asked. Then we'll go back to
question one, and Dr. Overturf's open
the questions for discussion.
So
the first question is, are the available data adequate to support the efficacy
of Menactra, in this case as defined by non-inferiority of the antibody
response to Menactra compared to the licensed polysaccharide vaccine Menomune,
when administered to individuals 11 to 15 years of age. If not, what additional data are needed.
The
second question and the last question for which the committee will vote is, are
the available data adequate to support the safety of Menactra when administered
to individuals 11 to 15 years of age?
If not, what additional data are necessary.
Now
the next two are discussion points.
First discussion item is, please discuss the adequacy of the data
regarding the use of Menactra with other vaccines likely to be used
concurrently, administered concurrently.
For example, Td. And the last
discussion item - please identify any issues that should be addressed in post
licensure studies.
So
I would open the ?? see if
there's any discussion regarding the meaning of any of the questions. If the meaning of the questions are clear,
then I'll be finished. Okay.
DR.
OVERTURF: If not, we'll go ahead and proceed with a discussion of
the first question. The first question
is, are the available data adequate to support the efficacy of Menactra, i.e.,
non-inferiority of the antibody response to Menactra compared to the licensed
polysaccharide Menomune when administered to individuals 11 to 55 years of
age. If not, what additional data are
necessary? Are there discussions or
questions? This is a question we will
vote on, and what we will do at the time of the vote is to proceed around the
room. If you have additional data that
you think is necessary, regardless of what your vote is in that regard, you
should state it at that time into the record.
Did you have a question, David?
No. Any other discussion
regarding this question? This is a very
quiet committee today.
This
time I think we'll start with Dr. Karron, and ask her for a yes or no vote, and
any questions regarding additional data that she feels is necessary.
DR.
KARRON: Yes, I believe that the data are adequate to support the
efficacy of Menactra; that is non-inferiority of the response to Menactra
compared to Menomune.
DR.
OVERTURF: Dr. Self.
DR.
SELF: Well, at risk of contradicting myself I will vote yes, I think
the data are adequate. But I'll also
say that I would like to see some more data, and that would have to do with the
relationship between the antibody response and risk for other serogroups.
DR.
OVERTURF: Dr. Densen.
DR.
DENSEN: I believe the data are adequate to support the
non-inferiority of the candidate vaccine to the current vaccine.
DR.
OVERTURF: Dr. Whitley.
DR.
WHITLEY: According to the standards specified by the Food and Drug
Administration and Aventis, I believe that Menactra should be approved for
efficacy.
DR.
OVERTURF: Dr. Word.
DR.
WORD: I would agree that there is adequate data to support the
efficacy of Menactra.
DR.
OVERTURF: Dr. Petteway, I believe you're a non-voting member for
this. Do you have any comments that you
want to make?
DR.
PETTEWAY: Well, the only comment is I think it's clear, I think that
the data does support non-inferiority.
DR.
OVERTURF: Yes, Dr. Stephens.
DR.
STEPHENS: I also agree the data are supportive that this vaccine is
non-inferior.
DR.
OVERTURF: Dr. Gellin.
DR.
GELLIN: Also in agreement that the data as presented are in
agreement with the ?? supporting
Menactra based on non-inferiority for efficacy.
DR.
OVERTURF: Cindy Province.
MS.
PROVINCE: Yes, I do believe that the available data are adequate to
support the efficacy of Menactra according to the conditions that have been
given.
DR.
OVERTURF: Dr. McInnes.
DR.
McINNES: I believe that the available data are adequate with regard
to efficacy for Menactra. I would like
to see additional data on persistence of antibody so that one might better
understand the possible priming, boosting.
And I think data on the kinetics of the antibody response would be of
great interest also in further understanding the biology of what is happening.
DR.
OVERTURF: Dr. Farley.
DR.
FARLEY: Yes, I think that the data do support the non-inferiority of
the product. I agree that having more
information on the subsequent dosing
and boosting would be of great interest.
DR.
ROYAL: I agree that the data demonstrate that Menactra is not
inferior to Menomune.
