UNITED STATES OF
AMERICA
FOOD AND DRUG
ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION
AND RESEARCH
VACCINES AND RELATED
BIOLOGICAL
PRODUCTS ADVISORY
COMMITTEE
102nd
MEETING
TUESDAY, MARCH 15,
2005
The
Advisory Committee met at 8:30 a.m. at the Holiday Inn Select, 8120 Wisconsin
Avenue, Bethesda, Maryland, Dr. Gary D. Overturf, Chair, presiding.
PRESENT:
GARY D. OVERTURF, M.D., Chair
MONICA M. FARLEY, M.D., Member
BRUCE GELLIN, M.D./M.P.H., Temp. Voting Member
SETH HETHERINGTON, M.D., Acting Non-Voting Ind.
Rep.
RUTH A. KARRON, M.D., Member
PHILIP S. LARUSSA, M.D., Member
DAVID MARKOVITZ, M.D., Member
PAMELA MCINNES, D.D.S., Temp. Voting Member
TRUDY MURPHY, M.D.
CINDY LYN PROVINCE, R.N./M.S.N./M.A., Consumer
Rep.
STEVEN SELF, Ph.D., Member
WALTER ROYAL, III, M.D., Member
DAVID STEPHENS, M.D., Temp. Voting Member
MELINDA WHARTON, M.D./M.P.H., Temp. Voting Member
BONNIE M. WORD, M.D., Member
FDA REPRESENTATIVES:
THERESA FINN, Ph.D. This transcript has not been edited or corrected, but
HENRY HSU, Ph.D. appears
as received from the commercial transcribing
BRUCE MEADE, Ph.D. service. Accordingly the Food and Drug Administration
CHRISANNA M. MINK, M.D. makes no representation as to its accuracy.
MARTHA MONSER, B.A.
ANN T. SCHWARTZ, M.D.
GSK REPRESENTATIVES:
VINCENT AHONKHAI, M.D.
LEONARD FRIEDLAND, M.D.
BARBARA HOWE, M.D.
SANOFI PASTEUR REPRESENTATIVES:
MICHAEL DECKER, M.D./M.P.H.
SCOTT A. HALPERIN, M.D.
DAVID JOHNSON, M.D./M.P.H.
LUC KUYKENS, M.D./M.P.H./D.T.M.
AGENDA ITEM PAGE
WELCOME/OPENING REMARKS:
Gary Overturf................................... 4
Christine Walsh................................. 4
INTRODUCTIONS:.................................. 7
SESSION I - TDAP INTRODUCTION/BACKGROUND:
Theresa Finn.................................... 9
Questions...................................... 17
BOOSTRIX VACCINE PRESENTATION/GSK TDAP:
Vincent Ahonkhai............................ 22/61
Barbara Howe................................... 28
Leonard Friedland.............................. 34
Questions...................................... 64
FDA PRESENTATION:
Ann Schwartz................................... 90
Questions..................................... 114
QUESTIONS/DISCUSSION/RECOMMENDATIONS FOR
COMMITTEE:
Discussion.................................... 130
Motion to Change Question 1 wording........... 147
Vote to Accept Motion......................... 147
Question 1 Vote............................... 149
Question 2 Vote............................... 152
SAFETY/IMMUNOGENICITY DATA & ADACEL
INTRODUCTION:
Martha Monser................................. 155
SANOFI PASTEUR:
Luc Kuykens............................... 159/183
David Johnson................................. 162
Michael Decker................................ 170
Questions..................................... 195
Scott Halperin................................ 198
Questions..................................... 204
FDA PRESENTATION:
ChrisAnna Mink................................ 218
Questions..................................... 245
SESSION II - OPEN COMMITTEE DISCUSSION:
Question 1.................................... 255
Question 2.................................... 255
Discussion Item............................... 255
Vote on Question 1............................ 256
Vote on Question 2............................ 258
DISCUSSION/RECOMMENDATIONS:................... 260
ADJOURN:
Gary Overturf................................. 263
P-R-O-C-E-E-D-I-N-G-S
8:34
a.m.
CHAIR
OVERTURF: Would the Committee Members,
please, take their seats? I would like
to call this meeting to order. This is
the meeting of the Food and Drug Administration, Center for Biologics
Evaluation and Research, Vaccines and Related Biological Products Advisory
Committee meeting, March 15th.
I would like to turn the meeting, first of all, over to Christine Walsh.
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 all
of you to the 102nd meeting of this Advisory Committee. At this time, I would like to introduce Ms.
Denise Royster. Is she here? She is probably at the desk. She is our Committee Management Specialist
for VRBPAC Committee and she has worked very hard in putting this meeting
together, and we thank her for her efforts.
Today's
session will consist of presentations that are open to the public. I would like to request that everyone,
please, check your cell phones and pagers to make sure they are off or in the
silent mode. I would now like to read
into the public record the Conflict of Interest statement for today's meeting.
The
following announcement is made part of the public record to preclude even the
appearance of a Conflict of Interest at this meeting. Pursuant to the authority granted under the Committee Charter of
the Director, Center for Biologics Evaluation and Research, has appointed the
following participants as temporary voting members: Drs. Bruce Gellin, Pamela
McInnes, David Stephens and Melinda Wharton.
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 disclosure is being
made:
Dr.
Ruth Karron has been granted a waiver under 21 USC 355(n)(4) of Section 505 of
the Food and Drug Administration Modernization Act for consulting with this
sponsor and a competing firm for less than $10,000 a year. Dr. Karron may participate fully in the
discussions of this meeting.
We
would like to note for the record that Dr. Seth Hetherington will be
participating as the Acting Non-Voting Industry Representative acting on behalf
of regulated industry. Dr.
Hetherington's participation is not subject to 18 USC 208. He is employed by Inhibitex and thus has a
financial interest in his employer.
Several years ago, Dr. Hetherington was employed by GlaxoSmithKline.
In
addition, in the interest of fairness, FDA is disclosing that Dr.
Hetherington's spouse is currently employed by GlaxoSmithKline. Her duties do not involve vaccine
research. She also holds stock options
in her employer.
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 exclusions will be noted for 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 over to you.
CHAIR
OVERTURF: I would like to welcome the
Members of this meeting and we'll try to stay on agenda today throughout and
make sure that we finish on time. At
this point, I would like to go around the table starting with Dr. Wharton and
ask each Member to introduce themselves and to say where they are from.
DR.
WHARTON: Melinda Wharton, National
Immunization Program, Centers for Disease Control and Prevention.
DR.
MARKOVITZ: David Markovitz from
University of Michigan.
DR.
HETHERINGTON: Seth Hetherington from
Inhibitex in Alpharetta, Georgia.
DR.
FARLEY: Monica Farley from Emory in
Atlanta.
DR.
MCINNES: Pamela McInnes, National
Institute of Allergy and Infectious Diseases, NIH.
MS.
PROVINCE: Cindy Province. I'm the Consumer Representative and I'm from
the St. Louis Center for Bioethics and Culture.
CHAIR
OVERTURF: I'm Gary Overturf. I'm from the University of New Mexico.
DR.
LARUSSA: Phil LaRussa, Columbia
University, New York.
DR.
GELLIN: Bruce Gellin, National Vaccine
Program Office, HHS.
DR.
SELF: Steve Self, Hutchinson Cancer
Research Center and the University of Washington.
DR.
MURPHY: Trudy Murphy, The National
Immunization Program at CDC.
DR.
STEPHENS: David Stephens, Emory
University, Atlanta.
DR.
KARRON: Ruth Karron, Johns Hopkins
University, Baltimore.
CHAIR
OVERTURF: At this time, we'll go ahead
and start with the agenda and, as I said, try to keep on time. The first speaker is Dr. Theresa Finn from
the FDA.
DR.
FINN: I'm on, right? Okay.
Good morning. The purpose of my
presentation today is to provide some general background to the vaccine
presentations that you will hear today.
Specifically, I will very briefly introduce the vaccines which will be
discussed today. I will also summarize
the outcome of the meeting of this Advisory Committee held June 5, 1997. At this meeting in 1997, Members discussed
whether acellular pertussis vaccines for use in older individuals, adolescents
and adults could be licensed based on serologic criteria.
Then
I will give a quick overview of the vaccine which will be discussed this
morning, Boostrix, and provide the questions and discussion item which you will
be asked to consider following the presentations. Two vaccines will be presented today. Both are tetanus toxoid, reduced diphtheria toxoid and acellular
pertussis vaccines absorbed.
Abbreviated Tdap or Tdap vaccines.
The
product for discussion this morning has the proposed name Boostrix. The proposed indication for this product is
active immunization against diphtheria, tetanus and pertussis as a single
booster dose to individuals 10 to 18 years of age. The Tdap vaccine which will be discussed this afternoon has the
proposed name Adacel, and the proposed indication for this is active
immunization against diphtheria, tetanus and pertussis as a single booster dose
to those 11 to 64 years of age.
I
now would like to briefly summarize a 1997 meeting of this Advisory Committee
which addressed the demonstration of pertussis efficacy in older age
groups. By June 1997, three DTaP
vaccines have been licensed for use as a primary series in children less than 7
years of age. Two of these, Tripedia
and Infanrix, are still on the market.
Since then a third DTaP, Daptacel, has been licensed for use n children
less than 7 years of age.
These
vaccines were all licensed for use following clinical endpoint efficacy studies
in infants. Then, as now, there was no
well accepted serologic or laboratory correlate of clinical efficacy of
pertussis vaccines. During the meeting
in 1997, Members heard about the changing epidemiology of pertussis in the
U.S. Namely, the increasing recognition
of pertussis cases in adolescents and young adults.
They
also heard about a planned Efficacy Study of an acellular pertussis vaccine,
the APERT Study. Following these
presentations, Members were asked to consider whether acellular pertussis
vaccines could be licensed for use in adolescents and adults based on a
serologic bridge to the antibody response of infants who had received a primary
series in a clinical endpoint efficacy study.
It should be noted that this strategy, a serologic bridge to efficacy
sera had been done before. It had been
used to bridge from infants to older children and to bridge from infant
clinical efficacy populations to U.S infants.
In
1997, Advisory Committee Members were asked to vote on two questions. The first is noted on the next slide. "Can demonstration of efficacy of a
given acellular pertussis vaccine, administered as a primary series to infants,
serve as the basis for efficacy of that vaccine when administered as a booster
dose to adolescents and adults?"
One
Committee Member deferred to clinical colleagues. Another did not vote yes or no.
The remainder of the Committee voted yes, that infant efficacy data
could serve as the basis for efficacy of an acellular pertussis vaccine
containing the same pertussis antigens when administered to older subjects.
The
second question Members were asked to vote on was "Is demonstration of a
comparable antibody response in adults/adolescents and infants an appropriate
indicator that the different age groups respond to the vaccine in equivalent
manners?"
This
was rephrased, as I've noted here, to ask whether antibody could be used to
bridge the two populations and conclude efficacy, acknowledging that it may not
be possible to conclude equivalent efficacy.
One Member voted no. One said
you could not use antibody levels in older subjects to infer the same level of
efficacy as seen in children. And one
couldn't give a yes or no vote. Eight
Members voted yes, it was possible to conclude efficacy in older subjects based
on a serologic bridge to infant sera.
Implicit
in the Committee's responses to the questions posed by CBER was that clinical
endpoint efficacy data in adolescents and adults would not be required for licensure
of Tdap vaccines in these age groups.
As I noted earlier, during the 1997 meeting, the Committee was made
aware that a clinical efficacy study of an acellular pertussis vaccine
manufactured by GSK to be conducted among adolescents and adults in the U.S.
was being planned by NIAID.
Subsequently,
during the two years, 1997 to 1999, this study was conducted. The vaccine evaluated in this study included
only the acellular pertussis component of GSK's vaccine Boostrix, not the
diphtheria and tetanus toxoids. The
results of that study have not been submitted to the Boostrix BLA and are not
being considered by CBER in our evaluation of the safety and efficacy of
Boostrix. Rather, evaluation of the
efficacy of the pertussis component of both of these products was based upon a
serologic bridge to infant sera.
Specifically,
efficacy was evaluated using a non-inferiority comparison. The immune response of older subjects was
compared to the immune response of infants, who had received a primary series of
the same pertussis vaccine antigens in a clinical endpoint efficacy study. Non-inferiority would be demonstrated if for
each antigen the upper limit of the 95 percent confidence interval on the ratio
of infant GMCs over the GMCs of older individuals was less than 1.5.
Obviously,
if the ratios were reversed in the calculation, non-inferiority would be
demonstrated and for each antigen the lower limit of the confidence interval
was greater than 0.67. If these
criteria were met for each pertussis antigen, we would conclude efficacy of the
pertussis component.
In
addition to the comparisons to the infant efficacy population, endpoints were
developed for evaluation of the response of older individuals to these Tdap
vaccines. These endpoints were designed
to evaluate the ability of the vaccines to induce a booster response to each of
the antigens in the vaccine. In
general, we consider a 4-fold rise as indicative of an increase in antibody to
an antigen.
However,
in individual with high pre-immunization antibody concentrations, a 4-fold rise
can be difficult to achieve. For such
subjects, a 2-fold rise in antibody concentration was used to define a booster
response. The details of these
endpoints will be described in the individual studies.
I
will now introduce the vaccine, which is the topic of this morning's
deliberations, Boostrix. The Tdap
vaccine, Boostrix, is manufactured by GlaxoSmithKline in Rixensart,
Belgium. The license application was
received July 3, 2004. The proposed
indication is, as noted on the slide, active immunization against diphtheria,
tetanus and pertussis in individuals 10 to 18 years of age as a single
intramuscular dose.
Boostrix
contains the same pertussis antigens as are in Infanrix, the product for the
younger age group, but at one-third concentration. The product contains 5 Lfs of tetanus toxoid and 2.5 Lfs of
diphtheria toxoid. The adjuvant is
aluminum hydroxide. The product is
filled into single-dose vials or syringes and contains no preservative.
Following
the presentations by GSK and FDA, you will be asked to consider and vote on two
questions and to discuss one item. The
first question is on this slide.
"Are the available data adequate to support the efficacy of
Boostrix in individuals 10 to 18 years of age?"
The
second question, which we would like you to vote on, is as follows. "Are the available data adequate to
support the safety of Boostrix when administered to adolescents 10 to 18 years
of age?"
The
last item is for discussion.
"Please, identify any issues which should be addressed, including
post-licensure studies." And this
concludes my presentation and I'll be happy to take any questions if there are
any.
CHAIR
OVERTURF: At this time, the floor is
open to questions to Dr. Finn. Are
there any questions from the Committee Members or from the floor? Yes, Dr. LaRussa?
DR.
LARUSSA: I don't know if this is the
right time to go over this, but can you review how the 1.5 and .67 ratios were
chosen for the bridge to efficacy, and also, whether there was reliable data
that 2-fold difference in antibody titers could be distinguished?
DR.
FINN: Okay. First part, 1.5 and 0.67, which are essentially the same. Those are the levels that we have
traditionally used when we have evaluated bridges between populations, bridges
between, for example, the most recent example is probably the licensure of
Pediarix, which is a DTaP hepatitis B-IPV manufactured by GSK. That was licensed for use based on a bridge
to Infanrix. And the criteria that we
used are GMCs 1.5-fold differences or for certain antigens you can also use
seroresponse criteria, in which case you look at a difference.
And
traditionally, what we've used in that case has been a 10 percent margin. So the 1.5 and the 10 percent are what we've
traditionally used for lot consistency in bridging. And we use that. I should
add that for certain antigens you might want to look at a 2-fold difference in
GMCs. But for the majority, we talk
about a 1.5-fold difference.
And
then the other part of your question was?
I've forgotten.
DR.
LARUSSA: Let's go back to the first
part. I guess, what I was really asking
you was after having used the 1.5.
DR.
FINN: Yes.
DR.
LARUSSA: Are there examples where
subsequent efficacy data was collected in other ways to show that the 1.5 ratio
was appropriate?
DR.
FINN: You mean, you're now asking me
whether --
DR.
LARUSSA: Have you validated that 1.5?
DR.
FINN: I'm going to ask Bruce to respond
to that. Sorry, Bruce.
DR.
MEADE: I'm Bruce Meade from the Office
of Vaccines, CBER. I'm not sure I can
-- I mean, you're asking a very complex question about whether or not that has
been formally validated. Again, I think
those endpoints were derived, I mean, initially arbitrarily. There is no question that they were an
arbitrary criterion and it has led, for one thing, to reasonable sample sizes,
and that's one of the things you have to build into any criterion is to, you
know, do you lead to reasonable and rational sample sizes and trials that can
be done.
And
then the third issue is, you know, the question is do we have any evidence that
that's, you know, actually been appropriate?
And again, I think the data we would point to would be, you know, we
have used that criterion, for example, when we compare the populations in
Sweden I and the other efficacy trials and use that criteria in the U.S. And to the extent that we know that the
acellular is currently licensed in the U.S. met those criteria and are also
effective in the U.S. I mean, those are
the kind of data that we would need to evaluate that. So that's the basis of it, at this point.
DR.
FINN: You had another half of a
question, too?
DR.
LARUSSA: Yes, can you reliably tell
2-fold differences in antibody titers?
DR.
FINN: Again, I think Bruce could speak
more specifically to that. And it would
likely depend on the assay.
DR.
LARUSSA: Okay.
DR.
MEADE: That's certainly one of the
criteria that we evaluate as part of when we review the validation information
submitted by the manufacturer. And we
have done that working with some statisticians at NIH and other
institutions. We have tried to look at
what variability would be -- has to be achieved in order to have that. And basically, if the coefficient variation
are less than 20 percent for the comparisons, you can reliably detect a 2-fold.
So
that's kind of one of the criteria we look at.
And once we know, have the data to see what variability has been
demonstrated by the manufacturers, we can determine what's the probability of
seeing that 2-fold rise by chance alone.
And those are evaluated to be sure that that's a reliable indicator.
DR.
HSU: Henry Hsu, Biostatistician,
CBER. I like to kind of emphasize that
during the decision process statistical consideration did play something. Dr. Bruce Meade just mentioned that inherent
variability of the assay has been kind of their looking. And we try to see that given the normal
running of the assay, how likely certain variability will occur. So back and forth with several sponsors
would come to kind of the conclusion and kind of the consensus that from
statistical point of view, this is kind of the level we will feel comfortable
to accept.
CHAIR
OVERTURF: Are there any other
questions? Dr. Self?
DR.
SELF: Just to follow-up. So the statement about 97 is that in '97
there is no well-accepted serologic or laboratory correlate?
DR.
FINN: Yes.
DR.
SELF: And that is the case still today?
DR.
FINN: Yes.
DR.
SELF: So this discussion is about
setting 1.5 is all about assay variability and nothing about the updated
information connecting it to actual efficacy?
DR.
FINN: No. No, you are correct.
CHAIR
OVERTURF: Any other questions that
anybody has, at this point? I think if
not, we can go ahead and progress to the next presentation, which is from GSK.
DR.
AHONKHAI: Thank you, Dr. Finn. Chairman, Dr. Overturf, Members of the
Committee, FDA, ladies and gentlemen, GlaxoSmithKline (GSK) is very pleased to
be here today to present to you the company's candidate adolescent booster
vaccine, Boostrix, which is a combination product against diphtheria, tetanus
and pertussis.
My
name is Vincent Ahonkhai. I am Vice
President, U.S. Regulatory Affairs, Vaccines at GSK. I will kick off our presentation with a brief introduction to the
product, essentially, to compliment Dr. Finn's presentation and make some
comments regarding the basis for licensure.
I will be followed by my clinical colleagues, Dr. Barbara Howe and Dr.
Leonard Friedland, who will present clinical details that are contained in our
Biologics License Application in support of Boostrix registration.
I
will then be back to make some concluding remarks. As mentioned previously, and I'm going to just go through some of
the things already mentioned to you in a few more details, the generic name for
the product is tetanus toxoid, reduced diphtheria toxoid and acellular
pertussis vaccine absorbed, Tdap acronym.
The
proposed brand name, which is the name we will be referring to for the rest of
the presentations is Boostrix. The
proposed indication is as follows:
Single-dose active booster immunization against diphtheria, tetanus and
pertussis or whooping cough in individuals 10 through 18 years of age. The product is a liquid combination of
tetanus, diphtheria toxoids, three acellular pertussis antigens, namely,
pertussis toxin LPT, filamentous hemagglutinin or FHA and pertactin or PRN.
As
you will note on this diagram, the vaccine antigens are the same as those used
in GSK's vaccine Infanrix DTaP licensed in the U.S. since 1997 and the
combination vaccine Pediarix, which contains DTaP-hepatitis B-IPV licensed in
the U.S. in 2002. However, one slide
back, please. However, as the vaccine
for Boostrix is for booster immunization, the concentrations of each of the
antigens has been lowered. Does the
tetanus and diphtheria toxoids present add a concentration of 5, 2.5 and 25
limit of flocculation, respectively?