DR.
OVERTURF: I'm sorry. I
didn't call Dr. Royal's name. That was
Dr. Royal's vote. Dr. Markovitz.
DR.
MARKOVITZ: Yes, I'd like to vote yes, that this has been
demonstrated and strongly echo the comments of Dr. McInnes and Dr. Farley, that
it's going to be very important to see that follow-up about boosting and
antibody persistence, because I think that's what will ultimately make this a
vaccine that people will really want to use.
DR.
OVERTURF: I also would vote affirmatively for this, but I think the
data strongly support this. I think
there is going to be needed data regarding persistence of antibody, and
particularly persistence of protected antibody, and also when boosting will be
required.
I
also would hope very much that there would be ?? that the data for children will be coming along very, very shortly,
because I think that's going to be an important long-term component, probably
controlling meningococcal disease, as
well.
The
second question is, are the available data adequate to support the safety of
Menactra when administered to individuals 11 to 55 years of age? If not, what additional data are necessary? So this question is now open for discussion
from any member of the committee. Are
there questions regarding this? So a
slightly different standard here because it's not truly a comparable
vaccine. It has actually more antigenic
components and, therefore, the non-inferiority is a little bit more difficult
to apply, because of the fact that you going to expect more reactions, which I
think the sponsor addressed. Ye, Dr.
Whitley.
DR.
WHITLEY: I just think to reiterate that point, don't forget the two
vaccines are given by different routes.
One is given subcutaneously, and the other is given intramuscularly, and
that does introduce a variable that needs to be considered.
DR.
OVERTURF: Are there any further comments or questions,
discussion? Well, this time we'll start
with you, Dr. Markovitz, if you could address that question.
DR.
MARKOVITZ: Yes. I mean, I
think similar to what might be expected by the comments that Drs. Overturf and
Whitley have made, this is slightly more reactogenic vaccine than is the
currently licensed version. But
nonetheless, I think it's safe. I'm
convinced that the safety data are good.
Because it's more reactogenic, I'd certainly want to see very close
follow-up once people are vaccinated in larger numbers, so I would vote yes,
for the safety issue.
DR.
OVERTURF: Dr. Royal.
DR.
ROYAL: Thank you. I would
vote that the data do demonstrate that the vaccine is safe.
DR.
OVERTURF: Dr. Farley.
DR.
FARLEY: I would say yes, the data are adequate to support the safety
of the new vaccine.
DR.
OVERTURF: Dr. McInnes.
DR.
McINNES: Yes, I found the data to be adequate to support the safety
of Menactra.
DR.
OVERTURF: Yes, Ms. Province.
MS.
PROVINCE: I do agree that the data are adequate to support the
safety of Menactra. And I just want to
make a general comment for the record about the importance of post-licensure
surveillance. That may be more
appropriately addressed under the discussion points, but I think it will be
very important to look at the safety data as it continues to come in, both for
the adverse events that have been detected so far, and is of extreme
importance, and continue to monitor this vaccine for even the possibility of
rare adverse events that might not have been adequately detected pre-licensure.
I think that that's just a growing issue involving public confidence in
vaccines.
DR.
OVERTURF: Thank you. Dr.
Gellin.
DR.
GELLIN: Given the caveat stated about the differences in antigen
content and the route of administration, I also believe that the safety data as
presented are adequate to license this vaccine based on safety. And agree with Cindy that there's a need to
have ongoing safety studies, particularly - and we'll get into this with the
next question - with concomitant administration, and if this is a vaccine that is then given to children, where there
are more vaccines administered.
DR.
OVERTURF: Dr. Stephens.
DR.
STEPHENS: I would agree this is, as the data suggests, this is a
safe vaccine. I would also agree with
the comment just made about concomitant vaccines, in particular Td concomitant
administration where I think the reactogenicity issues may be even more
pronounced. And other vaccines
concomitantly given is of concern.
DR.
OVERTURF: Dr. Petteway, do you have any comments?
DR.
PETTEWAY: It's clear that the data supports safety.
DR.
OVERTURF: Dr. Word.