The
pertussis antigens are included at concentrations of 8, 8 and 2.5 micrograms
each for PT, FHA, PRN versus 25, 25 and 8 micrograms for Infanrix and
Pediarix. Additionally, the
concentration of the adjuvant was also decreased and this level was justified
via a Clinical Dose-Ranging Study. The
pertussis antigens and final bulk formulated combination product are produced
by GSK Biologicals in Rixensart, Belgium.
The diphtheria and tetanus bulks are manufactured by Chiron Behring in
Marburg, Germany under a shared manufacturing agreement with GSK Biologicals.
The
vaccine is preservative-free and thimerosal-free. It will be available to the market in single-dose vials as well
as single-dose pre-filled tip-lock syringes for intramuscular injection. As noted, Boostrix is a combination of
well-known antigens at lower concentrations, which have been extensively
studied and used commercially in our Infanrix and Pediarix vaccines licensed in
the U.S.
To
date, in the U.S., over 51 million doses of Infanrix and over 10 million doses
of Pediarix have been distributed.
Additionally, the individual diphtheria, tetanus and pertussis
components of Boostrix are included in various DTaP- based combinations
manufactured by GSK Biologicals and marketed outside of the U.S. To date, over 130 million doses of various
DTaP-based combinations have been distributed.
A
similar formulation of Boostrix has been licensed outside of the U.S. since
1999. That known U.S. formulation is
identical in antigen content, but contains a slightly higher concentration of
aluminum adjuvant, namely, 0.5 milligrams versus 0.3 milligrams for the U.S.
product. And the known U.S. formulation
contains a preservative, namely, 2-phenoxyethanol. This known U.S. combination, this known U.S. formulation of
Boostrix was licensed in numerous countries outside of the U.S., including in
Germany, Australia and Italy. And to
date, over 1.9 million doses have been distributed.
To
provide some background to the clinical information you are about to hear, it's
important to know that the development of Boostrix, as was mentioned by Dr.
Finn, was based on establishing non-inferiority to a U.S.-licensed comparator
with respect to both immunogenicity and safety for diphtheria and tetanus
components.
As
a surrogate of protection it is well-recognized for diphtheria and tetanus, our
development goal was to demonstrate non-inferiority of Boostrix to a
U.S.-licensed Td vaccine from Massachusetts Public Health Laboratories normally
given in the indicated population for the pertussis component as there is no
generally accepted serologic correlate of protection against pertussis.
And
as just was in detail expatiated upon by Dr. Finn, we relied on the 1997
position of this Advisory Committee, which indicated that immunologic data from
efficacy trials in children can be used to predict efficacy of pertussis
vaccines in other older populations.
In
just a few moments, you will hear the details of the data resulting from the
clinical development of Boostrix from the clinical development of our product,
which supports licensure of it, of Boostrix, in the United States.
You
will see as a result of the clinical development data that I am describing that
Boostrix has met all pre-specified criteria for non-inferiority, that Boostrix
will confer protection against pertussis and that Boostrix has a safety profile
comparable to the U.S.-licensed Td vaccine.
Boostrix is a suitable alternative to immunization with Td vaccine and
offers the additional benefit of pertussis protection with no additional office
visit.
I
thank you for this introductory segment of our presentation and now, it's my
pleasure to introduce Dr. Barbara Howe, Vice President, Clinical Research and
Development for Vaccines North America, who will provide an overview of the
epidemiology of disease and introduction into the Clinical Development Plan for
Boostrix. Barbara?
DR.
HOWE: Am I miked? Thank you, Dr. Ahonkhai, and good morning,
everyone. I would like to begin with
this slide. We summarized the number of
pertussis cases reported in the United States from 1922 to 2003 and the
dramatic decline in the number of reported cases began after the introduction
of pertussis vaccines, particularly with widespread use of DTP in the 1940s.
The
pink number of reported cases was 270,000 in the 1930s and a low of 1,010 cases
was reported in 1976 representing a 97 percent decrease. Well, for reasons that are not fully
understood, the number of reported cases began to gradually rise again in the
'80s and then more dramatically in the 1990s as shown in the inset graph. Despite the initial success that pertussis
vaccination has played in reducing disease, pertussis is now the only vaccine
preventable disease for which children are routinely immunized, but where the
disease is on the rise.
This
slide now shows the annual reported pertussis incidence by age group with 1 to
4 year-olds in blue, 5 to 9 year-olds in green, 10 to 19 year-olds in yellow
and those 20 years of age and older in red.
As you can see, the incidence rate per 100,000 has actually gradually
increased in all age groups over time with the greatest incidence in infants
less than or equal to 2 months of age, they are actually not shown on this
slide, those are individuals too young to be vaccinated, but also in
adolescents 10 to 19 years of age.
While
increased disease recognition, improved diagnostic techniques and active
surveillance have no doubt played a role in the rise of the incidence of
pertussis, this rise is also likely to be real due to several factors such as
the fact that there is less opportunity for natural boosting brought about by
widespread child immunization and the known waning of immunity over time.
Not
only is pertussis incidence rate high in those 10 to 19 years of age but, as
can be seen on this slide, in 2004 the absolute number of cases reported to
occur in individuals within the single decade, 10 to 19 years of age, was
greater than that reported in all adults greater than 20 years of age.
Why
consider vaccinating the adolescents against pertussis? Well, as was just shown, adolescents
represent a high proportion of the reported cases and the incidence in the
population is growing. Pertussis is
known to be under-reported and under-recognized.
While
the rates of hospitalization, serious complications and death among adolescents
are low, cough illness is generally prolonged and the health impact in terms of
medical visits, antimicrobial treatment and illness is significant. Economic costs due to pertussis in the
individual and in society related to management of the illness and loss of
productivity are incurred, and health economic experts have concluded that
adolescent immunization against pertussis could be beneficial and cost
effective.
Lastly,
adolescents are known to serve as the reservoir of infection for other family
members, especially infants who are either unvaccinated or under-vaccinated by
virtue of their age and in whom the disease, the morbidity and mortality, can
be severe.
Coinciding
with back to school immunization and sports physical requirements, the majority
of the routine Td boosters are administered to adolescents and those are
administered particularly in the spring and summer months. The current recommendation for a routine
preadolescent visit at 11 to 12 years of age makes vaccination in this age group
feasible and actually provides a platform for immunization where combining Td
with routine pertussis vaccine will offer protection against pertussis without
the need for an additional visit or injection.
Now,
I would like to give you an overview of the clinical studies that were
submitted in support of licensure of Boostrix in the United States and a total
of 14 studies were conducted worldwide of which eight were conducted in
adolescents. Two of these were
extensions of previous studies in order to assess persistence of immunity.
Data
from the four studies highlighted in yellow up here on the slide will be
reviewed in greater detail later in the presentation. Study 001 was the Pivotal Adolescent Study conducted in the U.S. This involved more than 4,000 adolescents 10
to 18 years of age and compared the safety and immunogenicity of Boostrix with
a U.S.-licensed Td vaccine, and this was Boostrix 0.3 milligram aluminum
formulation.
Study
004 was a Supportive Study conducted in Finland, which involved more than 500
adolescents 10 to 14 years of age and compared the safety and immunogenicity of
Boostrix, the 0.5 milligram aluminum, to another, that is a second
U.S.-licensed Td vaccine.
Antibody
persistence following Study 004 was subsequently evaluated out to three and
five years post-vaccination respectively in Studies 017 and 030. Study 029 was a Supportive Study conducted
in Belgium in adolescents 10 to 18 years of age and this evaluated the safety
and immunogenicity of Boostrix adjuvanted with three different doses of
aluminum. Safety and immunogenicity of
the 0.5 milligram and 0.3 milligram aluminum formulations were comparable and,
therefore, the 0.3 milligram aluminum content formulation was chosen for
development in the U.S.
Then
additionally, there were summary safety data from nine additional studies
involving subjects 4 to 78 years of age providing supportive safety data for
the file. The briefing document shows
the number of subjects enrolled as 1,343 while this slide shows 1,341, which is
the number that are actually vaccinated in those studies.
In
total, more than 5,500 subjects were vaccinated with Boostrix and that's
regardless of the aluminum content of which more than 4,400 were adolescents
and more than 3,200 of these adolescents received the 0.3 milligram aluminum formulation
intended for the U.S.
Note
that all of the pivotal and supportive studies were prospective, randomized and
blinded studies, which evaluated healthy adolescents who were up-to-date with
respect to their DTP immunization and with their last DTP given at least five
years earlier. All studies, other than
those that evaluated persistence, immunogenicity was evaluated one month
post-vaccination.
Safety
was evaluated for a period of 30 days post-vaccination, except in Pivotal Study
001 where subjects were followed for a longer period, that is six months
post-vaccination. And as there were no
vaccines that were recommended for routine universal vaccination during the
time frame that Boostrix was under study in the U.S., concomitant vaccine
studies were not conducted.
Now,
I would like to turn the podium over to Dr. Len Friedland who is the Director
of Clinical Research and Development for Bacterial Vaccines in the U.S., and he
is going to present the immunogenicity and safety data from the pivotal and
supportive studies in the file.
DR.
FRIEDLAND: Good morning and thank you,
Dr. Howe. I am very pleased to be here
today to present an overview of the immunogenicity and safety results from the
clinical trials listed on this slide. I
will focus much of the presentation on the immunogenicity and safety results
from Pivotal Registration Study 001.
In
addition, I will also present antibody persistence data from Study 030, safety
data on limb swelling from Study 029 in addition to Study 001, and serious
adverse event data from all studies in the licensing application.
I
plan to start with the immunogenicity results.
For diphtheria and tetanus, the immunological endpoints in the clinical
studies included anti-diphtheria and anti-tetanus rates greater than or equal
to 0.1 and greater than or equal to 1.0 international units per mL as measured
by ELISA. For both diphtheria and
tetanus, antibody concentration greater than or equal to 0.1 IU per mL by ELISA
is regarded as a seroprotective antibody concentration.
Anti-diphtheria
and anti-tetanus booster responses were evaluated. The booster responses were defined as, essentially, a 4-fold rise
from pre-vaccination antibody concentration.
Diphtheria and tetanus antibody geometric mean concentrations were also
evaluated.
In
the Pivotal Registration Study, the pre-specified non-inferiority limit was 10
percent between Boostrix and U.S.-licensed Td vaccine for differences in
diphtheria and tetanus seroprotection rates and booster responses.
There
is no generally accepted serologic correlate of protection for pertussis. For pertussis, the immunological endpoints
in the clinical studies included anti-PT, -FHA and -PRN seropositivity rates
defined as concentrations greater than or equal to 5 ELISA units per mL.
Anti-PT,
-FHA and -PRN booster responses were also evaluated. The booster responses were defined as a 4-fold rise from
pre-vaccination concentration for subjects with pre-vaccination concentrations
less than 20 ELISA units per mL, and a 2-fold rise from pre-vaccination for
subjects with pre-vaccination concentrations greater than or equal to 20 ELISA
units per mL.
PT,
FHA and PRN geometric mean concentrations were also evaluated. In the Pivotal Registration Study, the
pre-specified non-inferiority limit was 1.5 between Boostrix in adolescents and
Infanrix in infants. For the GMC ratio,
Infanrix divided by Boostrix for PT, FHA and PRN.
I
will first present the immunological results from the Pivotal Registration
Study 001. The immunologic objectives
included demonstrating that the diphtheria and tetanus immune response was not
inferior to Td, that the pertussis immune response in adolescents was not
inferior to the immune response of Infanrix in infants and, lastly,
manufacturing lot consistency.
The
study designed for Pivotal Study 001 is shown in this schematic. Healthy adolescents 10 to 18 years of age
were immunized with a single dose of Boostrix or a single dose of Massachusetts
Public Health Laboratories U.S.-licensed Td vaccine. The composition of the study vaccines is presented in the upper
right corner.
Subjects
were randomized 3:1 to receive one of three lots of Boostrix or one lot of Td,
and randomization was stratified such that 75 percent of those enrolled were 10
to 14 years of age in an effort to focus the database on the younger group of
adolescents, that age group closest to which the Advisory Committee on
Immunization Practices currently recommends routine Td vaccination. Subjects were to have previously completed
diphtheria, tetanus and pertussis immunization according to the
U.S.-recommended immunization schedule.
4,114
adolescents were vaccinated between November of 2002 and July 2003. Subject age, gender and race were similar
between the Boostrix and the Td groups.
While the data are not shown on this slide, the immunogenicity results
were evaluated by gender and race with respect to the subjects at large and
between Boostrix and Td vaccinees.
The
exploratory descriptive analyses do not appear to show immunogenicity
differences between whites, blacks, hispanics and orientals nor between males
and females. In those subjects where
the type of DTP vaccine previously received was documented, subjects in both
groups had a similar priming history with whole cell and acellular pertussis
vaccines.
The
majority of subjects in both groups were likely whole cell-primed, 92 percent
of the subjects who had previously received five doses and 6 percent of
subjects had previously received four doses of DT-containing vaccines. In addition, approximately, 85 percent of
subjects in each group received their last DT-containing vaccine within the
last 5 to 10 years.
Now,
on to some of the results. The first
primary objective was to demonstrate lot-to-lot consistency of three production
lots of Boostrix in terms of immunogenicity of all five antigens one month
after vaccination. Lot-to-lot
consistency would be demonstrated if the lower limit and the upper limit of the
95 percent confidence interval for the ratio on GMCs between each pair among
the three lots for all five antigens were within the predefined equivalence
limit of 0.67 to 1.5.
As
shown on this slide, lot-to-lot consistency was demonstrated in terms of
immunogenicity for all antigens contained in Boostrix, diphtheria, tetanus, PT,
FHA and PRN. The sponsor is aware that
FDA's recommendations regarding manufacturing lot consistency have evolved to
include computing the 95 percent confidence interval on GMC ratios instead of
the 90 percent confidence interval.
We
are pleased to show on this slide using this more stringent criteria that
post-hoc analysis using the 95 percent confidence interval for the GMC ratio
also demonstrated lot consistency. As
lot consistency was demonstrated, all of the following data from Study 001 will
be presented on pooled Boostrix lots.
The
second and third primary immunogenicity objectives were to demonstrate
non-inferiority of Boostrix compared to Td with respect to anti-D and anti-T
seroprotection rates, meaning greater than or equal to 0.1 IU per mL, and also
booster response rates one month after vaccination. Non-inferiority would be demonstrated if the upper limit of the
treatment differences, Td minus Boostrix, was less than 10 percent.
As
shown in the left hand panel, anti-diphtheria and anti-tetanus concentrations
at or above the recognized seroprotective level of 0.1 were achieved by greater
than or equal to 99.9 percent of the subjects in both the Boostrix and the Td
groups. The right hand panel shows the
percentage of subjects who achieved concentrations 10 times above the
recognized seroprotective level.
Antibody
concentrations greater than or equal to 1.0 are considered to be associated
with long-term protection. Rates at
this much higher threshold were very high.
Greater than or equal to 97.3 percent of the subjects in both the
Boostrix and the Td groups achieved anti-diphtheria and anti-tetanus
concentrations greater than or equal to 1.0.
Shifting
focus now to diphtheria and tetanus booster responses defined as, essentially,
a 4-fold rise from pre-vaccination concentration. This slide shows that diphtheria booster responses were achieved
by 90.6 percent of Boostrix and 95.9 percent of Td subjects and tetanus booster
responses were 89.7 percent in those who received Boostrix and 92.5 percent in
those subjects who received Td.
The
results from the Pivotal Registration Study clearly demonstrate that the two
vaccines are both immunogenic against diphtheria and tetanus. With respect to the primary endpoints of
anti-D and anti-T seroprotection rates and D and T booster responses,
non-inferiority of Boostrix versus Td was demonstrated. As treatment differences, Td minus Boostrix
met the predefined criteria of less than or equal to 10 percent for all
parameters.
This
slide shows, through reverse cumulative distribution curves, the anti-D and
anti-T concentrations achieved one month after vaccination. Reverse cumulative distribution curves are a
graphical tool that provide a complete distribution of antibody data and allows
a visual assessment of details of the distribution. In this case, the curves show the post-vaccination concentrations
for all subjects.
The
RCCs show that the post-vaccination distribution of anti-D and anti-T
concentrations in the subjects after both Boostrix and Td administration are
far to the right of the seroprotective cutoff value of 0.1 for D and for T. After vaccination with both Boostrix and Td,
subjects achieved anti-D and anti-T GMCs many fold higher than the
seroprotective cutoff.
Turning
attention to pertussis immunogenicity.
The primary immunogenicity endpoint measured for pertussis was a booster
response one month after vaccination for all three pertussis antigens contained
in Boostrix. The predefined
immunogenicity endpoint was the lower limit of the 95 percent confidence
interval in subjects with a booster response to each of the three antigens was
greater than or equal to 80 percent.
This
primary objective was met as the lower limit of the 95 percent confidence
interval for booster response was 83 percent to PT, 92.4 percent to FHA and
94.5 percent to PRN.
Given
the absence of recognized serologic correlates of protection against pertussis,
the efficacy of Boostrix was evaluated by comparing the booster responses
achieved in Pivotal Study 001 in adolescents to those measured in a previous
immunogenicity portion known as Study 039 of a German Household Contact
Efficacy Study in infants in which GlaxoSmithKline's DTaP vaccine, Infanrix,
demonstrated 88.7 percent efficacy against World Health Organization-defined
typical pertussis.
Efficacy
remained high even when milder definitions of pertussis were considered. For example, 81.3 percent efficacy against
pertussis with greater than or equal to seven days of spasmodic cough. The GMCs observed in Boostrix Study 001 were
to be considered non-inferior to those observed in Infanrix Study 039 if the
upper limits of the 95 percent confidence intervals on the GMC ratio, Infanrix
divided by Boostrix, were less than 1.5.
For
all three antigens, non-inferiority of pertussis antibody responses was
demonstrated as the upper limit of the 95 percent confidence interval on the
GMC ratio, Infanrix divided by Boostrix, was less than 1.5. Put another way, this means that GMC
responses after a single dose of Boostrix in adolescents compared to after a
three dose primary series of Infanrix in infants were 1.9-fold higher for PT,
7.3-fold higher for FHA and 4.2-fold higher for PRN.
The
blue curves in this slide represent the RCC for adolescents in Study 001 before
vaccination with Boostrix and show that for all three pertussis antigens, the
RCCs are largely to the left of the red curves, which represent the RCCs
achieved by infants after three doses of Infanrix in the immunogenicity portion
of the infant efficacy trial.
One
month after vaccination with Boostrix, RCCs for all three antigens, the yellow
curves, are shifted to the right of the curves from the infant efficacy trial
demonstrating that Boostrix achieves similar or higher pertussis concentrations
than after the primary series of Infanrix in the infant efficacy trial.
Based
on the immunogenicity data, we conclude that the diphtheria and tetanus immune
response induced by Boostrix was not inferior to Td, that the Boostrix booster
response for all three pertussis antigens met predefined criteria, that the
pertussis antibody response in adolescents vaccinated with Boostrix was not
inferior to the response in infants vaccinated with Infanrix, and that
manufacturing consistency for all five antigens contained in Boostrix has been
demonstrated.
I
will next present antibody persistence data from Study 030. Supportive Study 030 was a five year
serologic follow-up study of subjects who participated in Study 004. Study 004 was a randomized, controlled study
in Finland in which 510 healthy adolescents 10 to 14 years of age were
immunized with a non-U.S. formulation of Boostrix containing 0.5 milligrams
aluminum or Lederle's U.S.-licensed Td vaccine.
The
subjects who were randomized to the Td arm went on one month later to receive
an investigational acellular pertussis vaccine. Subjects were to have previously completed diphtheria, tetanus
and pertussis immunization according to the recommended immunization schedule
in Finland which, at the time, was four doses of DTP whole cell at 3, 4, 5 and
20 to 24 months of age. Serologic
follow-up of all subjects at both three and five years was attempted and in
Study 030, 267 of the 450 adolescents immunized with Boostrix five years
earlier were contacted and evaluated.
This
slide demonstrates the evolution of anti-D and anti-T GMCs over five year
follow-up after vaccination with pooled lots of Boostrix and the U.S.-licensed
Td vaccine. Over five years after
vaccination, subjects in both the Boostrix and Td group maintained anti-D and
anti-T GMCs above pre-vaccination levels and well above the seroprotective
levels of 0.1. GMCs for both antigens
in both groups had only a modest decline since the last follow-up sample taken
two years previously.
As
previously mentioned, immunologic correlates of protection for pertussis have
not been demonstrated. Five years
following vaccination, GMCs solicited by FHA and PRN antigens were still higher
than pre-vaccination levels while GMCs for PT approached pre-vaccination
levels. GMCs for all three antigens had
only a modest decline since the last follow-up sample taken two years
previously.
From
Study 030, we conclude that at five years GMCs to D, T, FHA and PRN remained
higher than pre-vaccination levels and that GMCs to PT approached
pre-vaccination levels. In addition to
the persistence data from Boostrix Study 030, follow-up data from Italian
infants vaccinated with a three dose primary series of Infanrix without a
booster dose in the second year of life and the NIH-sponsored pertussis vaccine
efficacy trial demonstrated, at 6 years of age, maintenance of a high level of
efficacy, 86 percent against World Health Organization-defined typical
pertussis.