DR.
WORD: I think it does support the safety of Menactra.
DR.
OVERTURF: Dr. Whitley.
DR.
WHITLEY: I believe the vaccine's data support safety, but I want to
contribute to the caveat that was made earlier; and that is, I think
surveillance studies need to be in place when this vaccine is licensed
recognizing that the total number of people who participated in the clinical
trials were only 7,500. And by my
standards, that's a bit slim in terms of understanding the safety profile.
Furthermore,
we all know that once we go beyond clinical trials, what happens in the real
world is very different. And so being
able to monitor that, and reinforce public confidence is essential.
DR.
DENSEN: I agree with my colleagues that the vaccine is safe, and I echo the comments of Dr. Whitley.
DR.
OVERTURF: Dr. Self.
DR.
SELF: I agree the data are adequate to support the safety of
Menactra, and concur with Whitley and others about surveillance post-licensure.
DR.
OVERTURF: Dr. Karron.
DR.
KARRON: I agree that the data are adequate to support the safety of
Menactra, and agree with others' comments about the need for post-licensure
surveillance.
DR.
OVERTURF: I also will vote affirmatively for the confidence in the
data on the safety of Menactra. I also
feel that with recent history as the test, that 7,500 patients sounds like a
lot but it turns out to be a fairly slim number, particularly for those very rare adverse events, so
post-marketing surveillance will be a critical part of this vaccine's future.
Now
at this point, we're going to open up the discussion to the adequacy of the
data regarding use of Menactra with other vaccines likely to be concurrently
administered, such as Td. And we've
already commented on Td. When and if we
begin to extend this vaccine to much younger children ?? yes, I'm sorry. Dr. Frasch.
DR.
FRASCH: I just want to clarify that concurrent doesn't only mean
given at the same time as, but within reasonable proximity of, like a week or
so on either side.
DR.
OVERTURF: My comment would be that there are vaccines which are
given in college health services, and are recommended. Often college students do not get the second
dose of MMR until college. The other
vaccine, which is a live vaccine, they also may not get vaccinated for
Hepatitis A and Hepatitis B prior to college, and some of those are
recommended, as well. So there will be
a need for at least some additional data for safety and the effects on
immunogenicity of this vaccine. So at
this point, I'll open the question up for discussion, and see if there are
additional comments by the committee members.
Any additional comments? Dr.
Word.
DR.
WORD: I think you've mentioned a number of other vaccines that need
to be addressed when you administer this, but it's not just that we're just
talking about the adolescent population.
You're extending it out, and besides just routine healthy immunizations,
you have to think about people who do participate in international travel. And there are a number of other vaccines
that may be administered at those time periods, like Yellow Fever, Japanese
Encephalitis. I mean, you're not going
to need a lot, but when you're dealing with some of these adolescents
particularly go out of the country, they go to missions. And also, I think Dr. Karron brought up the
question about oral Typhoid, even though many of us don't use it as much, we
use the injectable because of the conflicts occasionally with Malaria
prophylaxis. There are some people who
still use oral Typhoid.
DR.
OVERTURF: Are there any other questions? There's actually a number of those travel vaccines, including for
people going on extended stays in rural countries, Rabies vaccine, pre-exposure
prophylaxis is recommended. Others
receive dosing of things like Yellow Fever vaccine for certain kinds of
settings, as well. So in addition to
Typhoid and also the Hepatitis A vaccine that I mentioned, so I think there
will be a number of the travel vaccines that will have to be looked at.
DR.
WHITLEY: Procedurally, Gary, what do we have to do? Do we have to make a formal statement for
the agency on discussion items, since this is a non-voting item, or what do you
want from the committee?
DR.
OVERTURF: We do not have to have a vote. What's required here is a discussion for the sponsor and for the
FDA to help direct them into studies that need to be done further for
concurrently given vaccines.
DR.
WHITLEY: Then I think we should make a definitive statement that the
data regarding the use of Menactra plus Td, versus administration of Td
followed a month later by Menactra need to be clarified so that the immune
response, persistence of immunity, and kinetics of immune response are all
identified under those circumstances.
DR.
OVERTURF: I agree. I think
also safety needs to be addressed in that regard. When the vaccine is given with some of these other vaccines,
that's going to be necessary. Actually,
the data that's presented today I think we all would agree is very limited and
only begins to scratch the surface with what's needed. Dr. Stephens.
DR.
STEPHENS: I think there also needs to be some additional data about
the use of this vaccine in individuals that have previously received the
polysaccharide vaccine. We heard some
data today and it hadn't been, as I understand it, reviewed by the FDA, but
there was data presented, a little bit of data in that regard. But I think this is an important group,
because a number of college kids, obviously, a number of the population have
already been vaccinated with a polysaccharide, and we need to have some
understanding, a better understanding of how this vaccine would be used in
those groups, laboratorians, for example.
It's
also true that there needs to be a better understanding of what happens when
the polysaccharide is used after this vaccine.
We didn't hear any data from my perspective, or I didn't hear any data
about that today; although, I think that data does exist, and I think it may be
an effective booster. But some more
data about the concurrent use or the previous use of polysaccharide vaccine in
conjunction with this vaccine needs to be obtained.
DR.
OVERTURF: Yes.
DR.
WHITLEY: Can I just amplify on what Dave said for one minute. And I think it goes back to the question
that I posed earlier; and that is, the day-28 data need to be extended far
out. And I understand that data will be
forthcoming in children, and you have it, but it should be also available in
other populations, as well, because that will be crucial in terms of the people
who just get Menactra, versus those who have the polysaccharide vaccine
followed by Menactra.
DR.
OVERTURF: All right. I think
we'll probably ?? the
likelihood is that we'll be exposing a fairly sizeable large population
immediately to this vaccine, particularly in the adolescent age group. And we don't know much past a few months, so
I think that's where the critical early information needs to come from. Yes, Dr. Farley.
DR.
FARLEY: I agree. I'm
concerned if we have a successful vaccine campaign of 11 year olds ,we will be
uncertain what to be advising them to do when they're going to be college
freshmen in dormitories, so I think we have a lot to learn for that very high
risk population.
DR.
OVERTURF: Is it fair to ask the sponsor if any of those kinds of
studies are planned, with some of the initial populations that were immunized
at 11 to 12 or 15 years of age. Are any
of those planned for long-term booster studies? Just introduce yourself again.
DR.
DECKER: I'm Dr. Michael
Decker. I heard several issues raised
that are closely related. We showed you
the data from MTA19, which are being submitted or may have just been submitted
to FDA for their formal review. And
that involves a three-year follow-up with the cohort from the MTA02 participants. We're continuing to follow these
children. One reason why it was a
subgroup that was reimmunized there was to leave some children behind who could
be evaluated, and potentially reimmunized at five years, or at successive time
points. So it's our intention to follow
this MTA02 cohort on out. And remember
now, they're a full four years ahead of the public that has not received the
vaccine at all yet. So we recognize
precisely the question was raised. In
fact, to me that's one of the most compelling questions, is if we immunize a
cohort of 11 year olds as I hear that ACIP is considering, the question will be
raised when they approach colleges are they covered, do they need a
booster? And so we have this cohort who
were immunized at 11 years old already in the study, and the adolescents limit
18, but it includes ?? it will
provide data that will address this question.
And you saw what it looked like three years out. We're waiting to see in about year, we're
going to see what it looks like five years out, and so on. And so we have that going.
I
don't want to talk much at all about the data for persons younger than 11,
because that's not the subject of today's meeting, but I know it's of great
interest to people. And we have done
similar work in that group, and are following them on out. So I believe that we will have data that
will directly address the things that we all need to know.
DR.
OVERTURF: Dr. Royal.
DR.
ROYAL: I'd like to put in a plug for studies being pursued that
might increase our understanding of the mechanisms that might be associated
with any increased efficacy that might be seen going back to the comment about
not only were the formulations different, but also the routes of administration
were different, which makes it a bit difficult to understand whether it's the
formulation or the intramuscular injection that's really responsible for the
increased immunogenicity. So such
studies may not necessarily involve humans, and it may be difficult to do in
humans, but I would be very much in favor of them being done.