Taken
together, these data and the bridging data from Study 001 suggest that Boostrix
will afford protection against diphtheria, tetanus and pertussis through at
least five years after vaccination.
Summarizing
the immunogenicity. Based on the data
from Pivotal Study 001 and the supportive studies, we conclude that the
diphtheria and tetanus immune response induced by Boostrix was not inferior to
TD, that the pertussis booster response for all three pertussis antigens met
predefined criteria, that the pertussis antibody response in adolescents
vaccinated with Boostrix was not inferior to the response in infants vaccinated
with Infanrix, that manufacturing consistency for all five antigens contained
in Boostrix has been demonstrated and that persistence data from Study 030
suggest that Boostrix affords protection against diphtheria, tetanus and
pertussis through at least five years after vaccination.
At
this point, I would like to switch gears and turn your attention to the
clinical trial safety results. The
Safety Program for Boostrix was designed to provide an expanded safety database
in adolescents and to compare the safety profile of Boostrix with that of
U.S.-licensed Td vaccine. The clinical
safety experience with Boostrix in the U.S. file comes from data on 5,518
subjects. 3,289 adolescents who
received the U.S. formulation with 0.3 milligrams aluminum and 2,229 subjects
of all ages who received Boostrix formulated with either the 0.5 or 0.13
milligram aluminum formulations.
Nine
studies in the licensing application were performed to support licensure
outside of the U.S. with the 0.5 milligram aluminum formulation. These nine studies provide safety supportive
data in the U.S.-licensed application on 1,341 of the previously mentioned
2,229 subjects of all ages. The
solicited and unsolicited adverse event data from these nine additional safety
supportive studies were provided in safety synopsis format in the licensing
application and will not be presented today.
The
safety data I will present today are the solicited and unsolicited adverse
event data from Pivotal Study 001, limb swelling data from Studies 001 and 029
and serious adverse event data from all of the studies included in the
licensing application.
The
following categories of safety information were collected in all studies. Solicited local and general adverse events
were collected for 15 days after vaccination, all unsolicited adverse events
were collected for 31 days after vaccination and specific adverse events were
collected for an additional extended safety follow-up period through six months
after vaccination in Study 001. Serious
adverse events were collected for the duration of all studies.
As
a reminder, in Pivotal Study 001, 4,114 healthy U.S. adolescents 10 through 18
years of age received Boostrix or U.S.-licensed Td vaccine. The objective was to compare the safety
profile of Boostrix to Td. The primary
safety objective in the pivotal study was to demonstrate that Boostrix was not
inferior to Td, in terms of Grade 3 injection site pain. Grade 3 pain was defined as injection site
pain that was spontaneously painful and/or prevented normal every day
activities.
Non-inferiority
for Grade 3 pain would be demonstrated at the upper limit of the 95 percent
confidence interval for treatment differences, Boostrix minus Td, is less than
or equal to 4 percent. Over the 15 days
after vaccination Grade 3 injection site pain was reported by 4.58 percent of
subjects who received Boostrix and 4.04 percent of subjects who received
Td. Therefore, non-inferiority was
demonstrated as the upper limit of the treatment differences is 1.87 percent,
which is below the predefined clinical limit of 4 percent.
In
the 15 day follow-up period after vaccination, any injection site pain was
reported by 75.3 percent of subjects in the Boostrix group and 71.7 percent of
subjects in the Td group and Grade 2 or 3 pain was reported by 51.2 percent of
subjects in the Boostrix group and 42.5 percent of subjects in the Td
group. These differences in the
incidents of any pain and Grade 2 or 3 pain are statistically different.
As
previously mentioned, the incidents of only Grade 3 pain, which was a
co-primary endpoint was below 5 percent in both groups and not statistically
different. No significant differences
in the rates of injection site redness, injection site swelling and increase in
mid-upper arm circumference of all intensities were observed between subjects
in the Boostrix and Td groups.
In
the 15 day follow-up period after vaccination, the incidents of solicited
general adverse events of fever, headache, fatigue and gastrointestinal
symptoms were similar and not statistically different in the Boostrix and Td
groups with the exception of Grade 2 or 3 headache. A statistically significant difference in Grade 2 or 3 headache
between the groups was not evident in the 72 hour period after vaccination.
Exploratory
analyses were performed in sub-populations based on age at the time of
vaccination, gender, race, vaccination history and type of DTP vaccine previous
administered. In these subgroup
analyses, the differences between the Boostrix and Td vaccine groups were, in
general, consistent with respect to what was observed in the overall total
vaccinated cohort.
The
safety objectives were also evaluated by gender, race and age with respect to
the subjects at large. These
exploratory descriptive analyses do not appear to show safety differences
between whites, blacks, hispanics and orientals. Minor differences were observed based on gender with females
receiving both Boostrix and Td reporting more pain, headache and fatigue than
males. And older subjects receiving
both Boostrix and Td reporting more pain than younger subjects.
I
would like now to turn your attention specifically to injection site
swelling. Injection site swelling after
repeat vaccination with DTaP, DTPw and Td vaccine have been well-described. For example, Dr. Rennels from the Center for
Vaccine Development in Baltimore evaluated several clinical studies,
retrospectively, and reported that entire proximal limb swelling occurs in 2 to
6 percent of children prime with DTaP vaccine and then given fourth and fifth
consecutive doses of DTaP vaccines.
Recognizing
that large swelling is an adverse event of specific interest, Studies 001 and
029, prospectively, solicited the incidents of large injection site
swelling. The methodology used to
define a case of large swelling involved daily measurement of injection site
swelling diameter in both studies and in addition Study 001 incorporated daily
measurements of mid-upper arm circumference.
Note that subjects in Study 029 were primed with whole cell DTP and most
subjects in Study 001 were primed with whole cell with at least three doses of
whole cell DTP.
By
way of reminder, Study 029 was a supportive study conducted in Belgium in
adolescents 10 to 18 years of age which evaluated the safety and immunogenicity
of Boostrix adjuvanted with three different contents of aluminum. Subjects in Studies 001 and 029 were
instructed to contact and visit their investigator if they developed a swelling
reaction after vaccination. The
criteria used to define a case of large injection site swelling differed
between Studies 029 and 001.
The
criteria in Study 029 were injection site swelling greater than 100 millimeters
or diffuse or noticeable increase in limb circumference. In Study 001, the criteria were injection
site swelling greater than 100 millimeters, a 50 millimeter increase in mid-
upper arm circumference compared to pre-vaccination baseline measurement or
diffuse swelling that interfered or prevented normal every day activities.
In
Study 001, only two subjects reported an episode of large injection site
swelling. One subject in the Boostrix
group who had previously received five doses of DTP, type unspecified, and one
subject in the Td vaccine group who had previously received three doses of DTP
whole cell and two doses of DTaP. Both
events of large injection site swelling had an onset within three days, had no
joint involvement and were not characterized by significant arm circumference
increase. These events were associated
with pain and local redness and both events resolved without sequelae.
In
Study 029, in which subjects received Boostrix adjuvanted with three different
doses of aluminum and there was no Td comparator, five subjects reported an
episode of large injection site swelling.
One subject was vaccinated with the Boostrix 0.5 milligram aluminum
formulation and four subjects with the 0.3 milligram aluminum formulation. This difference is not statistically
different. In all cases, the
investigators classified the swellings as large local swelling without
involvement of the adjacent joints. All
five events had an onset within two days, had no joint involvement, were
associated with pain and local redness and resolved without sequelae.
The
low incidence of large injection site swelling in Studies 029 and 001 ranging
from 0.03 to 0.8 percent is lower than the 2 to 6 percent rate reported after
fourth and fifth consecutive doses of DTaP in younger children and does not
signal a new or unexpected safety issue.
Of interest will be the incidents of large injection site swelling
events in adolescents who will be vaccinated with Boostrix beginning later this
decade in the U.S. and will be primed throughout life with all acellular
pertussis containing vaccines.
Post-approval,
a study report will be submitted to the FDA on a cohort of 300 German
adolescents who recently completed enrollment in a clinical study where they
received a sixth consecutive dose of acellular pertussis containing vaccine.
I
would like now to turn your attention to the incidents of unsolicited adverse
events in Study 001. The sample size of
3,000 subjects vaccinated with Boostrix in Pivotal Study 001 allows to detect
an adverse event occurring at a rate of greater than 0.1 percent with a 5
percent error. In the month after
vaccination, the incidents of unsolicited adverse events between Boostrix and
Td were similar. This slide shows those
unsolicited adverse events which were reported to occur in at least 1 percent of
subjects.
In
the Boostrix group, the most frequent unsolicited adverse events was
pharyngitis followed by upper respiratory tract infection, rhinitis, injury,
coughing, injection site reaction pain and dysmenorrhea. Subjects in Study 001 were followed for an
additional five month extended safety follow-up period. Over this time frame, the rates of
unsolicited adverse events between Boostrix an Td were similar over all and not
statistically different with regard to new-onset chronic illness, emergency
room visits, physician office visits for non-routine medical conditions and
serious adverse events.
The
adverse events in the follow-up period are largely driven by emergency room
visits, which occurred at a frequency lower than that what would be generally
expected among 4,000 adolescents followed for six months, according to CDC
data. The majority of visits in both
the Boostrix and Td groups were secondary to accidental injuries.
In
the month after vaccination with Boostrix or U.S.-licensed Td vaccine in
Pivotal Study 001, no serious adverse events were reported in the 4,114
vaccinated subjects. 10 serious adverse
events were reported in the month after vaccination in Studies 004, 029 and the
nine additional safety studies. Eight
of the SAEs were reported in the 1,341 vaccinated subjects in non-U.S. studies
who received either the 0.5 or the 0.3 milligram aluminum formulation of
Boostrix and the two other SAEs were reported in subjects who received a
comparator. All 10 serious adverse
events were reported by the investigator as unrelated to vaccination.
In
Pivotal Study 001, all subjects were followed through six months after
vaccination. Let me remind you that
there were no serious adverse events reported in the 30 days after vaccination. Over the extended safety follow-up period,
between one and six months after vaccination, 16 subjects reported 22 serious
adverse events. All were reported by
the investigator as unrelated to vaccination.
14 or 0.5 percent of the subjects received Boostrix. 20 serious adverse events were reported in
this group. Our conclusion is that
there is no common theme among these serious adverse events.
Two
or 0.2 percent of the subjects who received Td reported a serious adverse
event. The rate difference in the
occurrence of serious adverse events between the Boostrix and Td groups is not
statistically different. There were no
deaths reported in the clinical studies.
There were four pregnancies reported in Study 001 and no pregnancies
reported in Studies 004 and 029. One of
the pregnancies in Pivotal Study 001 may have occurred during the initial 31
day period after vaccination. This
subject received Td and delivered a healthy term infant.
The
other three pregnancies occurred in the sixth month extended safety follow-up
period. The outcomes were one
spontaneous abortion in a subject who received Boostrix and healthy infants
delivered to subjects who received Boostrix and Td.
To
summarize the safety results, the clinical safety experience with Boostrix in
the U.S. file comes from data on 5,518 subjects. 3,289 adolescents who received the U.S. formulation with 0.3
milligrams aluminum and 2,229 subjects of all ages enrolled in studies with
Boostrix formulated with either 0.5 or 0.133 milligrams aluminum. The vast majority of these 2,289 subjects
received a 0.5 milligram aluminum formulation.
Based
on the safety and reactogenicity data from Pivotal Study 001 and the supportive
studies, we conclude that Boostrix is not inferior to Td with respect to the
incidents of Grade 3 pain at the injection site. That with the exception of any pain and greater than or equal to
Grade 2 pain, the over all safety profile of Boostrix is comparable to
U.S.-licensed Td vaccine. This
concludes the immunogenicity and safety presentation. I welcome back Dr. Ahonkhai to conclude the GSK presentation.
DR.
AHONKHAI: Thank you, Dr.
Friedland. I will now like to summarize
our presentations and thank you for your patience. Based upon the information that Dr. Friedland has just presented,
it can be expected that Boostrix will be effective. Boostrix met all pre-specified non-inferiority criteria for
efficacy. The diphtheria and tetanus
components are as immunogenic as the U.S.-licensed Td vaccine. Moreover, Boostrix induces a pertussis
booster response and the pertussis component is at least as immunogenic as our
Infanrix vaccine.
As
to safety, the components of Boostrix have been extensively studied and
administered commercially for several years in various DTaP-based combinations. In our clinical development program, safety
was demonstrated in over 5,500 subjects and the safety profile of Boostrix has
been shown to be comparable to the U.S.-licensed Td vaccine. Over all, Boostrix has matched all
pre-specified non-inferiority criteria for safety.
Lastly,
it is also important to comment on the risk/benefit profile of this new
combination booster vaccine and its use in the adolescent population. From a risk standpoint, as has been shown,
the safety profile of Boostrix is comparable to the currently recommended
U.S.-licensed Td vaccine with regard to benefits. The immunogenicity of this is also comparable to the Td vaccine
with respect to diphtheria and the tetanus components.
I
would like to remind the Committee of the epidemiology data that were presented
earlier, namely, there has been a rather striking increase in the incidents of
pertussis in the adolescent population.
Boostrix is expected to confirm protection against pertussis in this
population thereby helping to decrease associated morbidity which in itself is
an added benefit to the currently recommended immunization of Td only.
Additionally,
by combining pertussis with tetanus and diphtheria in one vaccine, protection
against pertussis is afforded without an additional injection nor an additional
office visit beyond the regularly scheduled visit at 11 to 12 years of age.
In
closing, I would like to note the following:
Boostrix has been distributed and used in numerous countries outside of
the U.S. for several years. It is with
great pleasure that GSK now looks forward to bringing this important vaccine to
the U.S. market. Mr. Chairman, Dr.
Overturf, this concludes the GSK formal presentation. We are ready to provide explanations and to take questions. Thank you very much.
CHAIR
OVERTURF: Well, I would like to ask one
question. Now, regarding the limb
swelling issue, could somebody clarify in the studies that were cited that
looked at infants and children who have received doses prior to 7 years of age,
was the limb swelling primarily, I assume, in the lower extremity? And obviously, you were looking primarily at
upper limb swelling in the adolescent population. Does that perhaps explain the difference that one is a dependent
and the other one is not?
DR.
HOWE: I do believe that probably most
of the published literature is on limb swelling in infants or it's actually
fourth and fifth doses, so it's in the toddlers and preschoolers who receive a
fourth or fifth consecutive dose of DTaP and the studies have differed, but
many of them have continued to give in the lower limbs compared to the upper
limb, even though in some of the older kids you could give in the deltoid.
I'm
not sure that that's really the full explanation for the difference. I just want to point out that in the studies
that were done in adolescents, the 029 and 001 Study, somewhat of a fabricated
definition of limb swelling, in that we were using a more sensitive and
prospective surveillance system, meaning that we in 001 prospectively measured
the limbs increase in mid-arm circumference on a daily basis and then asked,
based on certain triggers, for individuals to come in for an evaluation. It's very different than what was done and
what's in the literature for the younger kids, where these were basically
spontaneous reports of very visibly swollen limbs.
CHAIR
OVERTURF: In regard to that criteria
that you used, I believe it was, one was 100 millimeters and another was 50
millimeter difference, were there observed differences that were less than
those cutoff points? Because that was
the data that was presented.
DR.
HOWE: Actually, maybe we should put the
slide up for the criteria for 029 and 001.
The trigger in the study where there was not mid-arm circumference
measured prospectively, that is in the 029 Study, was 100 millimeter or greater
swelling at the injection site itself.
Okay. And in the cases that came
in, all of those cases had 100 millimeters or greater injection site
swelling. That's most likely why they
came in, that was the trigger.
In
001, in addition to that trigger, we also, because we prospectively measured
the limb circumference on a daily basis, we used greater than 50 millimeter
increase in the mid-arm circumference.
And the two cases that came to attention in 001, neither one of them had
that much of an increase in the mid-arm circumference. I think one had 8 millimeters, I forget, the
other one --
DR.
FRIEDLAND: 10 millimeters and one was
13 millimeters in mid-upper arm circumference over the measurement from
pre-vaccination measurement.
DR.
HOWE: Yes.
DR.
FRIEDLAND: The additional criteria
in --
CHAIR
OVERTURF: Are we miked? Can you mike us?
DR.
HOWE: We need to use this one now.
DR.
FRIEDLAND: Okay. Neither of the subjects who had a large
injection site swelling in Pivotal Study 001 met criteria because of increases
in mid-upper arm circumference. The
increases in mid-upper arm circumference from pre-vaccination measurements were
8 and 13 millimeters in the two cases.
DR.
HOWE: Very small.
DR.
FRIEDLAND: One of the subjects
presented because he had functional impairment which was the third
criteria. A large swelling which
prevented every day activities. The
other subject presented because the injection site swelling had ceded 100
millimeters.
DR.
HOWE: Right.
CHAIR
OVERTURF: So my question specifically
is were data collected for levels less than 50 millimeters, other than those
that spontaneously came to your attention?
DR.
FRIEDLAND: Oh, yes. We can bring back up the study about the
solicited local adverse events in Study 001 where we report -- subjects are
reported injection site swelling along different intensities for swelling,
which Grade 3 swelling was greater than 50 millimeters.
CHAIR
OVERTURF: I understand that. But there was no data on total limb
swelling?
DR.
HOWE: We also have some data that
summarizes for the daily measurements of the increase in mid-arm circumference
of both the vaccinated and unvaccinated arms, something in the order of 25
percent, that included again if we could -- I don't know if we can get the
slide that shows or in the briefing document, interestingly, we decided to
measure mid-arm circumference in the unvaccinated arm as a control. And if you were to subtract out the
proportion of individuals who reported an increase in mid-arm circumference in
the unvaccinated arm from the vaccinated arm in both the booster group as
compared to the Td group, it's about a 6 percent difference. Does that help?
CHAIR
OVERTURF: Thank you. Yes, Dr. Markovitz?
DR.
MARKOVITZ: Yes, I'm a little bit
troubled by the racial makeup of your subjects. The American population is not 85 percent white. And I'm wondering what -- although that
obviously makes it hard to draw conclusions about whether there are any
differences between racial groups. So
not to detract from the fact that there is a lot of strong data here, but I'm
wondering what the problem is, because it seems to be all racial groups other
than caucasians are under-represented.
DR.
FRIEDLAND: Thank you for your
comment. This study was conducted in 45
centers throughout the United States.
And while the representation of the subjects in the clinical trial is
not exactly representative of the U.S. population, there are reasonable numbers
of subjects particularly in the black racial makeup and in the hispanic
makeup. Therefore, we looked at the
data more specifically to see if there were any immunogenicity differences
between blacks, hispanics, caucasians, orientals. And the exploratory analyses did not show any differences in
immunogenicity among these groups.
We
also looked between subjects receiving Boostrix and Td, so we looked both
between Boostrix and Td and at the subjects at large. I can mention that based on our clinical trials with vaccines,
these numbers of racial representation are good and they are getting better as
time is marching on in our clinical development program. We recognize as a company that we need to do
better in enrolling minority subjects in our clinical trials. We have company-wide initiatives to look at
this and to work on this not only to enroll minority subjects, but also to work
with minority investigators. And we
hope that future clinical trials have a better representation.
DR.
MARKOVITZ: I would just like to also
point out, I mean, besides the sort of classic idea of under-represented
minorities, hispanics and blacks, there is only 1 percent asian, so it's really
an across the board problem that seems to be -- I'm glad you're planning to
address that. But it would be nice to
see that. This seems to be a problem
with not just the studies from your company but others.
CHAIR
OVERTURF: Dr. LaRussa?
DR.
AHONKHAI: You're absolutely correct and
this is something that we continue to work on.
We are not there yet. There's no
question. We will continue to do
everything in a positive manner.
CHAIR
OVERTURF: I'm sorry, Dr. LaRussa?
DR.
LARUSSA: Two questions. What about the anti-Diphtheria and the
anti-Tetanus titers? You showed nice
distribution curves to show that the distribution of the antibody titers after
the boost was similar to what you would see after Td. I guess what I'm concerned about is that the GMTs are quite a bit
lower. So for Td they were 14.2. For T they were 14.2 versus 7.4 and for D
they were 20.8 versus 15.8.
And
since these are in general persistence of antibody as related to the peak of
the antibody titer after the immunization, I'm wondering whether there is any
concern or any plan on looking for long term persistence to T and D antibodies
after Boostrix. And I'll just ask a
second question. Well, go ahead.
DR.
FRIEDLAND: In Pivotal Study 001, as you
point out, the anti-D GMC was 14 in the group who received the Td and,
approximately, 7 in the group who received Boostrix. In Study 004, immunogenicity data which I did not present today,
but are in the briefing document, they weren't presented today because of
brevity of time, there is another U.S.-licensed Td comparator, that being the
Lederle Td vaccine.