DR.
OVERTURF: Another issue in mechanism might be also to look more
closely at those sub-populations which actually have complement
deficiency. That will be a difficult
study, although at least in many populations, the estimated number of
individuals who are deficient have those complement deficiencies vary from a 5
or 10 percent number, all the way up to as much as 30 percent, depending which
population you're looking at. It will
be interesting to see what the immunology is in those patients who received
those vaccines in that particular population, particular group.
DR.
DENSEN: I have two comments, one just related to your last
comment. I think the variation, the
number of complement deficient patients in different populations depends on the
incidence of meningococcal disease and the population in general. But in an endemic population, it runs pretty
consistently about 10 percent.
I
would like to encourage the FDA to organize studies that would look at the
principles that might emerge when you give mixed vaccines, so you give this
vaccine with another vaccine, so that we could understand whether or not there
are general immunologic principles about combining vaccines that could be
derived, or whether these combined administrations always represent unique
events related to the vaccine properties itself. So that as we move forward, we would have a handle on some of the
very real questions that have been raised here, and we wouldn't have to solve
that problem each time, if there are emerging concepts.
DR.
OVERTURF: Dr. Word.
DR.
WORD: Just a question - I guess I thought of it when you started
talking about some of the people who have some complement deficiencies,
but people routinely are recommended to
receive meningococcal vaccine because of underlying health problems. Where will they fit in, because the wording
here is just for individuals 11 to 55, and so many of them would be of the age
where they're getting a booster, or if there splenectomized. I'm not quite sure how ?? is it only going to be for healthy people? I mean, the way it's worded, it seems like
it's for anyone between 11 and 55.
DR.
OVERTURF: Well, I think the populations that were studied were
healthy populations, so whether ?? that
actually is not really technically an issue for this committee.
DR.
WORD: Okay.
DR.
OVERTURF: How the vaccine is used, and how it's recommended to be
used once it's approved is for other agencies.
And the point I was trying to make is that there does need to be
additional studies of those populations specifically. Whether it will be used or not immediately is up to other
groups. Dr. Stephens.
DR.
STEPHENS: The real question is whether this is a better vaccine than
the polysaccharide, and I think the data - we'll get to that probably in
question four, but the real data is not there, in my view, that this is a
better vaccine. We have a lot of
promises. We have the experience in the
U.K. with different vaccines. One of
the hopes is that this vaccine will induce a herd immunity response, a
significant herd immunity response. We
don't have any data about that with this particular vaccine. I think very clearly we would like to - I
would certainly like to see some data looking at mucosal antibody, looking at
potential of herd immunity for this particular vaccine.
Sixty
percent of the preventive cases in the U.K. were due to herd immunity, a very
powerful correlate, immune correlate of conjugate vaccine, certainly see with
the pneumococcal conjugate, as well as the Hib conjugate. There is hope that this conjugate will do
similar kinds of herd immunity effects, but we don't have any information,
other than the promise that there may be a herd immunity effect. So that's one
issue that I think we need to make sure that's at least raised with the
manufacturers as this vaccine moves forward.
Second
issue is memory - does memory protect?
I don't whether memory protects or not.
That's a big question in the meningococcal world about whether memory is
going to protect, whether it's simply ?? waning of antibody, as Dr. Farley points
out, is going to be a real issue. And
whether memory response, whether it may be a laboratory phenomena, but is that
memory response going to protect for meningococcal disease?
There
is some data, as we've mentioned this morning in the U.K. suggesting that at
least in toddlers who were getting a different immunization schedule, that even
though they generate these memory responses, they don't protect after one year,
so that's of concern with these conjugate vaccines. So I think the whole issue of memory and whether it's going to be
protective or not, and whether a boosting response is going to protect is
another important area for this particular vaccine. Is it going to be better than the currently available
polysaccharide, and those are important questions from a public health
standpoint, anyway, that need to be considered as this vaccine moves forward.