In
that study, the GMC after Boostrix was I think 6.8 and after the Lederle Td,
the anti-D GMC was 8.1. So we saw
different results in another study with another U.S.-licensed comparator. I would like to point out that in the RCC
curve, which you are referring to, if we look at subjects closer to the
seroprotective cutoff, the RCCs were super-imposable between Boostrix and
Td. So we only saw separation in
antibody concentrations at levels close to 100-fold above the conservative
cutoff of 0.1 by ELISA.
DR.
LARUSSA: I guess what I was concerned
about is what's going to happen 5 and 10 years out from that point.
DR.
FRIEDLAND: Yes.
DR.
HOWE: And we do know from the follow-up
to Study 004 that the anti-D GMCs are similar out to five years and that
between three and five years is a very modest, actually a very minor amount of
decay and therefore we think beyond five years as well if that's likely to
occur. The other point is that very
high proportion of individuals had anti-D titer greater than or equal to 1.0
and that is the cutoff that tends to be associated with longer term
protection. And then the long-term data
that we have sort of validates that.
DR.
LARUSSA: Okay. So my second question is that your vaccine
has been licensed in a number of countries since 1999, I think you said. Are there any countries where it has been
used in the systematic manner in this age group and do you know anything about
what has happened to the incidents of pertussis after the introduction of the
vaccine? This gets back to the question
of whether you can actually use bridging serologic data to simulate efficacy.
DR.
AHONKHAI: Well, we have had the benefit
of licensure in several countries, as noted.
Just to remind the Committee, it's only in the recent past that
countries have recognized the importance of this critical disease in the
adolescent population. So even although
the company was far ahead of this by licensing, having this developed years
ago, it was only in the past five years or less that we've seen more uptake
based upon firm recommendations and the data are coming, they are just not
there yet.
CHAIR
OVERTURF: Dr. Gellin?
DR.
GELLIN: Okay. Thanks. Following up on
Phil's question about the future, and this is a question both for the company
and for the FDA. What are you plans or
what are the FDA requirements about looking on into the future as the cohort of
children shifts from those who are primed with whole cell, the majority are
whole cell either entirely or in part, to a cohort that is going to be
increasingly and entirely acellular-primed.
DR.
HOWE: Thanks for pointing out, Bruce,
actually that it's clear that over time now we're going to be evolving from a
population of adolescents who are primarily prime with whole cell, the mixed
sequence is of acell and then whole cell and acell and then fully
DTaP-primed. I mean, the nature and the
design of the type of study that we might look at in the post-marketing setting
to evaluate the safety of Boostrix following five doses of DTaP have not been fully
discussed with the FDA, but we are discussing that or have been discussing it
now.
As
was mentioned, there is one smaller study that we did do in Germany looking at
a sixth dose of PA containing in the form of Boostrix following five doses of
DTaP and that data will be submitted to the FDA after licensure.
CHAIR
OVERTURF: Yes, Dr. Royal?
DR.
ROYAL: Thank you. I would like to go back to the epidemiology
of pertussis infection. In the graph
that you showed demonstrating the change in the incidence of the infection over
the past 25 years. But to what extent
do you think that the young people that you immunize represent those patients
who are actually developing the infection?
Certainly when you think about what's happened since 1980, we know
deficiency has appeared from HIV, therapies are more commonly used that affect
one's immune response. You have to
wonder to what extent some of those patients might not have been getting
regular care at a pediatrician's office or in a health care clinic.
So to what extent are you able to perhaps
comment on your ability to bring in those types of patients or even to what
extent can we explain the rise in the incidence of the infection over the past
25 years, which you can imagine might greatly impact the success of your
vaccine, once it gets out into the population?
DR.
HOWE: So when we look at the
age-specific incidents of pertussis over time, it's my understanding that the
incidents in those age groups in which the vaccine is indicated and where
individuals are fully vaccinated, the 1 to 4 year-olds has been relatively
stable over time. Actually, I can maybe
turn the floor over to some of the epidemiologic experts we have on the panel
here to confirm that. But that most of
the increase in disease incidents has been in the unvaccinated groups, either
too young to be vaccinated by virtue of their age or because pertussis
vaccination is not recommended in those 7 and above, the older age groups. I don't know if either Melinda or Trudy want
to add to that.
CHAIR
OVERTURF: Dr. Murphy?
DR.
MURPHY: There are a couple of
points. The first is that there has
been a lot of emphasis on the increase and disease. And I think what we have to acknowledge is that there has been a
lot of pertussis out there that we haven't recognized for a long time. And so as we see increases reported,
increased number of cases reported, part of what we're seeing is increased
recognition of those cases that are already there. We still think that our reported number of cases under-represent
the total burden of disease to a major extent.
And
some of those increases we can attribute to some very large outbreaks, the
recent increases, in some states and also in increased use of diagnostic PCR
testing, which has helped the states and local health departments make a
diagnosis when they were not able to make it before. But I think there's no doubt there's a lot of pertussis among
adolescents and there are some data that suggest that we probably have had some
increase. And most people feel that the
major factor is waning immunity.
I
think there was another part of your question and that had to do with, perhaps
I didn't understand, but vulnerable children, children who have other diagnoses
and I don't think we have a lot of data on those cohorts. And then the last comment has to do with
very young infants and among infants too young to be immunized, there was again
an increase in reported cases during the 1990s, in particular, and we have had
increase in reports of deaths among babies too young to be vaccinated.
We
think that those increases are more likely to represent real increases, because
people recognize pertussis and have done so consistently, but there is still
the possibility of reporting bias. And
among the other age groups of recently immunized children, there have been
increases in reporting again perhaps reflecting the increase in
diagnostics. But those increases have
been relatively small comparatively.
CHAIR
OVERTURF: Dr. Stephens, you had a
comment?
DR.
STEPHENS: Just a follow-up on Bruce's
and other questions about the background.
I mean, obviously, the data reflects boosting in a whole-cell- pertussis
background. And you mentioned the
German study and obviously that situation is going to rapidly change. You mentioned the German study. Can you give us any data from that
study? Is that available regarding both
safety and immunogenicity in an acellular pertussis background? That's one question.
The
second question really is about concomitant vaccines. And you indicate in your brochure that there's really no data on
concomitant vaccines. Can you just
comment on the use of concomitant vaccines with your product?
DR.
FRIEDLAND: Sure. Thank you for your question. I'll take the first swing. First, regarding the data from the group in
Germany, these data have not been submitted to the FDA as per agreement with
the Agency and I can give just a broad overview of the results, as the Agency
hasn't in detail looked at the results.
There
were 319 children who had previously received five doses of GSK DTaP vaccine
throughout their life beginning in 1992 in our initial Infanrix Studies. We were able to contact and immunize 319 of
these individuals last year for their sixth consecutive dose. I can say that there was no evidence of
increased reactogenicity getting the sixth dose of acellular pertussis
containing vaccine compared to when the same subjects received their fifth dose
of vaccine.
In
addition, we also looked at large injection site swelling with the same
criteria used in Pivotal Study 001 and the rate was low. Three subjects of the 319 met criteria for
large injection site swelling. Again,
these data will be submitted to the FDA right after licensure.
DR.
AHONKHAI: Just to add that these are
really preliminary data and I think in the fullness of time it would be
available, but just not at this point.
DR.
HOWE: I think the take-home messages
was reassuring that we saw only 1 percent, a very low rate, even in fully PA
vaccinated individuals.
DR.
STEPHENS: And I think that's
helpful. Any immunogenicity done?
DR.
HOWE: We would prefer not to comment on
that, because it hasn't been submitted to the FDA.
DR.
STEPHENS: And the concomitant vaccines?
DR.
HOWE: Yes, so if I can maybe shed some
light on the company's thought process with regard to concomitant
vaccination. You know, the first thing
we considered was whether or not there were any vaccines that would be
routinely administered at the same time as Boostrix, and this had been mentioned
during the presentation. During the
time when Boostrix was under development in the U.S., the only routine
vaccination at the 11 to 12 year-old visit was Td vaccine. So therefore there were no vaccines that
would be likely to be given to 100 percent of those adolescents who were coming
in to get Boostrix.
We
then considered vaccines that might be given as catch-up. And of the catch-up vaccines, really all of
the vaccines that children might come or adolescents might come in and receive
as catch-up vaccinations, the proportion of adolescents who were eligible for
catch-up were relatively low. For MMR
it was less than 5 percent, varicella about 15 percent and for Hep B about 30
percent.
Recognizing
that the, you know, routine recommendations for neonatal immunization with
hepatitis B were in place beginning in about 1992, and that those cohorts of
children are now getting older, the proportion of adolescents who come in and
who are eligible for Hep B vaccination actually will be decreasing and dwindling
over time.
I
think another fact was that we knew that there is data that demonstrates that
when you give DTaP that's full strength infant DTaP and hepatitis B vaccine,
there is no negative impact on the safety or efficacy of either of the
products. And, in fact, we actually
have a combination vaccine that has both DTaP and hepatitis B combined in it,
and that's our Pediarix with IPV.
CHAIR
OVERTURF: Dr. Karron, you had a
question?
DR.
KARRON: What is the definition of Grade
2 pain?
DR.
FRIEDLAND: The definition of Grade 2
pain is pain that the subject reports at the injection site when they move
their limb.
DR.
HOWE: If I can just add to that, that
means there really was no functional impairment assessment associated with
that. In other words, it didn't
necessarily have to interfere with any activity or prevent activity. It's just that they were reporting that it
hurt when it moved.
CHAIR
OVERTURF: Dr. Farley?
DR.
FARLEY: There was mentioned of the use
of the ELISA, the greater than or equal to 5 ELISA units per mL for the
antibody levels to the pertussis antigens.
And I wondered, it looked on one of the graphs as if the pre-vaccine
levels were often above that, and I wondered if there was any relationship you
saw to their earlier vaccine history in terms of whether they had a whole cell
vaccine or acellular pertussis for their priming prior to the study with what
their pre-immunization levels were at the time of this study?
DR.
FRIEDLAND: Thank you. With regard to the second part of your
question, no, we did not do that analysis and I cannot report about that
correlation. Because many of the
subjects had pre-vaccination antibody concentrations above 5 for the pertussis
antigens, our primary pertussis immunogenicity endpoint was a booster response,
so we could see the response to vaccination recognizing that pre-vaccination
level given that there is no recognized seroprotective cutoff.
DR.
FARLEY: So what proportion of the
subjects started with the level above 5 or, you know, you had that break out of
when you went to a 2-fold increase versus the 4-fold increase. How many fell into the category of only
requiring a 2-fold increase for boost?
DR.
FRIEDLAND: I can get that result for
you after our break and I can report that now, but I don't have it on my cript
sheet.
DR.
FINN: That varied from antigen to
antigen. For PT and pertactin about 75
percent of subjects had to show a 4-fold rise.
For FHA it was the other way around.
About 75 percent had to show a 2-fold rise.
CHAIR OVERTURF: Thank you.
DR.
FRIEDLAND: Thank you.
CHAIR
OVERTURF: Dr. Hetherington?
DR.
HETHERINGTON: The health benefit
theoretically is greatest to those that have low levels of pre-existing
antibody. I wonder if you analyzed your
data for immune response by level of preexisting antibody? In other words, are those that are
presumably the most susceptible with undetectable preexisting antibody showing
a response to your vaccine? And is it a
similar proportion of patients as those with high levels of preexisting
antibody?
DR.
FRIEDLAND: For any particular
antigen? Because they are different for
diphtheria, tetanus and for the pertussis antigens, because for D and T we have
recognized levels. You're looking for
pertussis specifically?
DR.
HETHERINGTON: Right. Of those that have no preexisting pertussis
antibodies, what proportion of those respond according to your criteria?
DR.
AHONKHAI: I wonder if Dr. Finn --
DR.
HOWE: Actually --
DR.
AHONKHAI: -- has any data on that?
DR.
FINN: No.
DR.
HOWE: I mean, as a general rule in
individuals who were seronegative prior to vaccination, their booster response
was much higher and in many cases it was upward as high as 100 percent. And those who were initially seropositive,
the booster response was lower. But we
can give you the exact values for that.
DR.
HETHERINGTON: The question is really
what proportion of those patients who have low preexisting antibody whatever
level you want to choose demonstrate a response? And is that proportion different from the over all results of the
study?
DR.
AHONKHAI: Bear with us while we just
take caucus in here, taking a look at the data.
DR.
HOWE: Yes, so the way the analysis was
done was again initially seronegative versus those who had -- were seropositive
but had a titer less than or equal to 20 and then initially seropositive with a
titer greater or equal to 20. And just
to give you an example, this is for the PT response in initially seronegative,
the proportion who had a booster response was 88 percent. Initially seropositive, but less than 20
ELISA units per mL, the booster response was 87 percent. And then if individuals were initially
seropositive, but the baseline titer was greater than 20 ELISA units per mL,
their booster response was 77.5.
For
the other antigens, FHA and pertactin, looking at the same cutoffs it would be
96, 99 and 93.8 percent, 94, 98.8 and 92.7.
So a bit higher booster responses in FHA and pertactin, but over all it
does depend on the pre-vaccination status.
CHAIR
OVERTURF: Well, last comment before the
break. Dr. Murphy?
DR.
MURPHY: Actually, I had three
questions. It can wait if you
prefer. The first question is do you
have any data on using Tdap for the primary series in any age group?
DR.
FRIEDLAND: No, we do not have any data
with that scenario.
DR.
MURPHY: Okay. The second question is just this is more background, why would
the bridging studies be choosing the Household Study rather than the Italian
Study with the difference in age of the primary series?
DR.
FRIEDLAND: You want that one?
DR.
HOWE: Yes.
DR.
FRIEDLAND: Yes.
DR.
HOWE: So you're asking why do we choose
the Household Contact Study rather than the Italian Study?
DR.
MURPHY: Right.
DR.
HOWE: So Infanrix was the product or
GSK's DTaP full strength pediatric product was studied in both Household
Contact Study in Germany and an NIH- sponsored study in Italy. And both of those studies were large,
perspective, controlled studies which gave similarly high efficacy
results. 89 percent against WHO
pertussis in the German Household Contact Study and 84 percent in the NIH
Italian Study.
Basically,
we had run quite a number of serum specimens from our Household Contact
Study. You know, for the PT antigen, I
believe, we had like 2,800 results and for FHA and pertactin, we had 600 or 700
results in an immunogenicity study that was the initial portion of the efficacy
study in Germany, so we had access to a lot more sera. Additionally, we had nice QC data over time to
show that the assays were stable over time.
For
the NIH Italian Study, we actually had very limited access to the sera. We only had about 150 samples originally,
some of which were already depleted. So
it was a pretty easy decision actually to go with the German Household Contact
Study.
DR.
MURPHY: And then the last question
really may be for the FDA. As we see
the numbers of the GMC titers, we know that laboratory methods have been
validated and standardized, but can we compare them from one laboratory to
another? For instance, as we look at
the other product, how much can we look at one number and think that it means
something similar to that same number from another laboratory?
DR.
AHONKHAI: FDA.
DR.
HOWE: Theresa says the answer is no.
CHAIR
OVERTURF: We'll go ahead and take a
break now. And since we are about 10
minutes overdue, we will come back at 10:40.
Thank you very much.
(Whereupon,
at 10:23 a.m. a recess until 10:42 a.m.)
CHAIR
OVERTURF: I would like to call the
meeting to order following the break and we will now hear the FDA presentation
on the GSK vaccine. Dr. Schwartz?
DR.
SCHWARTZ: Thank you. Good morning. My name is Ann Schwartz and I will be presenting a review of the
immunogenicity and safety data submitted by this license application for the
tetanus toxoid, reduced diphtheria and acellular pertussis vaccine with the
proposed trade name Boostrix.
An
outline of my presentation is detailed on this slide and will cover a
description of Boostrix and its relationship to Infanrix, the basis for
licensure of Boostrix as a single intramuscular dose in children and
adolescents 10 to 18 years of age, a presentation of the immunogenicity
endpoints and results of the Pivotal Study 001 conducted in the United States and
a presentation of the serologic bridge to Infanrix pertussis efficacy.
I
will also present an overview of the safety data from Study 001 and 11 other
non-IND studies performed outside the United States. Questions for the panel's review and discussion will be presented
at the end of this presentation.
The
formulation of Boostrix intended for U.S. licensure and use in the Pivotal U.S.
Study is presented in this slide. Also
on the slide is the formulation of the DTaP vaccine Infanrix. Boostrix is a reduced antigen diphtheria
tetanus and pertussis vaccine without preservative containing 0.3 milligrams of
aluminum as adjuvant.
GSK
manufactures a similar vaccine which contains 0.5 milligrams of aluminum, plus
2-phenoxyethanol as preservative for use outside the United States. This will be referred to in the presentation
as Boostrix 0.5 milligrams to differentiate it from the formulation for U.S.
licensure. As noted in the slide and in
the previous presentations, Boostrix is antigeniticly comparable to GSK's DTaP
vaccine, Infanrix, licensed for use in children less than 7 years of age.
The
proposed basis of licensure as agreed with the FDA is based upon the
following: Demonstration of safety,
this includes safety of Boostrix relative to a U.S.-licensed tetanus and
diphtheria vaccine; demonstration of non-inferiority of anti-diphtheria and
anti-tetanus seroprotection and booster response rates as compared to Td;
demonstration of a booster response to each of the pertussis antigens contained
in Boostrix and demonstration of the serologic bridge to pertussis efficacy.
Manufacturing
consistency of three lots of Boostrix based upon immune responses to all
antigens was evaluated and demonstrated.
In the interest of time, I will not present these data.
The
application contains one pivotal study conducted in the United States, Study
001, which evaluated the safety and the immunogenicity of a single-dose of
Boostrix relative to a Td vaccine manufactured by Massachusetts Public Health
Biologic Laboratory.
The
primary objective of this pivotal study noted in the slide were as
follows: To demonstrate non-inferiority
of Boostrix compared to the controlled Td vaccine with respect to
anti-diphtheria and anti-tetanus toxoid seroprotection rates; to demonstrate
non-inferiority of Boostrix compared to the controlled Td vaccine with respect
to anti-diphtheria and anti-tetanus booster response rates; to demonstrate that
anti-PT, anti-FHA and anti-pertactin booster responses occur in vaccinees
administered Boostrix and lastly, to demonstrate non-inferiority of Boostrix
compared to Td with respect to Grade 3 pain at the injection site.
An
overview of the study design is shown on this slide. Study 001 was a prospective randomized observer-blinded
comparative study conducted at 45 centers in the United States. Participants 10 to 18 years of age were
stratified into two age groups, 10 to 14 and 15 to 18 years of age, before
enrollment and randomized to four groups.
Three groups received one of three lots of Boostrix and the fourth group
received the comparator Massachusetts Td vaccine.
This
slide shows the inclusion/exclusion criteria which pertain to diphtheria,
tetanus and pertussis vaccination history.
Participants were to have previously completed routine childhood
vaccinations against diphtheria, tetanus and pertussis diseases according to
the recommended vaccination schedule at the time. Because of the time of the study and the age of the participants,
most would have received whole cell DTP vaccination for the three dose infant
primary series.
However,
since acellular vaccines were licensed for use as fourth and fifth doses of the
DTP series in 1991 and 1992, subjects may have received an acellular vaccine
for the fourth and/or fifth dose of the series depending on their age. The protocol specified that at least five
years were to have elapsed since the receipt of the preschool dose of DTP
vaccine and that subjects who had received a Td booster within the previous 10
years were to be excluded from the study.
This
slide compares the formulations of Boostrix and the Massachusetts Td vaccine
per 0.5 mL dose. The Td vaccine used in
Study 001 contains 2.0 Lf of both tetanus and diphtheria toxoids per 0.5 mL
dose. This Td vaccine also contains
0.45 milligrams of aluminum as aluminum phosphate and thimerosal as
preservative.
This
slide summarizes safety surveillance and monitoring procedures used in
001. Subjects were monitored for 30
minutes post-vaccination to assess for immediate reactions. Solicited local and systemic adverse events
were collected on diary cards for 15 days post-vaccination. Unsolicited adverse events and serious
adverse events were recorded for six months following vaccination.
An
overview of the study procedures is presented here. Each participant received one dose of either Boostrix or Td
vaccine intramuscularly. Blood samples
were obtained prior to vaccination and 30 days post-vaccination to measure
antibody response to the tetanus, diphtheria and pertussis components of the
vaccine. All antibody responses were
measured by ELISA and all assays were performed at GSK laboratories in
Rixensart, Belgium.
Six
months following vaccination, subjects received a phone call to query about the
occurrence of serious adverse events, the new-onset of chronic illnesses and/or
non-routine medical visits during the five months since visit two.
For
the analysis of safety and immunogenicity, the populations were defined as
noted in this slide. The primary
analysis for safety was performed on the total vaccinated cohort. This included all subjects who had received
one dose of vaccine and for whom safety data were available. Analyses were performed based on the vaccine
received. The total vaccinated cohort
for immunogenicity included all vaccinated subjects with available
immunogenicity data. Again, analyses
were performed according to the vaccine administered.
The
primary immunogenicity analysis were performed on the according to protocol
cohort for immunogenicity. This
included all subjects who were vaccinated according to treatment assignment who
met protocol specifications, who had blood samples obtained according to
protocol specifications and for whom sufficient sera were available for
evaluation.
I
would now like to move to a presentation on the result of the Clinical Study
001. The demographics for Study 001 are
summarized on this slide. Of,
approximately, 4,100 subjects enrolled, 52 percent were male. 85.7 percent of the population were
caucasian with, approximately, 13 percent of the subjects identified as either
African American, Hispanic, Asian or other.
The mean age was 12.9 years with, approximately, 75 percent of the
subjects in the 10 to 14 year age range.
Almost 25 percent of the subjects were in the 15 to 18 year age range.
One
subject in the Td group was 9 years-old at the time of enrollment. The immunogenicity data from Study 001 will
be summarized in the following slides.
I would like to begin the presentation of the immunogenicity results be
defining the endpoints for evaluation of the immune response. I will define seroprotection and booster
response to the tetanus and diphtheria toxoids and present the pre-vaccination
antibody levels. Then I will show the
primary immunogenicity endpoints and analyses.
The
definition of booster response to pertussis antigens will be provided and those
primary immunogenicity results presented.
After presentation of the immunogenicity data from Study 001, I will
provide the results of the serologic bridge to Infanrix.
The
definition of seroprotection and booster response to the diphtheria and tetanus
toxoids are shown on this slide. For
both toxoids, seroprotection was defined as anti-toxin level greater than or
equal to 0.1 international units per mL.
For subjects with pre-vaccinations less than .1 IU per mL a booster
response was defined as a post-vaccination level greater than or equal to 0.4
IU per mL. For those subjects with a
pre-vaccination level greater than or equal to 0.1 IU per mL, a booster
response was defined as a 4-fold rise relevant to the pre-vaccination sample.
This
slide shows the percent of subjects in each group with pre-vaccination
anti-tetanus and anti-diphtheria toxoid levels greater than or equal to 0.1
and/or 1.0 international units per mL.
As you can see, over 84 percent of subjects had pre-vaccination antibody
levels greater than or equal to 0.1 international units per mL to
diphtheria. Over 96 percent of the
subjects had anti-tetanus toxoid greater than or equal to 0.1 international
units per mL.
Also
presented in this table is the percentage of subjects with greater than or
equal to 1.0 IU per mL prior to vaccination.
Approximately, 18 percent of the subjects had a greater than or equal to
1.0 IU per mL to the diphtheria toxoid.
And, approximately, 37 percent had antibody concentrations at or above
this level to tetanus toxoid.
The
primary endpoints for the evaluation of response to diphtheria and tetanus
toxoids are presented on this slide.
The immune response to diphtheria and tetanus components of Boostrix
were compared to the immune response of those subjects who received Td
vaccine. For each antigen, the percent
of subjects with anti-diphtheria and anti-tetanus levels greater than or equal
to 0.1 international units per mL and the percent of subjects demonstrating
booster response were evaluated one month post-vaccination.
For
each of these endpoints, non-inferiority of Boostrix would be demonstrated at
the upper limit of the two-sided 95 percent confidence interval on the
difference of Td minus Boostrix was less than or equal to 10 percent.
Shown
here are the differences in the anti-diphtheria seroresponse and booster
response rates one month post-vaccination.
Almost 100 percent of subjects in both groups had post-vaccination
seroprotective levels greater than or equal to 0.1 IU per mL. Approximately, 91 percent of subjects who
received Boostrix and 96 percent of the subjects who received Td showed booster
response to diphtheria toxoid.
As
shown in the last column, the upper limit of the 95 percent confidence interval
on the difference was less than 10 percent for each of the primary
endpoints. Therefore, non-inferiority
was demonstrated. Also shown here in
the last row is the difference in the percent of subjects with anti-diphtheria
toxoid levels greater than or equal to 1.0 international units per mL. Although not a pre-specified endpoint, the
upper limit of the 95 percent confidence interval was also less than 10
percent.
Presented
here are the differences in the anti-tetanus response rates between Boostrix
and Td one month post-vaccination. All
subjects who received either Boostrix or Td had levels greater than or equal to
0.1 international units per mL one month post-vaccination. Approximately, 90 percent of subjects who received
Boostrix and, approximately, 92 percent of those who received Td had a booster
response to tetanus toxoid.
Again,
for each of these primary endpoints, non-inferiority was demonstrated as the
upper limit of the 95 percent confidence interval on the difference, Td minus
Boostrix, was less than 10 percent.
Also shown here in the last row is the difference in the percent of
subjects with anti-tetanus toxoid levels greater than or equal to 1.0 IU per mL
post-vaccination. Although not a
pre-specified endpoint, the upper limit of the 95 percent confidence interval
was also less than 10 percent.
For
the pertussis component of Boostrix, a Boostrix booster response to each of the
pertussis antigens, PT, FHA and pertactin, was defined based upon
pre-vaccination antibody levels. For
those subjects with a pre-vaccination level less than 5 ELISA units per mL, a
booster response was defined as an antibody concentration greater than or equal
to 20 EU per mL one month post-vaccination.
For
those subjects with pre-titers greater than 5, but less than 20 EU per mL, a
4-fold rise would be indicative of boosting.
And for those subjects with pre-titers greater than 20 ELISA units per
mL, a 2-fold rise one month post-vaccination defined a booster response.
Presented
here are the primary endpoints for the evaluation of the immune response to the
pertussis component of Boostrix. For
those subjects who received Boostrix, an acceptable booster response to each
pertussis antigen would be attained if the lower limit of the 95 percent
confidence interval on the observed booster response rate was greater than the
predefined criterion of 80 percent.
This response rate was based on data from previously conducted studies
with a non-U.S. formulation of Boostrix.
This
slide shows the booster response of subjects 10 to 18 years of age to the
pertussis antigens contained in Boostrix.
For each antigen, the lower limit of the 95 percent confidence interval
on the observed rate was greater than the predefined criterion of 80 percent.
All
immunogenicity analyses, which I have just presented, were based on the ATP
cohort for immunogenicity. However,
since 9.5 percent of the subjects were excluded from the ATP cohort for
immunogenicity, the immunogenicity analyses were also performed using the total
vaccinated cohort as pre-specified in the protocol. In the analysis performed using the total vaccinated cohort, the
predefined criteria for all primary endpoints was also met. This data will not be shown.
I
would like to now move to the serologic bridge to pertussis efficacy. A serologic bridge of Boostrix to Infanrix
was performed to demonstrate that the response of individuals 10 to 18 years of
age immunized with one dose of Boostrix was not inferior to the response of
infants following a three dose primary series of Infanrix.
This
was done by comparing the anti-pertussis geometric mean antibody concentrations
of adolescent immunized with Boostrix in Study 001 to the immune responses
observed in infants immunized with the three dose primary series of Infanrix in
a household contact clinical efficacy study.
Infanrix Study 039 and the Household Contact Study 050, both conducted
in the 1990s, are summarized in the next slide.
Study
039 was a safety, immunogenicity and lot consistency study of Infanrix. Infants were vaccinated with Infanrix at 3,
4 and 5 months of age. The cohort of
children in Study 039 provided the population for a Household Contact Study to
evaluate the clinical efficacy of Infanrix.
This is Study 050.
In
Study 050, the protective efficacy of a three dose series of Infanrix was
calculated to be 89 percent with a 95 percent confidence interval: 77 to 95 percent, against WHO-defined
pertussis, which was 21 days or more of paroxysmal cough with infection
confirmed by culture and/or serologic testing.
For
the purpose of the serologic bridge of adolescents to infants, the primary
cohorts for analysis were the total vaccinated cohort from Boostrix Study 001
and the Infanrix Study 039. In Study
039, the total vaccinated cohort was defined as subjects who had serologic data
for at least one pertussis antigen. Due
to the study design, the majority of subjects had anti-pertussis toxoid data
only.
The
assays for Boostrix Study 001 sera were performed in 2003 and the assays of the
infant sera were performed in 1994. All
assays were performed at GSK's laboratory in Belgium. Assay methodology and validation reports were submitted to the
file and found to be satisfactory. The
data submitted demonstrated stability of the anti-pertussis assays over time.
The
predefined criteria for non-inferiority of the serologic bridge of Boostrix to
Infanrix are presented in this slide.
If the upper limit of the 95 percent confidence interval on the ratios
of the GMCs, Infanrix to Boostrix, was less than 1.5 for each pertussis
antigen, non-inferiority of the anti-pertussis responses following Boostrix
would be demonstrated.
This
slide presents the primary serologic bridge analysis. GMCs one month following a three dose series of Infanrix in
infants were compared to those following a single dose of Boostrix in
adolescents. As you can see, for each
of the pertussis antigens, anti-PT, anti-FHA and anti-pertactin, the GMCs in
adolescents who received Boostrix were higher than those observed in infants
who had received the three doses of Infanrix.
For
each antigen, the upper limit of the 95 percent confidence interval on the
ratios of GMCs was less than 1.5. Thus,
the predefined non-inferiority criteria for the comparison of Infanrix to
Boostrix were met for the total vaccinated cohort. When these analyses were repeated using the ATP cohort from each
study, the non-inferiority criteria were also met.
I
will now move to a discussion of safety.
I will first present the safety data from the Pivotal Study 001 and then
summarize the data from 11 non-IND studies that were using the 0.5 milligram
formulation of Boostrix.
The
overall safety database was 3,289 subjects ages 10 to 18 years of age who
received a single dose of Boostrix. An
additional 2,163 subjects ages 4 to 78 years were analyzed for safety after the
receipt of a single dose of Boostrix formulated with the higher 0.5 milligrams
of aluminum in 11 non-IND studies. This
number differs from that provided by GSK, because in nine of these studies we
have only included the number of subjects in the ATP cohort for safety.
This
slide summarizes the safety analysis performed in Study 001. The primary safety endpoint was to
demonstrate non-inferiority of Boostrix compared to Td with respect to Grade 3
pain within 15 days of vaccination.
Solicited local adverse events were recorded for 15 days
post-vaccination. Solicited local
adverse events included pain, redness, swelling and increased mid-arm
circumference of both the vaccinated and unvaccinated arm. Solicited systemic events during the 15 days
post-vaccination included fever, headache, fatigue and gastrointestinal
symptoms.
Information
was recorded on a subject diary card and was analyzed for events occurring
within 72 hours and 15 days post-vaccination.
The occurrence of unsolicited adverse events and serious adverse events
were reported for six months post-vaccination.
The
primary safety endpoint for 001 was an assessment of the non-inferiority of
Boostrix compared to Td with respect to Grade 3 pain within 15 days of
vaccination. Grade 3 pain was defined
as a spontaneously painful arm and/or pain that prevented normal activity by
the subject. Non-inferiority would be
demonstrated if the upper limit of the two-sided 95 percent confidence interval
on the difference of Boostrix minus Td was less than or equal to 4 percent.
Pain
was the most frequently reported solicited local adverse event in both
vaccination groups. Presented here is
the incidence of pain at the injection site during the 15 day follow-up period. The rate of Grade 3 pain was similar between
the groups, 4.6 percent in the Boostrix group and 4 percent in the Td
group. The upper limit of the 95
percent confidence interval for the difference in the rate of Grade 3 pain was
1.87. This is less than the
pre-specified limit of 4 percent. Thus,
non-inferiority of the incidence of Grade 3 pain was demonstrated.
Although
the incidence of any Grade 2 pain within 15 days was statistically higher in
Boostrix recipients, as compared to those who received Td, approximately 4
percent and 9 percent respectively, the clinical relevance of this finding is
uncertain. The rates of pain within 72
hours were similar to those shown on this slide.
Presented
here is the incidence of other solicited local adverse events, redness,
swelling and increased mid-arm circumference within 72 hours of
vaccination. The rates were similar for
both the Boostrix and Td groups. For
example, approximately, 4 percent of subjects in both groups experienced
redness greater than 20 millimeters at the injection site and, approximately, 5
percent of subjects in both groups had swelling greater than 20 millimeters at
the injection site. The incidence of
these local adverse events within 15 days of vaccination were very similar to
the rates shown on this slide.
This
slide shows the rates of solicited systemic adverse events within 15 days of
vaccination. Solicited adverse events
included fever, headache, fatigue and gastrointestinal symptoms. Headache and fatigue were most commonly
reported solicited systemic adverse events in both vaccine groups occurring
each in, approximately, 40 percent of the subjects.
Within
15 days, the incidence of Grade 2 headache, that is headache that interfered
with normal activity, was slightly higher in the Boostrix group, approximately
16 percent, versus 13 percent in the Td group.
The incidence of these solicited systemic events was lower within 72
hours of vaccination. However, there
was no differences between the groups.
Within
the six months post-vaccination, 15 subjects vaccinated with Boostrix reported
a serious adverse event. Two subjects
vaccinated with Td reported a serious adverse event. No serious adverse events were reported during the 30 days
post-vaccination.
Four
pregnancies occurred during the study, two in subjects who had received
Boostrix and two in Td recipients. Both
pregnancies in the Boostrix recipients occurred about four months
post-vaccination. One of these subjects
experienced a spontaneous abortion within the first trimester, which is also
included here as a serious adverse event.
All other subjects delivered healthy infants.
This
listing presents the serious adverse events, regardless of the investigator's
assessment of causality, which occurred within six months. There was a time interval post-vaccination,
32 to 161 days, following vaccination with either Boostrix or Td. As I mentioned in the previous slide, no
events occurred within 30 days following vaccination. The most commonly occurring serious adverse events were wounds/
fractures, drug overdoses and drug abuse.
With
the exception of the case of appendicitis and tooth abscess, which occurred in
subjects who received Td, all other events occurred in subjects who received
Boostrix. Our review of the nature and
timing of these adverse events raise no particular concerns about the safety of
Boostrix.
The
protocol for Study 001 specified that subjects would receive a phone call five
months following the second clinic visit, approximately, six months
post-vaccination. During that phone
call, subjects were asked about the occurrence of new chronic illnesses,
emergency room visits and non-routine medical visits.
The
onset of new chronic illnesses was reported by 22 subjects in the Boostrix
group, 0.7 percent, versus nine subjects, 0.9 percent, in the Td group. The most commonly reported new illnesses,
which occurred at rates of less than 1 percent in the Boostrix group, were
gastrointestinal illnesses, allergy, impaired concentration and asthma. The occurrence of ER visits and non-routine
medical visits was slightly higher in the Boostrix group, but a review of the
events do not show any concerning incidents or trends.
11
additional non-IND clinical studies were submitted to support the evaluation of
safety. Two of the studies were
submitted as full study reports and the remaining nine studies were submitted
in synopsis form. The Boostrix
formulation in most of these studies differed from that intended for U.S.
licensure. Safety monitoring varied
from study to study. However, serious
adverse events were captured for at least 30 days post-vaccination.
In
these 11 studies, a total of 2,372 additional subjects received Boostrix or the
0.5 milligram aluminum formulation of Boostrix and were monitored for
safety. A tabulation of serious adverse
events is presented here.
Eight
serious adverse events were reported among participants who had received
Boostrix. Diagnoses included diabetes
mellitus, diabetic hypoglycemic seizure in a known diabetic, concussion,
alcohol intoxication, syncope, uveitis, appendicitis and polypectomy.
In
summary, in Pivotal Study 001, the primary immunogenicity and safety endpoints
were met. There were no unexpected
adverse events or serious safety concerns.
In addition, non-inferiority of a single dose of Boostrix to a primary
series of Infanrix in infants was demonstrated.
This
concludes my presentation of the clinical data submitted to support the
licensure of Boostrix. If anyone has
any questions, I will be happy to take them at this time.
CHAIR
OVERTURF: Are there questions for Dr.
Schwartz? Yes, Dr. Markovitz?
DR.
MARKOVITZ: Yes. I would like to ask you the same question,
basically, that Phil LaRussa asked GSK presenters about the somewhat lower GMCs
in the tetanus and diphtheria recipients of Boostrix, as opposed to the
Massachusetts vaccine. What did the FDA
think of that?
DR.
FINN: Those were not pre-specified
primary analyses and we did look at them and yes, in one I case, I think it was
with respect to the anti-diphtheria GMCs, there may have been -- I think it was
a 2-fold higher GMC in the recipients of the Massachusetts Td.
But
I think we have to remember that when these studies were initiated, there
really wasn't a lot of data on Td vaccines, and I think that is why the primary
endpoints that we chose and that we asked the sponsors to evaluate were
seroprotection and booster response, and we did not ask them to look at GMCs.
I
think we did not know. We could not
have anticipated that result, and I think you have to evaluate that in the
context of all the Tds that are on the market right now and for which we have
very little data.
DR.
MARKOVITZ: So when you evaluate that,
your conclusion is?
DR.
FINN: That it's not clinically
relevant.
CHAIR
OVERTURF: Dr. Self?
DR.
SELF: I would like to ask about the
table with data for the serologic bridge.
There are GMCs associated with Infanrix and Boostrix. Just to be clear, these were assays that
were done by the same labs or these were different labs?
DR.
SCHWARTZ: It's the same laboratory
separated from 1994 to 2003.
DR.
SELF: So the same lab, but sort of 11
years apart.
DR.
SCHWARTZ: About 10 years.
DR.
SELF: Okay. And then looking at the pattern of responses across antigens, but
within time, the patterns look rather different and I wonder if you could
comment on those. Do those cause any
concern about comparability?
DR.
SCHWARTZ: I'm not sure I understand the
question.
DR.
SELF: So if you look at the column
associated with Infanrix, the GMCs for PT, FHA and PRN have sort of different
orderings than they do for the assays associated with Boostrix. Is that within sort of normal variation or
is that difference in pattern something that is concerning at all in the
comparison across?
DR.
SCHWARTZ: I think I will ask Dr. Meade
to respond to that. It would be Slide
30.
DR.
MEADE: Which slide? Slide 30?
Again, I'm not sure I have -- I'm Bruce Meade, Office of Vaccines, CBER. Again, I think I'm still not exactly sure.
DR.
SCHWARTZ: You have to go through a lot
of slides.
DR.
MEADE: Maybe if we go to the slide, you
can make sure we follow the question.
DR.
SELF: Yes. Okay. So for example,
looking at the anti-FHA and the anti-PRN.
For the Infanrix, the FHA has a lower GMC and for Boostrix it has a
higher. So you know, there is a little
different ordering. Does that cause you
any -- is there any concern about that?
DR.
MEADE: It caused me no concern, no.
DR.
SELF: No concern? So that's with --
DR.
MEADE: They are all quantitatively, you
know, very high. And you know, again, I
think we're looking at both the fact that there was a strong booster response
and the fact that the quantity is much higher.
Again, there is a lot of interesting biology behind the different
antigens, FHA, pertactin and fimbriae, and there are interesting differences
among the antigens and how they develop in individuals. So again, we did not really evaluate that.
CHAIR
OVERTURF: Any other questions?
DR.
FINN: Actually, could I just follow-up
with that, the FHA part? Bruce, I think
you just touched on it when you said that there is interesting biology, but
there is some cross-reactivity between FHA and antigens from other species, so
it could be that, you know, what you're seeing here is a reflection of the fact
that these kids perhaps see other antigens that are similar to FHA and that
could also be the reason why we have a higher proportion of subjects in the FHA
showing a 2-fold booster than in the other antigens.
DR.
SELF: So you attribute this to biology
and the difference between the antigens or the vaccines, rather than a
difference in 11 years in the assay?
DR.
FINN: Potentially. I don't think any of us really know. I don't think any of us really know, but I
was just told that I should mention that it's a Haemophilus influenzae antigen that is cross-reacted with FHA.
CHAIR
OVERTURF: Dr. Stephens?
DR.
STEPHENS: This is a general question
about the mixing and matching of these acellular pertussis vaccines and just to
get the FDA's comment about. These
likely will be used clinically as primary series versus booster series and,
obviously, we don't have those kind of data and I just would like to get your
comments, if you would, about that issue.
DR.
SCHWARTZ: Are you referring to the fact
that Infanrix may be used for adolescents and infants may receive the Boostrix?
DR.
STEPHENS: As one possibility.
DR.
SCHWARTZ: Okay.
DR.
STEPHENS: And then, obviously, we're
looking at a whole-cell-pertussis background, as we mentioned earlier.
DR.
SCHWARTZ: Yes.
DR.
STEPHENS: But I'm more interested in
the mixing and matching that these acellular products will --
DR.
FINN: So you're basically asking about
acellular pertussis vaccines in a mix-and-match for doses one to five followed
by this product in adolescents?
DR.
STEPHENS: That's one example.
DR.
FINN: Yes. I think that one way to look at that would be when the cohort for
children becomes available for post-marketing studies, there are two
possibilities.
We
could evaluate or ask GSK to evaluate, and the other manufacturers, a cohort of
kids who received, who were primed with all Infanrix and that actually might be
hard to do, because you would, essentially, have to start that cohort now
unless you could find a center, which has been using Infanrix since 1997
solely. And the other way to address
it, the mix-and-match part, is just to take all comers and evaluate immunogenicity
on that.
The
difficulty may be to design -- if you want to parse it out in analyses to those
who had received five doses of the same vaccine, four doses plus a different
one for one, it might be difficult. You
may just have to, as a primary analysis, take all comers, but that is a couple
of ways you could do it.