DR.
OVERTURF: Dr. Royal.
DR.
ROYAL: I concur with all of the points made by Dr. Stephens, and I'd
like to sort of just get something out of my head and ask whether one might
have expected to see some change in the response to Menomune merely by instead
of administering subcutaneously, to give it IM.
DR.
OVERTURF: Does the sponsor want to address that question? Dr. Frasch.
DR.
FRASCH: If you look at the very early trials in the early 1970s,
which Dr. Gotschlich and colleagues were involved with, and at that time they
did not know whether they were going to give the vaccine subcu or IM. And
limited studies were done at that time, and there was no difference in the
immune response to the vaccine given IM versus subcu. The only difference was some differences in adverse reactions,
but not immunogenicity.
DR.
OVERTURF: Are there any other comments on discussion Point
Three? Dr. Gellin.
DR.
GELLIN: I mean, just to round it out, given that the age range is 11
to 55, we have identified a number of populations that would have different
vaccines given concomitantly, adolescents, laboratorians potentially,
international travelers. I would throw
the military on that list, as well, and I don't know if there's any here can
speak to that, but knowing it's a vaccine that's probably of interest to them,
that's probably another set of studies given the databases they have that looks
at vaccine safety.
DR.
OVERTURF: Dr. Karron.
DR.
KARRON: And just to amplify on Dr. Gellin's comment, we actually saw
data in the aggregate presented from age 11 to 55. I think as there are post-licensure studies done, it would be
interesting to see some breakdown by age regardless of the issue of concomitant
vaccines administered to see if responses are equivalent across the age range.
DR.
OVERTURF: Are there other comments?
I'd like to then go ahead and proceed to question number four; which is,
please identify any issues - I think we've partly begun to address this - that
should be addressed in post-licensure studies.
Are there any additional issues that haven't been addressed? I think in addition to breaking things down
by - we've already mentioned host, and age, probably racial and ethnic
backgrounds need to be looked at more closely also. Dr. Whitley.
DR.
WHITLEY: I think the qualifier on that, and Barbara and I were just
talking about it a minute ago, is that not only under-represented minorities,
but the populations that may not best be served by current nutritional balances
in the United States, where you would you expect a less advantageous an immune
response, and I wouldn't make that comment just for this vaccine, but for
vaccine development in general.
DR.
OVERTURF: Yes, Dr. Farley.
DR.
FARLEY: I think that obviously the post-marketing surveillance is
important, but I think general surveillance for meningococcal disease and the
distribution, ongoing activities of surveillance where we look for so-called
replacement, or shifting towards predominance of B disease, for instance,
serogroup B disease because it's not in the vaccine, obviously following
that. I think it would be very
interesting to look at carriage studies, depending on what the recommendations
actually are, whether it's going to be a solid block of the population that it
will be recommended for, and whether you can look at that age group for reduction
in carriage of the vaccine serogroups.
DR.
OVERTURF: Yes, Dr. Stephens.
DR.
STEPHENS: Just to echo what Dr. Farley was saying, I think the U.K.
really had a very aggressive program as they went forward with their conjugate
vaccine to look at issues of carriage, and to look at issues of serotype or
serogroup replacement. And those
studies are still ongoing, and still very helpful. And I think similar kinds of studies really need to be done in
this country to look at the effects of this conjugate. Again, it depends to some degree on how it's
introduced, and how it's used, but those were very important studies in
understanding how that vaccine in that country was and is working.
DR.
OVERTURF: Just to echo some of the previous comments, actually those
of Dr. Stephens, I think the issue about how ?? whether this is a better vaccine really is going to be a very early
critical issue, because many assumptions are being made about this vaccine, and
I'm not sure that the data yet is completely adequate to suggest that. I think it's going to be difficult for
practitioners and providers to make a decision a little bit about which one of
these vaccines they want to use. So I
think that will be an early immediate issue, mostly because many of the issues that
we've talked about which leave big blank spaces in the knowledge about this
vaccine. Dr. Self.
DR.