DR.
STEPHENS: I guess the comment is this
is important to the FDA?
DR.
FINN: Yes. I should also add that safety of these products is also very
important to FDA.
CHAIR
OVERTURF: Before we proceed, there was
a question I really wanted to ask GSK, and that was when you look at the data
that are presented, particularly for the 15 to 18 year-old age group, the
numbers are quite small. Actually,
there were 25 percent of the 001 Study that included 15 to 18.
My
question really was is there a further breakdown in those age groups? How many were actually at 18, 17 and so
forth?
DR.
FRIEDLAND: We did not analyze with a
further breakdown between the strata of 10 to 14 and 15 to 18.
CHAIR
OVERTURF: Yes, Dr. Wharton?
DR.
WHARTON: I also have a question for
GSK, if they would be prepared to comment on their further development plans
for use of this product in persons over age 18 and in use of repeated doses,
that is as might be used in a decennial booster to replace the current use of
Td as a decennial booster?
DR.
FRIEDLAND: I think it was a two part
question. Regarding repeat doses, Td
vaccine is recommended on an every 10 year interval. Right now there is no cohort available to study for repeat
dosing. The first group given Boostrix
in clinical trials was in 1997 and we will certainly consider that cohort as it
becomes of age for repeat dosing.
If
you could repeat the other part of the question, Dr. Wharton?
DR.
WHARTON: Conducting studies in older
age groups, do you expand the indications beyond adolescents?
DR.
FRIEDLAND: Right now our focus has been
on adolescents, the group where the epidemiological data shows that the disease
burden is highest, the group where cost effective analyses have demonstrated
that immunization could be beneficial and cost effective and, most importantly
or as importantly, where an immunization platform exists where it's feasible to
actually immunize these adolescents when they come in at their recommended 11
to 12 year-old visit and, particularly by combining the vaccine, no extra
visit.
We
cannot comment further on our future development plans regarding study outside
of the group. Right now we have
prioritized adolescents as our first step.
CHAIR
OVERTURF: Yes, Dr. Farley?
DR.
FARLEY: On a similar track, if this is
approved for use in 11 and 12 year-olds, some of them may have received already
their Td boost at that age or 12 and 13 year-olds may have had it and, clearly,
those who had had it were excluded from this study and they had it, I believe,
within 10 years that were excluded, is there any data that is accumulated for
individuals who have had the combination of Td and this vaccine, because
otherwise those children won't be able to get it for 10 years, for the entire
high risk period.
Have
there been either accidental combinations or something, that there have been
observational studies, and has it been associated with any increased local
reactions or systemic reactions?
DR.
FRIEDLAND: Yes. For immunization with Td with five years or
more elapsing, for that we're relying upon the studies conducted outside of the
United States where Td was allowed with at least five years having
elapsed. In those studies there have
not been any trends towards increased reactogenicity or serious adverse events
in subjects who received Td under that group.
Within
the Boostrix 001 Study, although it was an exclusion, children did sneak into
the study. There were 63 subjects who
received Td. None of those subjects
reported a serious adverse event nor a case of large injection site swelling.
CHAIR
OVERTURF: Are there any other questions
from the Committee? I think I had
requested during the break from the floor, and if there's any questions, I
think we should let those questions come now.
DR.
LONG: For GSK. I'm Sarah Long, an infectious disease doctor
from St. Christopher's Hospital in Philadelphia and representing the Committee
on Infectious Diseases of the American Academy of Pediatrics.
I'm
interested in the longevity of antibody.
Do you have data that would allow us to know what percentage of
individuals who received Boostrix had antibodies against pertussis toxin that
were above pre-booster levels and for how many years?
DR.
FRIEDLAND: Yes. We have data out to five years in Study 030,
and if we look at the ratio of post-vaccination to pre-vaccination GMCs for
anti-PT, that ratio is above 1 even at the lower limit of the 95 percent
confidence interval at five years.
DR.
LONG: Okay. And what percentage of individuals who got Boostrix still had
measurable anti-PT five years out?
DR.
FRIEDLAND: I don't know offhand. I would have to look into my notes about the
percentage who had a PT level greater than 5 at five years.
DR.
LONG: Yes, yes.
DR.
FRIEDLAND: I would have to go back into
my notes. Does the FDA have that by any
chance? No. I can't call on you this time?
DR.
LONG: Since that's the only one for
which there is no free lunch, there is no cross-reacting experiences.
DR.
FRIEDLAND: What I --
DR.
LONG: And it's one important antibody.
DR.
FRIEDLAND: What I can say is that we
have looked at the data that has been published from the group in Italy, from
the NIH study, and they have documented that in the setting of maintained
efficacy, excellent efficacy, against World Health Organization- defined
pertussis at 86 percent at 6 years of age in children who have not been
boosted, that they have demonstrated that anti-PT antibody levels do decline,
but CMI to anti-PT is maintained throughout that time suggesting that
cellular-mediated immunity, particularly to PT, plays a large role in long-term
protection for pertussis. So what we
saw has been similar to what's documented at NIH while efficacy is maintained
and CMI is maintained as well.
DR.
LONG: Except that you will still want
to know about those antibodies, because presumably pre-booster those are people
we know are getting pertussis and are susceptible whether they have CMI or not. So the antibody is at least one marker, and
those areas in which it's the long-term studies have been followed still have a
good bit more pertussis than we do, so there might be some natural boosting
going on.
DR.
AHONKHAI: I think we'll be happy to
look at this and provide that information as is appropriate hereafter.
CHAIR
OVERTURF: Yes, Dr. Hetherington?
DR.
HETHERINGTON: I'm not sure Dr. Long's
first question was answered. The
question was what proportion of patients have post-vaccination levels above
pre-vaccination levels out five years?
You responded giving the ratio of geometric mean titers, which basically
doesn't answer the same question. You
can skew that population and that result by a sub-population.
So
the question is is there a breakdown of the data based on the proportion of
patients above some level, whether it's pre-vaccination level or some minimum
level considered reasonably associated with protection?
DR.
FRIEDLAND: Dr. Howe would like to
respond.
DR.
HOWE: We do have the data analyzed by
the proportion who have a titer greater than the cutoff of 5 EL.U. per mL. We don't have that with us right now, but we
would be able to get it during one of the breaks.
CHAIR
OVERTURF: Are there any other further
questions at this time? Well, at this
time, we will proceed to the open public hearing and I will turn the meeting
over briefly to Christine Walsh.
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, will you, please, read the
open public hearing statement?
CHAIR
OVERTURF: Both the Food and Drug
Administration and the public believe it is in a transparent process for
information gathering and decision making.
To ensure such transparency at the open public hearing session of the
Advisory Committee, FDA believes that it is important to understand the context
of an individual's presentation.
For
this reason, FDA encourages you, the open public hearing speaker, at the
beginning of your written or oral statement to advise the Committee of any
financial relationship that you may have with the sponsor, its 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 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.
MS.
WALSH: I have received one written
request from B. Sachau who was not able to attend this meeting. Their comments are listed in the Committee's
red folders posted in the public viewing notebook at the registration desk and
will be posted on the FDA website after the meeting.
Is
there anyone else in the room who would like to address the Committee at this
time? Continue on.
CHAIR
OVERTURF: Okay. With that we will continue on and, at this
point, we are going to consider the questions before the Committee. Dr. Schwartz, are you going to present those
questions?
DR.
SCHWARTZ: Questions and discussion
items for the Committee. "Are the
available data adequate to support the efficacy of Boostrix in individuals 10
to 18 years of age?" And we'll ask
for a vote on that. Number 2. "Are the available data adequate to
support the safety of Boostrix when administered to individuals 10 to 18 years
of age?" And an item for
discussion. "Please, identify any
issues which should be addressed, including post-licensure studies."
CHAIR
OVERTURF: Before we proceed with the
questions, I will open it up for discussion, which is actually the last part of
this, for Committee Members. Yes, Dr.
Word?
DR.
WORD: I guess just in terms of
post-licensure studies, and I think Dr. Wharton had mentioned something also,
the question I have is that, you know, we're looking at the antibodies or
protection waning over a certain time period, so you targeted adolescents. And my question is, you know, quite
honestly, why does everyone just assume it's the adolescent that's introducing
it into the household and not young adults?
And
so I guess part of my question is I would like to see something done with some
adult populations, particularly women of child-bearing age, because, quite
honestly, the people that I -- the children that I have had have had mothers
who have had pertussis and have coughed all through labor and delivery.
Yet,
their obstetrician has said their pregnancy and labor and delivery was
uncomplicated, and they have been coughing and hacking through the entire
course. And I just had a colleague who
is an internist who coughed all through, because he had patients who were
diagnosed with bronchitis. I mean, that
was one. So looking at post-licensure
studies, looking at that.
I
think the other thing, because right now there is a big emphasis on trying to
make that transition from the healthy adolescent into the healthy adult. As you pointed out that when you first
started your studies, you did not have meningococcal vaccine, but I think when
you're looking at concomitant administration, this is a group that you're
targeting.
And
so that to me would be a natural progression for them to go to look at
concomitant administration, because I agree, I think you have a cohort of
children who have received hepatitis B, so you're not going to have enough to
be able to do that study.
CHAIR
OVERTURF: Yes. I would emphasize that, obviously, there
needs to be more data in the future on persistence of antibody to all three
components of the vaccine and the various components, specifically of pertussis
for at least the interval of time that we are going to request for repeated
immunization.
My
feeling is that this is moving us to the direction and if we're really
successful, we may never really know some of that epidemiology you just
requested, because if it successfully controls disease, we may see lower attack
rates in adult populations that we now have, but we don't know about perhaps.
So
I would think that in addition to epidemiologic data and serological data and
safety data in adult populations, that is something that is going to be really
required. And I would echo the issue
about pregnancy and also child-bearing women, because that's, in my clinical
practice, a major source of pertussis in the infant, in the child, prior to the
time that we have full immunization. So
I think we all would strongly recommend more data in that regard.
Are
there other questions or suggestions?
Dr. Murphy?
DR.
MURPHY: I agree with the suggestions
that have been made and I guess I had a couple others. The elderly frequently gets left out in our
discussions. We talk about young adults
and we don't have nearly as much data as we would like to in the elderly, but I
think that's something we need to make sure we don't forget.
In
addition, we're making the assumption that we can always replace Td with Tdap
and perhaps that will turn out to be the case with duration of protection if it
turns out that that lasts for at least 10 years, but of course there are people
who don't believe that adults, all adults, need a decennial booster. So one of the things I would like to
encourage us to look at is AP vaccines in adults, perhaps not adolescent, but
certainly in adults, including elderly adults.
CHAIR
OVERTURF: Yes, Dr. LaRussa?
DR.
LARUSSA: This may seem like a
nitpicking point, at this point, but I'm a little bothered that we're being
asked to vote on efficacy where, in fact, we are presented with no data on
efficacy and the data we evaluated is on the basis of non-inferiority of
serological data. And I'm just worried
that as the word efficacy sort of filters into the proceedings of the
Committee, people are actually going to start to believe that we looked at
efficacy data.
CHAIR
OVERTURF: Yes, Dr. Finn?
DR.
FINN: You raise a very good point and
we actually debated this, because we absolutely acknowledge this is not
clinical efficacy. And so the true term
for this, regulatory-wise, is effectiveness.
But we actually made a conscious decision not to use the word
effectiveness and to use efficacy, because we figured that, you know, to the
broader community efficacy encompasses both.
But we do acknowledge that this is not clinical efficacy.
And
so when I first wrote that question, I had up there effectiveness, and we
decided to change it to efficacy, because we felt that it was a term that
everybody would understand. But I would
like to go on the record to say that we acknowledge that and the word should be
effectiveness, which encompasses serologic data and would encompass a bridge to
a clinical efficacy study.
CHAIR
OVERTURF: Since we're in a transition
period, would it not be appropriate to perhaps in the question, in parentheses
after the word efficacy, put in "effectiveness, equivalency."
DR.
FINN: Yes, I'm way for that. I mean, my first version had
efficacy/effectiveness.
CHAIR
OVERTURF: Yes?
DR.
STEPHENS: I had similar concerns about
the use of the term efficacy in this particular statement and was writing down
based on immunological bridging equivalent effectiveness, is how I would view
it.
CHAIR
OVERTURF: We may have to take a
separate vote. We may have to change
the word. Are there further comments? What I would suggest is if we use the term
equivalent effectiveness, that we modify the question and at least put it in
parentheses after the word efficacy.
That would be one alternative.
The other alternative would be to replace the word efficacy with
equivalent effectiveness.
DR.
WORD: I was going to say I think I
would agree with Dr. LaRussa and I think Dr. Stephens. I would probably remove the word efficacy,
because I think it will only lend to confusion further down the road, and I
think your suggestion of just rewording it and saying what exactly it's based
on.
CHAIR
OVERTURF: Are there further -- we can
come back to this question before we provide a vote and if so, if we need to, I
can call for a motion, which would change the wording slightly. But before we do that, the question really
is is there further discussions regarding the last question, which is
identifying further post-licensure studies.
Yes, Dr. Farley?
DR.
FARLEY: I think we have already
discussed this, but just to reemphasize the follow-up on those who have had the
entire series, primary series with the acellular product, continuing to look at
that and any influence on the ultimate effectiveness of the Boostrix.
CHAIR
OVERTURF: Yes, Dr. Hetherington?
DR.
HETHERINGTON: What we're really talking
about is equivalence in immunogenicity and behind that with regard to clinical
effectiveness, there are some assumptions.
That is that the immune response in the adolescents is holistically
similar to the immune response in infants where the efficacy data really lies,
the clinical efficacy data I should say.
I
think we all feel that the long-term data about the impact of the introduction
of this vaccine on the epidemiology of the disease is going to be crucial. Are we just going to push out this peak of
activity from the 10 to 19 year-olds to the 20 to 30 year-olds or 30 to 40
year-olds or is the total disease burden actually going to be reduced over
time?
I
think it's a very difficult question, but it's something that, in order to get
the bang for the buck in the health care world, needs to be addressed in
post-marketing studies.
CHAIR
OVERTURF: Yes. Dr. Karron, I think, was first.
DR.
KARRON: Just to follow-up on Dr.
Farley's and Dr. Stephens' earlier comment, not only response in those children
who have been primed with acellular components but, I think as was suggested by
Dr. Stephens before, with a variety of acellular products. And I think probably the most expedient way
to do that is to just look at all comers, because I agree it will be difficult
to stratify by four and one or three and two or whatever.
CHAIR
OVERTURF: Yes, Dr. Stephens?
DR.
STEPHENS: Just another issue that I
think we haven't talked about is the herd immunity potential of this particular
product or other products, and certainly I would like to see in post-marketing
studies more emphasis on herd immunity protection, which could be significant.
CHAIR
OVERTURF: Are you specifically
suggesting effects on carriage or are you just talking about herd protection?
DR.
STEPHENS: Well, I think carriage is one
part of that. I think certainly
effectiveness does rely also upon potential herd immunity benefits and,
certainly, that should be -- it can be, as we're well-aware with other
bacterial vaccines, an important component of those vaccines.
CHAIR
OVERTURF: Dr. Word?
DR.
WORD: Sorry. I think Dr. Farley brought this up about because of the admission
criteria, eligibility criteria, you had a cohort of individuals who may have
received tetanus. What's going to
happen with them? I guess I'm looking
at the post-marketing studies and I'm not quite sure what they said.
They
said they had some data I think from overseas, but in terms of what are you
going to do for the practitioners? Say
this is approved, then you say well, what do you do with that group of
individuals who just recently received a tetanus, a Td? Do they mean that they can't get this?
So
I don't know if they are going to be able to, you know, bring in a cohort of
people and say we have this safety data or we can say what happens, because I'm
not sure her question was really answered.
I know you say you have it, but then I'm saying well, what's going to
happen here in the U.S.?
CHAIR
OVERTURF: Do you want to respond, Dr.
Farley? No?
DR.
WORD: Well, no, it wasn't really a
question for her. I think it's towards
GSK, because I'm thinking of a practitioner in an office. If they look at a package insert and you go
to market it and you say this is for this age group, but we didn't allow anyone
who had received the vaccine within 10 years, and we say okay, does that mean
that they don't get any protection against pertussis?
CHAIR
OVERTURF: Yes?
DR.
HOWE: What Dr. Friedland had mentioned
was that although the eligibility criterion in the Pivotal Study 001 precluded
use of Td in those who had less than 10 years elapsed since the most recent
DT-containing vaccine, that a number of the studies done outside the U.S. did
allow a five-year interval so, you know, between 5 and 10 years to have
elapsed. So it was not as stringent
criteria outside the U.S. and that the safety data from those studies was
generated under those conditions.
And
then he mentioned that there were a number of individuals who did get enrolled
into, yes, in whom we didn't see any hint of any increased reactogenicity in
terms of serious adverse events or limb swelling.
CHAIR
OVERTURF: Yes, Dr. Hetherington?
DR.
HETHERINGTON: I guess this question
might go to the FDA and it might be too early, but the question is in the
context of that last question, what would the label say? Would it contraindicate this vaccine for
individuals who have had Td within 5 years or 10 years? Would there be just a warning or a
precaution? What is the level of
guidance that is going to be given in the label for the practitioners to answer
Dr. Word's question?
DR.
FINN: The short answer is I don't
know. The longer answer is we will
likely be silent and what we will likely say is that this vaccine is indicated
for use in subjects 11 to whatever age who have completed and reiterate the
inclusion/exclusion criteria that pertain to the majority of subjects, i.e.,
completed a primary series in infancy and early childhood and not say anything
about a Td vaccine. I don't know if we
would make it a contraindication.
CHAIR
OVERTURF: Yes, Dr. Hetherington?
DR.
HETHERINGTON: As a follow-up to that,
do you anticipate any way in which data would be collected on patients who have
received it within some shortened interval?
DR.
FINN: Sorry. I missed that, because I was being --
DR.
HETHERINGTON: Yes, I'm sorry, it
was --
DR.
FINN: Actually, let me add
something. I was just reminded that the
Td package inserts do contain a statement saying that administration of Td
vaccine more frequently is likely to lead to an increase in reactogenicity, and
I'm sure that statement will be in there even though, as currently planned,
this will be a single dose, no repeat immunizations, but we may borrow some
language from Td.
CHAIR
OVERTURF: Dr. Royal?
DR.
ROYAL: What I would like to recommend
is probably beyond what is usually expected with post-marketing studies and
post-licensure studies, but I would like to see some emphasis on more than just
the biologic responses that are associated with institution of a specific
vaccine, and also some information presented related to maybe health policy
changes that go into play in promoting the success of a new therapy or an
immunization approach when we hear the data in the future.
CHAIR
OVERTURF: Dr. Farley?
DR.
FARLEY: A similar interest I have is
for us to try to do some clinical bridging to effectiveness in a clinical
setting, whether with an indirect cohort case control study, but to encourage
some attention to actually showing clinical effectiveness once this is
introduced.
And
I think that brings us to needing better tools to diagnose and an awareness of
how to diagnose and when to look for it and those sorts of things, which go
well beyond what this Committee looks at, but I think are very important.
CHAIR
OVERTURF: Were there any other
comments, discussion? I'm willing to
entertain a motion if somebody was willing to make it regarding a change in the
statement, which we can do, in terms of the language, specifically the word
efficacy. Is there a motion to change
that? Yes?
DR.
FINN: I would like to say that we do
not include the word equivalent in there, because I think I made a point --
ALL: We can't hear you.
DR.
FINN: I'm sorry. I wanted to say that I'd rather that we
didn't include the word equivalent in the language, I think you had mentioned
earlier equivalent effectiveness, because I don't think we can conclude
equivalent effectiveness and I think that point was made during the 1997
VRBPAC, that we can't necessarily conclude equivalent efficacy or
effectiveness, that we should really perhaps change the word we say to support
the effectiveness of Boostrix. That is
a correct -- regulatory-wise, that would be the correct way to phrase it.
CHAIR
OVERTURF: Dr. LaRussa?
DR.
LARUSSA: Can we say immunologic
effectiveness?
DR.
FINN: I think that's already -- FDA has
a guidance document on clinical studies where they talk about effectiveness,
and it's in that they talk about effectiveness and they specifically say that
effectiveness studies are, for example, serologic studies such as we have
described today. So I think it's sort
of redundant. I don't think we
necessarily need that.
CHAIR
OVERTURF: Yes. I think effectiveness has a dual meaning,
too, because we use it in other vaccines that both mean clinical effectiveness
as well as serological effectiveness.
We already accept this, for instance, for influenza vaccines and other
vaccines that we look at, and there are terms of serological equivalency and
non-inferiority that are also, I think, implicit in some of those terminologies
as well.
Dr.
Karron, did you have -- well, then I would ask for someone to make a motion to
change the word efficacy to effectiveness.
DR.
STEPHENS: So moved.
CHAIR
OVERTURF: Is there a second?
DR.
LARUSSA: (Seconds by hand.)
CHAIR
OVERTURF: Dr. LaRussa seconds
that. So I will poll the Committee by
starting at Dr. Karron going around the table and ask for your acceptance of
that motion. The motion has been made
and seconded to change the word efficacy to effectiveness in Question 1.
DR.
KARRON: Yes, I agree with the change.
DR.
STEPHENS: Yes.
DR.
MURPHY: Yes.
CHAIR
OVERTURF: Excuse me. I'm supposed to call your name, I
guess. That was Dr. Stephens. Dr. Murphy?
DR.
MURPHY: Yes.
CHAIR
OVERTURF: Dr. Self?
DR.
SELF: Yes.
CHAIR
OVERTURF: Dr. Word?
DR.
WORD: Yes.
CHAIR
OVERTURF: Dr. LaRussa?
DR.
LARUSSA: Yes.
CHAIR
OVERTURF: I also will vote yes, Dr.
Overturf. Ms. Province?
MS.
PROVINCE: Yes.
CHAIR
OVERTURF: Dr. McInnes?
DR.
MCINNES: Yes.
CHAIR
OVERTURF: Dr. Farley?
DR.
FARLEY: Yes.
CHAIR
OVERTURF: Dr. Royal?
DR.
ROYAL: I vote yes.
CHAIR
OVERTURF: Dr. Hetherington, did you
have any comment from industry?
DR.
HETHERINGTON: No, I agree with the
concept.
CHAIR
OVERTURF: Dr. Markovitz?
DR.
MARKOVITZ: Yes.
CHAIR
OVERTURF: Dr. Wharton?
DR.
WHARTON: Yes.
CHAIR
OVERTURF: Dr. Gellin is abstaining,
because he had to leave for an emergency.
So hopefully, he'll be back for the afternoon voting.
If
there is no further discussion, then we can proceed to answer our opinion on
the first question, which would now read "Are the available data adequate
to support the effectiveness of Boostrix in individuals 10 to 18 years of
age?" And since I started with Dr.
Karron the last time, I'll start with Dr. Wharton?
DR.
WHARTON: The efficacy is
well-established in infants based on available clinical studies and the data
support effectiveness in the age group under question, so yes.
CHAIR
OVERTURF: Dr. Markovitz?
DR.
MARKOVITZ: Yes.
CHAIR
OVERTURF: Dr. Hetherington, again, do
you have any comments from the industry?
DR.
HETHERINGTON: I agree with the overall
votes so far.
CHAIR
OVERTURF: Dr. Royal?
DR.
ROYAL: Again, I vote yes.
CHAIR
OVERTURF: Dr. Farley?
DR.
FARLEY: I vote yes.
CHAIR
OVERTURF: Dr. McInnes?
DR.
MCINNES: I vote yes.
CHAIR
OVERTURF: Ms. Province?
MS.
PROVINCE: I vote yes.
CHAIR
OVERTURF: I also vote yes, Dr.
Overturf. Dr. LaRussa?
DR.
LARUSSA: Yes.
CHAIR
OVERTURF: Dr. Word?
DR.
WORD: Yes.
CHAIR
OVERTURF: Dr. Self?
DR.
SELF: Yes.
CHAIR
OVERTURF: Dr. Murphy?
DR.
MURPHY: Yes.
CHAIR
OVERTURF: Dr. Stephens?
DR.
STEPHENS: Yes.
CHAIR
OVERTURF: Dr. Karron?
DR.
KARRON: Yes.
CHAIR
OVERTURF: The second question is
regarding "Are the available data adequate to support the safety of
Boostrix when administered to individuals 10 to 18 years of age?" And before we proceed with that, we have not
talked too much about safety, but are there any concerns or questions or
discussion that the Committee would like to make at this point?
My
concern will always be the same, is that the numbers always seem quite small
when you start out, particularly as you look at individual groups and
particularly when you look at groups, for instance, in the individuals that may
be closer to their recent immunization and whether the safety would be less
secure in those individuals closer to the five-year interval between their
first five boosters, as opposed to those who were further apart. So obviously, that's one of those areas
that's going to need to be very carefully looked at as we proceed to additional
booster doses.
So
I think we can proceed to the second question and, at this point, I will start
with Dr. Karron and ask whether she is in affirmative or negative. Dr. Karron?
DR.
KARRON: Yes, I think the available data
are adequate to support the safety of Boostrix when administered to individuals
10 to 18 years of age. I would also say
though that I would look forward to post-licensure studies that look at safety
in individuals who are primed with entirely acellular components of vaccine.
CHAIR
OVERTURF: Dr. Stephens?
DR.
STEPHENS: Yes, I agree with and I agree
with her comments as well.
CHAIR
OVERTURF: Dr. Murphy?
DR.
MURPHY: Yes, I agree with both of the
previous voters and, in addition, I think it's very important to look at short
intervals after Td. Yes.
CHAIR
OVERTURF: Dr. Self?
DR.
SELF: I vote yes.
CHAIR
OVERTURF: Dr. Word?
DR.
WORD: I vote yes.
CHAIR
OVERTURF: Dr. LaRussa?
DR.
LARUSSA: Yes.
CHAIR
OVERTURF: I also vote yes, Dr.
Overturf. Ms. Province?
MS.
PROVINCE: I also vote yes and I echo
the concerns and interest expressed regarding the post-licensure surveillance
regarding safety.
CHAIR
OVERTURF: Dr. McInnes?
DR.
MCINNES: I vote yes.
CHAIR
OVERTURF: Dr. Farley?
DR.
FARLEY: I vote yes.
CHAIR
OVERTURF: Dr. Royal?
DR.
ROYAL: I vote yes.
CHAIR
OVERTURF: Dr. Hetherington, comments
from industry?
DR.
HETHERINGTON: I have no additional
comments.
CHAIR
OVERTURF: Dr. Markovitz?
DR.
MARKOVITZ: Yes.
CHAIR
OVERTURF: And Dr. Wharton?
DR.
WHARTON: Yes.
CHAIR
OVERTURF: With that vote, we conclude
the morning's business and we're actually a little bit ahead of time. I'm not sure whether we can move things up
for the afternoon. Can we move them a
little?
UNIDENTIFIED
SPEAKER: Yes, as long as it's not too
far in advance. So if you just want to
have maybe lunch?
CHAIR
OVERTURF: Yes, we can reconvene at 1:00
rather than at 1:40. Thank you very
much.
(Whereupon,
the meeting was recessed at 11:52 a.m. to reconvene at 1:06 p.m. this same
day.)
A-F-T-E-R-N-O-O-N
S-E-S-S-I-O-N
1:06
p.m.
CHAIR
OVERTURF: I would like everybody to
take their seats, please, and we'll get started here very shortly. I would like to invite everybody back to the
Session II, which is going to be the open Committee discussion on the safety
and immunogenicity data per Tdap vaccine manufactured by Aventis Pasteur, Ltd.
or is that sanofi aventis?
UNIDENTIFIED
SPEAKER: Sanofi pasteur.
CHAIR
OVERTURF: Okay. All right.
And the first speaker will be Martha Monser from the FDA.
MS.
MONSER: Okay. Thank you. Good
afternoon. Welcome back from lunch, as
we're slowly trickling back in. As the
Chairperson of the Review Committee for Adacel, I'm just going to provide a
brief introduction which will be followed by presentations from the vaccine's
manufacturer and from the FDA clinical reviewer on the file, Dr. ChrisAnna
Mink.
The
BLA was received from Aventis Pasteur, Ltd. located in Toronto, Ontario on
August 13, 2004 and the proposed indication is for active immunization for the
prevention of diphtheria, tetanus and pertussis in adolescents and adults, aged
11 to 64 years, as a booster. The
vaccine is supplied in a single-dose vial to deliver a .5 mL intramuscular
dose.
This
next slide presents three vaccines manufactured by Aventis, which contain
pertussis antigens and/or tetanus and diphtheria toxoids. Daptacel is indicated as a four dose series
in infants through children 6 years of age and it was licensed for use in the
United States in May 2002. Td for adult
use was licensed in the United States in November 2003. And this vaccine is indicated for primary
and booster immunizations for individuals 7 to 59 years of age.
Of
note, the manufacturing and testing methods for the components in Adacel are
identical to those used for Daptacel and Td.
Adacel, as you can see here, differs from Daptacel in that it contains
reduced amounts of the diphtheria and the pertussis toxoids. The Td vaccine listed here is not the
comparator vaccine for the clinical trials for Adacel used to support U.S.
licensure.
At
the time these clinical studies were conducted, this Td wasn't yet licensed in
the United States. It was, however,
used in some of the earlier Canadian trials that have been submitted to the BLA
as supportive studies.
Now,
I'll just go briefly over the basis for Adacel's licensure, which will probably
be no surprise after we have heard this morning's presentation. For safety, a pivotal study was designed to
demonstrate the non-inferiority of Adacel as compared to a U.S.-licensed Td
vaccine. For the tetanus and
diphtheria, Study Td506 was designed to demonstrate the non-inferiority of the
percentage of subjects attaining seroprotective levels and this was defined as
a level of 0.1 international units for mL and the non-inferiority of the
booster responses, again compared to a U.S.-licensed Td vaccine.
For
the pertussis antigen, studies were designed to demonstrate boosting responses
to each of the antigens and, as recommended previously by VRBPAC, the
non-inferiority of the immune responses following immunization with Adacel and
the immune responses observed in the Sweden I Infant Trial following three
doses of Daptacel was also assessed.
In
addition, there was one study conducted to demonstrate the consistency of
manufacture based on the safety profile and the immunogenicity of three
consecutively produced Adacel lots. And
while not part of the basis for licensure, we will also hear this afternoon
data from two concurrent immunization studies.
Following
the presentations from the manufacturer and from the FDA, you're going to be
asked to vote on two questions. And I
have changed the first one as the vote was made this morning to be "Are
the available data adequate to support the effectiveness of Adacel in
individuals 11 to 64 years of age?"
And then secondly, "Are the available data adequate to support the
safety of Adacel?" And finally for
discussion, we would like you to identify any issues which should be addressed,
including post-licensure studies.
If
there are any questions, I'll entertain them, but if not, we'll turn the podium
over to Aventis.
CHAIR
OVERTURF: Are there any questions from
the Committee for the FDA, at this point?
Okay. We'll turn the meeting
over to Aventis.
MS.
MONSER: Okay.
DR.
KUYKENS: Thank you, Martha. Mr. Chairman, Member of the Advisory
Committee, ladies and gentlemen, good afternoon. I'm Luc Kuykens, Vice President of Regulatory Affairs for sanofi
pasteur. Sanofi pasteur is pleased
today to have the opportunity to present Adacel, our adolescent and adult
tetanus, diphtheria and acellular pertussis combination vaccine.
Following
this introduction, Dr. Johnson will review the epidemiology of pertussis
disease and its importance in adolescents and adults. Dr. Decker will review the immunogenicity data of our application
and I will review the safety profile.
Why
pertussis vaccination for adolescents and adults? Pertussis causes significant morbidity in adolescents and adults
and not only in children. Pertussis
vaccination in adolescents and adults has the potential to reduce pertussis
disease and has a consequence transmission from adolescents and adults to young
infants. Adacel was designed with these
public health needs in mind.
The
composition of Adacel reflects the current U.S. standards of care, adult Td
vaccine manufactured by sanofi pasteur, U.S., and our licensed pediatric DTaP
vaccine Daptacel. Adacel contains
tetanus toxoid and diphtheria toxoid at a dose of 5 and 2 LF, respectively, and
this is the same dose as our Td vaccine.
In addition, Adacel contains sanofi pasteur's five component acellular
pertussis vaccine. Pertussis toxoid, filamentous
hemagglutinin, pertactin and fimbriae Types 2 and 3.
The
dose of these pertussis vaccine components are the same as for Daptacel, except
for pertussis toxoid which is reduced to 2.5 micrograms per dose in order to
achieve the right balance between immunogenicity and safety in the target
populations of adolescents in adults.
Sanofi pasteur's five component acellular pertussis vaccine is unique,
in that it contains both pertactin and fimbriae 2 and 3.
The
importance of these components was established in the Household Contact Study
nested in the Sweden I Pertussis Efficacy Trial. Efficacy correlated with having high pertactin and fimbriae
antibody titers. This finding was
confirmed in two additional Household Contact Studies. All components of Adacel are licensed in the
U.S. in Daptacel and Td vaccine. Adacel
is manufactured in the same facilities as those vaccine.
The
objective of the Adacel Clinical Development Program was to demonstrate
non-inferiority to the standard of care Td vaccine for safety and
immunogenicity for tetanus and diphtheria and through the Sweden I Efficacy
Trial for pertussis, which has shown 85 percent efficacy. In addition, we started concomitant
administration of Adacel with hepatitis B or influenza vaccines. The indication requested for active
immunization against diptheria, tetanus and pertussis in adolescents and adults
ages 11 to 64 years.
The
clinical experience gained with Adacel in the U.S. and Canada in U.S. and
Canadian trials include more than 3,000 adults and 3,700 adolescents. In addition, more than 6 million doses of
Adacel or Adacel combined with IPV have been distributed since 1999 in Canada
and Europe. In the U.S., Canada and
Europe, the Adacel formulation is exactly the same. The results of these clinical trials demonstrate that Adacel was
safe and well-tolerated and achieved the safety profile similar to that of Td
vaccine.
All
pre-specified immunogenicity criteria for non-inferiority to Td vaccine were
met. And antibody titer against pertussis
were substantially higher than those seen in infants in the Sweden I Efficacy
Trial. Adacel can be given either
separately or simultaneously with hepatitis B or influenza vaccines.
At
this point, I would like to invite Dr. Johnson to review the epidemiology of
pertussis in adolescents and adults.
DR.
JOHNSON: Thank you, Luc. Good afternoon. As was discussed this morning, routine use of pertussis vaccine
in children, which began in the 1940s, was associated with a substantial
decline in reported cases over the subsequent decades with a nadir of about
1,000 case reports in 1976. The
increase in pertussis reports beginning in about 1980 has become much more
dramatic over the last several years.
Possible reasons for this increase include better awareness of pertussis
on the part of practitioners, better diagnostic test, increased reporting and a
true increase in disease incidence.
Not
only have the overall case counts increased, but the age distribution of cases
has shifted. In the early 1990s, most
of the reported pertussis cases were in infants and young children. Over the last 14 years, there has been a
5-fold increase in pertussis among adolescents and adults. Note that pertussis is widely
under-reported, so that the figures you see on this slide are really just the
tip of the iceberg.
One
study estimated the annual incidence of pertussis to be approximately 500 per
hundred thousand population or over 1 million cases yearly in the U.S., with
the majority of these in adolescents and adults. Multiple studies over the last 20 years indicate that pertussis is
much more common than its case reports imply.
Depending on several factors, including the diagnostic tests and the
case definitions used, these studies found that anywhere from 12 to 52 percent
of adolescents and adults with prolonged cough were actually suffering from
pertussis.
Even
if the most accurate of these estimates is the lowest, 12 percent, that
translates into a great deal of pertussis among adolescents and adults. Special follow-up with adolescents and
adults who contracted pertussis in Quebec during 1998 revealed that morbidity
is substantial in these age groups.
Extended cough, paroxysms, whooping, post-tussive emesis, missed school
and work, disrupted sleep.
Complications of pertussis are also common in adolescents and adults,
between 16 and 28 percent. These
complications range from inguinal hernias to rib fractures, otitis media to
urinary incontinence. But the more
severe complications include cyanosis, pneumonia and hospitalization.
Even
more devastating than complications in adolescents and adults are
hospitalizations and mortality in infants.
Fatal cases of pertussis in infants too young to have been fully
vaccinated nearly doubled from the 1980s to the 1990s. Data from the last four years show an even
greater increase. If that increase
continues, we will witness during this decade yet another doubling of pertussis
deaths among infants under four months of age.
Now,
the increases we are seeing in rates of pertussis among adolescents and adults
are not unrelated to increasing death rates in infants. In a 2004 article, CDC and State Health
Department investigators reported on their efforts to document the source for
774 infant pertussis cases. Of the 264
infants for whom a source could be identified, 75 percent got pertussis from
family members, mostly from adult family members.
Sources
for the other 25 percent included neighbors, friends and daycare attendees or
workers. The source patients for these
infant pertussis cases were of all ages, but the clear majority were
adolescents, 20 percent, and adults 56 percent. Unfortunately, even health care professionals are implicated in
the transmission of pertussis, as demonstrated by studies spanning nearly a
century.
Adacel
vaccine is already playing a role in controlling pertussis. In Canada, Adacel was licensed in May of
1999. Thereafter, the National Advisory
Committee on Immunizations or NACI published a statement on Adacel noting that
it could be used to replace the adolescent or adult Td booster, but at that
time did not issue a recommendation for universal routine use. Nonetheless, three provinces or territories
launched programs using the newly available vaccine.
Reports
concerning their experience with Adacel are available from two of these, the
Northwest Territories and Newfoundland.
Investigators in the Northwest Territories found that for each year,
1993 through 1996, there were on average 11.4 pertussis cases per 10,000
population, mostly in young children.
After a switch from whole cell to acellular pertussis vaccine,
specifically Pentacel, a five pertussis component combination vaccine, for
infants and toddlers in 1997, the incidents of pertussis decreased to 7.9 cases
per 10,000 per year and shifted to older children and adolescents.
Their
Adacel Vaccination Program there began in 2001. Following that, the yearly average pertussis incidents dropped to
only 2.1 pertussis cases per 10,000 population. And the pertussis incidence rate was further decreased to just
0.2 cases in 10,000 population in both 2003 and 2004. Only one teenager there contracted pertussis during the last four
years. A 14 year-old who had not yet
received Adacel.
Newfoundland
provides yet another example of rapid population effects associated with Adacel
vaccination. Adacel replaced Td in
Adolescents Immunization Programs beginning with the 1999 school year. The vaccine was and continues to be
administered to students in grade 9, generally 14 year-olds, through school-based
programs. As of last summer,
approximately, 25,000 Adacel doses had been given in this province.
The
Newfoundland incident rates of pertussis paralleled the overall Canadian
rates. Note that the nationwide
pertussis increases of the mid-1990s also hit Newfoundland. After beginning its Adacel Vaccination
Program, Newfoundland had very little pertussis, except for a 2003 outbreak,
mostly among young adolescents, but no one involved in this outbreak had yet
received Adacel. In fact, since the
initiation of the Adacel Program, no pertussis disease has been documented in
any of those who have received this vaccine.
Following
a National Consensus Conference on Pertussis, NACI updated its statement on
adolescent/adult Tdap vaccine in a September 2003 publication strongly
recommending that a single booster be administered to adolescents and adults in
place of Td vaccine to protect against pertussis. All remaining provinces and territories launched an Adacel
Adolescent Program for ninth graders in 2003 or 2004.
Prince
Edward Island last fall offered Adacel to all children grades 3 through 12,
except those in grade 10, who had received it the previous year. This ambitious program was carried out in
the context of a study to determine a safe dosing interval for Adacel. A study overseen by Dr. Scott Halperin, and
that study looked at intervals as short as 18 months.
Quebec
took a broader approach last September by launching an Adolescent and Adult
Adacel Program with a particular focus on vaccinating close contacts of young
infants, the so-called "cocoon strategy" in which a protective
immunization barrier around infants is established.
In
this country, reports of pertussis continue to increase dramatically. Pertussis is common in adolescents and
adults causing significant morbidity and complications. Adolescents and adults are important sources
of pertussis transmission to vulnerable infants in whom mortality is
increasing. And from Canada, ongoing
epidemiological surveillance data demonstrate the potential for Adacel to
control pertussis.
Now,
Dr. Michael Decker will discuss the immunogenicity findings of the Adacel
Development Program.
DR.
DECKER: Thank you, David. Good afternoon. In support of the licensure of Adacel, we provided to FDA data
from seven clinical trials. The first
four of these show in this slide are the core clinical trials conducted in
support of U.S. licensure. In addition,
we submitted to the BLA safety data from the three trials at the bottom of the
slide, which were the trials conducted in Canada with the licensure of Adacel
originally in Canada. In total, these
studies encompass 6,884 Adacel recipients.
There
were 7,206 vaccinees evaluated for the safety objectives, about three-quarters
of whom received Adacel and the remainder Td.
And there were 4,342 in the immunogenicity cohorts, and again about
three-quarter of those received Adacel and the remainder Td.
This
slide shows the demographic distribution of the participants in the core
comparative trials, Td505 and Td506.
The general distribution was, approximately, 50/50, male to female
during their adolescence, about 2 to 1 female to male among the adults, in each
case reflecting the distribution of the persons who came to seek care in the
clinics conducting the studies. For
both adolescents and adults, 85 to 86 percent of the participants were
caucasian and the rest were a variety of non-caucasian groups.
Now,
in order to evaluate immunogenicity, there is a number of endpoints that we can
look at. I'm going to show you these
four different endpoints. We can look
at seroprotection rates, which are the proportion of the participants who
achieve some benchmark, for example a protective titer, and that's a primary
outcome measure in all of the core clinical trials. We can look at booster response rates, which are the percent of
participants who achieve some defined increase in titer stratified by what
their pre-titer was, as you heard discussed earlier today, and that's a primary
outcome measure in one core clinical trial.