SELF: So if that distinction hinges, at least in part, on herd
immunity or secondary transmission, I guess I would make a plug for considering
study designs to directly measure the differences in secondary transmission
rather than relying on some of the presumed surrogates that I've heard thrown
out since I think probably none of those are validated in any reasonable way
for rates of secondary transmission.
DR.
OVERTURF: Dr. Markovitz.
DR.
MARKOVITZ: Yes. I'd like to
echo what Dr. Farley said, because this idea of the serogroup changing to stay
one step ahead of the vaccine has actually been noted in the very earliest
studies. If you look at the oft quoted
studies of Artenstein, and then they were re-analyzed actually by Lee Sabbath
about 30 years ago, where they actually looked at the numbers and they found
that, indeed, there was this shift from the serotype you were protected
against, and now there was more of a different serotype, so this is actually a
very real thing that's been known about for quite a long time, and would be
well worth looking at in the post-marketing surveillance.
DR.
OVERTURF: Dr. Karron.
DR.
KARRON: This is really a question for the FDA, and it has to do with
issues of lot variability. And my
question is really what will routinely be done to look at issues of lot
variability. The data that we saw
today, there were some values that fell outside of the bounds. They were not considered to be biologically
significant, but I'd like to know what is routinely done.
DR.
FRASCH: Well, this is addressed actually in two aspects. One, we do routine lot release of every
batch that the company makes. And two,
we do yearly inspection of the company, and checking the batch records for the
vaccine. And we also periodically go
over the company, their specifications for the vaccine, not only does it meet
the specification, but is there any drift within the specifications. And so we try to keep up with the company,
and with our own records to see if there's any change in the physical/chemical
characteristics of the product.
We
have the problems of looking at the vaccine physical chemically, but then at
the same time we know that there's a lot of variation in different populations,
so a single studies is sometimes somewhat difficult to know if that's really a
variability in the vaccine, or a variability across the population. But the important point is that we do do
routine lot release of every batch of the vaccine, and we follow the
specifications.
DR.
KARRON: So that lot release testing is both physical chemical
characterization and immunologic characterization?
DR.
FRASCH: No, no. It's only
physical chemical characterization. No,
there's no requirement for a vaccine to be tested - I would guess you mean in
the clinic. No, there's no requirement
like that. That's for any vaccine.
DR.
OVERTURF: Dr. Stephens.
DR.
STEPHENS: This is another comment concerning one component of this
vaccine, and that's the A component. We
don't A disease to any great degree in this country, but this is the first A
conjugate really to come to approval, and in some parts of the world, sub-Sharan
Africa, for example, the A conjugate could make a huge difference in terms of
burden of disease. I would like to
encourage them to - and I think they are - to think about that particular issue
in terms of the use of this vaccine in
populations where A disease is much more prevalent. And to get more information about the A component of this vaccine
for that particular purpose.
DR.
OVERTURF: Are there other comments?
DR.
DENSEN: In addition to Dr. Farley's comments, I'd like to add what
may be an obvious comment; which is, that I think it would be very important to
do the surveillance for vaccine failures, particularly in some of the subgroups
such as the complement-deficient patients or splenectomized patients, because I
think the possibility is there that there will be a potentially higher failure
rate in those populations - that would be number one.
And
I guess I feel, David Stephens and others, that while I agree very strongly
with the comments about serogroup analysis and carriage rates and whatnot, and
that the efficacy of the vaccine has not been demonstrated per se, I think on
the other hand there are no data to suggest that the opposite is true. And I think I would not personally like to
come away from this session with the idea that I'm feeling negative about the
opportunity, the potential, because I think the potential is very great based
on the other conjugate vaccines that have been used.
DR.
OVERTURF: Any other questions, discussion? We were supposed to take a break at 3:30, but I'm going to ask
the members of the FDA if there's any other issues that we have not addressed
for today's session before I call for an adjournment. Then I think the meeting for the day is adjourned. We re-adjourn at 9 a.m. tomorrow morning.
(Whereupon,
the proceedings in the above-entitled matter went off the record at 3:05 p.m.)