I'll
show you geometric mean titers the normalized average of the post-immunization
titers and that is the primary outcome measure for the pertussis antibody
responses. It's descriptive if they are
in tetanus. And finally, I'll show you
some reverse cumulative distribution curves which provide a graphical
representation of the antibody distribution in the entire evaluated population
and these are, of course, descriptive.
In
order to evaluate the non-inferiority comparisons, there are two endpoints that
are used. For the seroprotection and
booster rate evaluations, the endpoint is the difference in rates between the
two groups with a 10 percent non-inferiority margin and for the GMTs it's the
ratio in the two groups of GMTs at a 1.5 margin. Adacel's link to efficacy, as you heard, is by bridging the Td506
Study results to the Sweden I Efficacy Trial.
Sweden
I was an NIH-sponsored randomized placebo and whole cell controlled prospective
double- blinded study that was conducted in Sweden from 1992 to 1995. It evaluated two candidate acellular
pertussis vaccines, one whole cell vaccine, then currently in widespread use in
the United States, and a DT control group.
Daptacel was one of the acellular vaccines evaluated. Infants received three doses of Daptacel at
2, 4 and 6 months of age.
They
were then followed for up to two years to determine the efficacy of the three
dose Daptacel regiment and it was shown to be 85 percent against WHO-defined or
classic pertussis. It was also shown to
be 78 percent efficacy against a very broad case definition that included any
laboratory confirmed pertussis with any duration of cough whatsoever.
The
pertussis immunogenicity results following one dose of Adacel in the U.S.
Pivotal Trial Td506 were compared to those following the three doses of
Daptacel in the Sweden I Efficacy Trial.
Sera from the Adacel recipients and stored sera from Sweden I were
reanalyzed contemporaneously in the same lab under the same conditions and
using the same validated assay.
Now,
I'll just skip over the next two slides, because the rationale for a serologic
bridge was really thoroughly covered this morning, and let's go straight to the
immunogenicity results. We'll start
with Study Td506, which is the pivotal comparative trial between Adacel and Td
Study conducted in both adolescents and adults at 39 U.S. sites and involving
4,461 vaccinees.
Enrollees
were stratified into five equal-sized age strata to ensure adequate evaluation
in each of the age groups, young adolescents, older adolescents, young adults,
mid-aged adults and older adults. I'm
going to show you several slides that look like this. What we have here, this is diphtheria. This slide shows diphtheria results. The Adacel recipients are in the blue tone. The Td recipients are in the browner tan
tone. We've got diphtheria pre-titers,
diphtheria post-titers seroprotection and diphtheria booster response rates.
What
you see here is whether we're talking about pre-titers, post-titers or
seroresponse rates, the results are essentially identical between Adacel and
Td. Now, drop out of this slide, the
results for the adults. And comparing
again the blue versus the brownish or orangeish tones here, pre-titers,
post-titers and booster response rates are again essentially identical between
the two groups. So not surprisingly,
all non-inferiority criteria were met.
Those
are the diphtheria results. Here are
the analogous results for tetanus. And
you see again very, very comparable results within each age strata across the
three measures, all non-inferiority criteria were met.
Now,
this slide displays the pertussis responses.
These are GMTs, but the slide is organized a little bit
differently. Again, the colors are
consistent. This is Adacel. This is Td.
FIM is set on a separate scale here, because the FIM antibody responses
are so very much higher than the other antigens. Not surprisingly, you have much higher pertussis antibody
responses from a vaccine that contains pertussis antigens than from one that
doesn't.
So
what's really interesting is the drop on this slide, the results from Sweden
I. Three doses of Daptacel given to
infants in Sweden I produced antibody levels for each of the antigens that
provided 85 percent protection to those infants, but Adacel produced antibody
levels dramatically higher in these adolescents and in the adults. And therefore, of course, the
non-inferiority criteria were met.
So
from Td506, we conclude that Adacel vaccine is non-inferiority to Td vaccine
for diphtheria and tetanus immune responses.
It is highly immunogenic with respect to pertussis responses and is
non-inferior to Sweden I, with respect to those pertussis responses.
Now,
I would like to turn to turn to Study Td505, which is a lot consistency trial,
conducted in 1,806 adolescents at 18 sites across the United States. The point was to compare three sequentially
manufactured lots of Adacel for consistency of immune response. So here we see clusters of three bars rather
than clusters of two or four bars. This
slide shows you the diphtheria pre and post and the tetanus pre and post
seroprotection rates. And you'll see
very, very similar responses for the three lots, equivalency criteria were met.
Here
the pertussis GMT's post-vaccination and you see again very similar responses
across the four antigens. Now, there is
some difference for one lot with FIM.
It's a little bit lower and non-inferiority was marginal for that
one. You've seen a slide like this
before. I won't explain it. All of the point estimates are in the
success range, but the upper 90 percent confidence limit for one comparison
slightly encroaches on the inferiority range.
So
it is useful with this in mind to look at a reverse cumulative distribution
curve. And you saw some of these this
morning, but let me just remind you that on the Y axis you have a rate, the
percentage of the population that achieved some given response. On the X axis, the response, and so it
starts at 100 percent, because everybody has at least nothing and goes out to
higher and higher levels until you get to levels beyond that which anyone
achieves.
These
are the pre-immunization curves for the three lots. These are the post-immunization curves for the three lots and lot
3, this slide looks at FIM and lot 3 here you see is a little differential,
both from the other two predominately in this range which shows the very
highest antibody levels more than 5,000, it looks like from this angle. So from this curve, I infer that the basis
for the difference in the GMCs for the FIM lots is primarily due to a slightly
smaller number of people with this one lot who developed the very highest
antibody levels. But they don't really
appear to differ much at all in the range of antibody that's similar to that
scene in Sweden I, and so therefore we don't believe that this difference is of
any clinical importance.
So
Td505 demonstrated equivalency for diphtheria seroprotection and booster
response rates and GMTs. For tetanus
seroprotection and booster response rates and GMTs. And for pertussis PT, FHA, pertactin and for two of the three
lots FIM GMTs, but one lot was borderline.
Now,
I want to turn to a couple of studies that evaluated the concomitant
administration of Adacel with another vaccine.
First, we'll look at concomitant administration of Adacel in hepatitis B
vaccine amongst 400 adolescents, half of whom received the two vaccines
simultaneously and the other half received them a month apart. And the objective is to demonstrate the
concomitant administration is not inferior with respect to immunogenicity as
compared to the separate administration.
So
what we have here, the paired bars, are the concomitant in blue or simultaneous
versus the sequential, a month apart, in white. Diphtheria pres, diptheria post, diphtheria boosters look
essentially identical between the two groups, all non-inferiority criteria were
met. Here are the analogous data for
tetanus and although there was a little bit of difference in the pres, the
posts and the booster response look identical.
Here
are the hepatitis B seroprotection response rates. This is measured against the criterion of 10 international units
per mL which is generally accepted as indicative of protection from hepatitis
B. What you see here again is virtually
identical results between simultaneous and sequential administration. Again, all non-inferiority criteria were
met.
And
finally, to the pertussis GMTs, whether given simultaneously or sequentially,
Adacel produced essentially equivalent immune responses to PT, FHA, pertactin
and FIM. So from this study, we
conclude that Adacel may be administered concomitantly with hepatitis B vaccine
and the simultaneous and sequential vaccination result in the comparable immune
responses for diphtheria, tetanus, pertussis and hepatitis B.
So
let's turn now to another study that evaluated concomitant administration of
Adacel and Fluzone influenza vaccine in adults. This study was conducted in almost 700 adults and the rest of the
study designed or was the same as what you just heard for Td501, so let's look
at the results.
For
diphtheria again, pres, posts, booster response rates are essentially
identical. For tetanus, the pres, and
especially the posts, are essentially identical. There is a little bit of a difference in the tetanus booster
response rates. However, we don't
believe that that's of any importance, because in terms of seroprotection, both
groups are clearly equally protected.
For
the Fluzone, the influenza, seroresponse rates for the three strains included
in that year's vaccine, again, you see that the pres and the posts are highly
comparable between simultaneous and sequential administration.
We
see something a little bit different now when we turn to the pertussis
GMTs. There is a systematically
somewhat lower GMT for the simultaneous as compared to the sequential
administration. Now, point of fact,
this difference did not fail non-inferiority for three of the four
antigens. It did for one of the
antigens. It's very important then to
see how the simultaneous administration compares to the Sweden I trial.
What
you see is that even for those receiving simultaneous influenza vaccine and
Adacel, the antibody levels very much exceed those shown to be 85 percent
protective in Sweden I. So from these
results we conclude that simultaneous and sequential vaccination resulted in
comparable immune responses for diphtheria, tetanus and influenza. Pertussis responses were somewhat reduced
with concomitant flu vaccine, but nonetheless markedly exceeded those from
Sweden I and therefore Adacel can be administered concomitantly with influenza
vaccine.
Now,
I would like to show you several more reverse cumulative distribution curves
which provide an overview of all of our clinical trial results and compare
those results to the Sweden I benchmark results. On each of the succeeding slides, the Sweden I results are the
heavy black line which always lies to the left. And the results for various study cohorts from Adacel are shown
in variously colored lines always to the right.
The
first four slides will show you results for adolescents PT, FHA, pertactin and
FIM. The results are always shifted to
the right showing superior pattern of antibody responses in the Adacel receiving populations. And similarly, results for adults PT, FHA,
pertactin and FIM.
Now,
as I mentioned, there were data submitted to the BLA in support of the safety
objective from the Canadian licensure trials and you'll hear about those safety
data a little bit later. In addition,
subset populations from the Canadian licensure trials have been followed ever
since those trials were conducted in order to determine the long-term
immunogenicity of Adacel. We have data
currently from follow-up at 1, 3 and 5 years and we'll have 8 year data next
year. We can show you the data we have,
if you would like, later during the discussion period.
So
the key immunogenicity findings for Adacel was that Adacel stimulated robust
antibody responses to all the included antigens. It achieved all pre-specified non-inferiority criteria for
immunogenicity versus Td. Pertussis
antibody levels in adolescents and adults following a one dose of Adacel
exceeded substantially levels that were seen in infants following three doses
of Daptacel and Adacel can be given concomitantly with hepatitis B vaccine or
influenza vaccine.
At
this point, I would like to ask Dr. Kuykens to come back up to provide the
safety data and our conclusions.
DR.
KUYKENS: Thank you, Michael. Safety results from these studies showed
that Adacel safety profile is similar to that of Td vaccine. The key objectives of our safety assessment
were to compare the safety profile of Adacel to that of Td vaccine. More specifically, to demonstrate that the
rates of selected local and systemic reactions, namely, erythema, pain,
swelling and fever were similar between the two vaccines. And secondly, to characterize the overall
safety profile of Adacel given separately or simultaneously with hepatitis B or
influenza vaccines.
By
every measure, the safety profile of Adacel was comparable to that of Td
vaccine. Immediate reactions were
collected for 30 minutes post-vaccinations.
The overall rates of immediate reactions were similar between Adacel and
Td vaccines. 0.55 percent of Adacel
recipients and 0.44 percent of Td recipients experienced at least one immediate
reaction. Rates were similar for most
reported events. There were no
anaphylactic reactions reported and no reaction was classified as a serious
adverse event. All these resolved
without sequelae.
Solicited
local reactions were collected daily on a diary card from day zero to 14 after
vaccination. The preestablished list of
reactions contained erythema, injection site swelling, pain, underarm lymph
node swelling and limb circumference.
Information on the severity of each of these reactions was collected
daily and this allowed us to determine the overall duration of an event, but
also the duration of the most intense portion of the event.
The
safety comparison objective for local reactions in Pivotal Trial Td506 was to
demonstrate that Adacel is not inferior to Td vaccine with regard to the
proportion of participants reporting any or moderate and severe erythema,
swelling or pain. The criteria for
non-inferiority was based on the upper limits of the 95 percent confidence
interval of the difference in the percentage of participants with the reaction
mentioned being less than 10 percent.
Event
rates for erythema and swelling in other lessons were similar after Adacel and
Td vaccination. We observed a slight
increase in any pain, 78 percent of adolescents experienced any pain after
Adacel versus 71 percent of Td recipients.
The large majority of pain was mild or moderate and the mean duration in
both Adacel and Td Study Groups was two days for any pain and 1.2 days for
severe pain. The non-inferiority
criteria of Adacel versus Td for adolescents were met in all cases, except for
any pain as just mentioned.
In
adults, the rates of local reactions were slightly lower than in adolescents. Rates for erythema, swelling and pain were
all similar between Adacel and Td vaccine recipients. All non-inferiority criteria for Adacel versus Td vaccine for
erythema, swelling and pain in adults were met.
Now,
in addition to Pivotal Study Td506, we compared rates of local reaction zero to
14 days after Adacel vaccination to those seen in the other three U.S.
licensure trials. For erythema in
adolescents the results were similar across all trials. Pivotal Trial Td506 is on the left of the
slide and the rates observed after Adacel vaccination and the other adolescent
trials, Td505 and Td501, are comparable.
The
rates of swelling were also similar across studies, as were the rates of
pain. Looking into the adult rates, the
rates of erythema were slightly lower in the Adacel arms in the Td502, the
study that looked at Adacel plus Fluzone compared to Td506. This can also be seen for swelling
regardless whether flu vaccine was given simultaneously or separately from
Adacel.
Rates
of pain are similar in both studies again and in all study groups. Most reports of pain were characterized by
the participants as mild. In addition
to the preselected reactogenicity endpoints, erythema, swelling and pain used
in the non-inferiority comparisons, we also collected the information on limb
circumference and underarm lymph node swelling.
For
limb circumference, a baseline measurement of the circumference of the limb
where Adacel was to be administered was performed in all subjects. Limb circumference was measured and recorded
by the participant every day for 14 days after vaccination. The mean baseline limb circumference was
26.4 centimeter in adolescents and 31.7 in adults, respectively. And the difference between Adacel and Td in
mean changes in limb circumference in Study Td506 was 1 millimeter in
adolescents and 2 millimeter in adults.
Looking
into more detail into these results in the Pivotal Study Td506, we know that
there's little difference in limb circumference after vaccination in
adolescents between Adacel and Td vaccine.
And similarly, little difference in limb circumference was seen between
the Adacel and Td Study Groups in adults.
For
underarm lymph node swelling, in Study Td506, rates between Adacel and Td were
similar with slightly higher in adults.
Rates after Adacel vaccination in the other studies were comparable to
those seen in the pivotal study.
Similar to solicited local reactions, solicited systemic reactions were
collected on a diary card daily from day zero to 14 after vaccination. The preestablished list of reactions contain
fever, headache, tiredness, body ache, chills, nausea, vomiting, diarrhea, sore
or swollen joints and rash.
Information
on severity of these reactions was collected daily. The safety comparison objective for systemic reactions in Pivotal
Trial Td506 was to demonstrate that Adacel was non-inferior to Td vaccine with
regard to the proportion of participants reporting any or moderate and severe
fever. Fever rates in Pivotal Study
Td506 were 5 percent in adolescents after Adacel administration compared to 2.7
percent for Td, but similar between the two groups in adults at 1.4 and 1.1
percent, respectively.
Non-inferiority
criteria were passed for any as well as moderate and severe fever in both
adolescents and adults. However, given
the very low observed rates of fever, we fully evaluated the difference in
fever rates and the lessons between the two study groups in terms of relative
risk showing a ratio of 1.8 with 95 percent confidence intervals of 1.1 and
3. Most of these fevers were mild in
severity and occurred within one day of vaccination. The average duration of fever in both adolescent and adult groups
was similar between Adacel and Td vaccine groups. 1.2 days for adolescents and 1.3 days for adults.
Fever
rates in the other adolescent studies after Adacel administration were similar
to those seen in the Td506 Pivotal Trial.
Most fevers were mild and short in duration on average lasting one day. In adults, a slightly higher fever rate was
seen when flu vaccine was given simultaneously with Adacel compared to Adacel
given alone as could be expected. Most
fevers were mild or moderate and the mean duration of fever was again one day.
The
rates of all other solicited systemic reactions were very similar between
Adacel and Td groups in adolescents.
Overall rates for any solicited systemic reactions were 65.5 percent
versus 61 percent, respectively. No
differences between groups were noted for any of the list of solicited systemic
reactions.
In
adults, the rates for any solicited systemic reaction were similar, 50.3
percent versus 47.6 percent and no differences between groups were noted for
any of the solicited systemic reactions.
Unsolicited adverse events were collected from day zero to 14 after
vaccination and through the end of the study for those events requiring a
medical contact. Overall rates were
similar between the Adacel and Td vaccine groups. Rates in adolescents for any unsolicited event were 24 percent
for Adacel and 25.6 percent for Td vaccine.
When
we further analyzed the rates of any unsolicited AEs that occurred in more than
1 percent of participants, we know that these are very similar between Adacel
and the Td vaccine group. Rates for any
unsolicited event in adults were 24.6 percent for Adacel, 20.9 percent for Td
vaccine. Rates of unsolicited AEs that
occurred in more than 1 percent of participants are again similar between
Adacel and Td vaccine groups.
As
part of the Adacel Clinical Development Program, we decided to look further
into events of special interest, specifically, whole arm swelling, new-onset of
diabetes mellitus, seizures and other immune disorders. There were two reports of new-onset diabetes
mellitus within 30 days of Adacel vaccination.
One diagnosis was made 23 days post-vaccination, an 11 year-old boy with
a family history of insulin-dependent diabetes mellitus.
A
second report was in a 56 year-old man who was hospitalized for an accidental
injury, 13 days after vaccination.
During that hospitalization, he was incidentally diagnosed with
non-insulin-dependent diabetes mellitus.
Three cases of seizures were reported during the Clinical Development
Program. Two in adolescents, one each
after Adacel vaccination and Td vaccination, both occurred more than four
months after vaccination. Both
participants had a medical history of seizure disorder.
The
third case occurred in a 51 year-old female with a history of migraines and
hypertension 22 days after Adacel vaccination.
All these events resolved without sequelae, all were classified by the
investigators as not related to vaccination.
There were no reports of autoimmune disease. No cases of whole arm swelling was spontaneously reported in the
four U.S. licensure trials.
We
also investigated any other plausible indication of whole arm swelling by
analyzing injection site swelling of more than 100 and 150 millimeters. No correlation was seen with increased limb
circumference. Serious adverse events
were collected throughout the study period up to six months after vaccination
for both studies Td506 and Td501. The
overall rate of participants reporting serious adverse events were similar
between Adacel and Td vaccine, 0.89 and 1.39 percent, respectively.
All
SAEs except two were reported by the investigator as unrelated to
vaccination. The first of these two was
a case of migraine and unilateral facial palsy in a hypertensive 23 year-old
female with a family history of Bell's palsy.
The event lasted three days and the participant recovered completely
without sequelae. The second event was
a case of radicular pain in the left upper arm which occurred 12 days after
vaccination in a severely obese 49 year-old female and the participant made the
full recovery as well.
During
the Adacel Clinical Development Program, there was one death reported across
the four U.S. licensure trials. This
was a case of suicide 70 days after vaccination in a 15 year-old female
participant.
Adacel
meets the need to reduce pertussis disease and morbidity in adolescents and
adults. Adacel was safe and
well-tolerated among adolescents and adults and achieved all safety
non-inferiority endpoints in the primary comparative trial versus Td vaccine
except for any pain in adolescents with rates of 78 percent in Adacel versus 71
percent in Td vaccine recipients. We
also saw a slight increase in any fever rates in adolescents.
Adacel
can be given either simultaneously or separately from hepatitis B or influenza
vaccine. Adacel achieved all
pre-specified non-inferiority criteria for immunogenicity versus Td vaccine and
generated pertussis antibody titers in adolescents and adults well above levels
seen in infants following three doses of Daptacel in the Sweden I Efficacy
Trial. Adacel can be given
concomitantly with hepatitis B or influenza vaccine.
The
result of the risk/benefit analysis for Adacel are positive. The increased risk of reactogenicity with
Adacel compared to Td in adolescents for mild pain and mild fever is outweighed
by the benefits of maintaining similar diphtheria and tetanus immunogenicity as occurred in standard of care Td
vaccine. Adacel offers the added
protection against pertussis and has the potential to reduce pertussis disease
in the general population and the transmission of pertussis from adolescents
and adults to the most vulnerable young infants.
This
concludes the presentation of the sponsor and we will be happy to answer any
questions from the Committee.
CHAIR
OVERTURF: The presentation by Aventis
is now open for discussion and comment.
So I'll ask Committee Members if there are any questions or comments
regarding the presentation. Dr. Karron?
DR.
KARRON: Yes, I have two questions. The first is that I wanted to comment that
it's very helpful to have the data unconcomitant administration of Adacel with
influenza and hepatitis B vaccine. I
was wondering if you have any data yet or you anticipate any data unconcomitant
administration with Menactra?
DR.
DECKER: That study was launched
essentially as soon as Menactra was licensed.
DR.
KARRON: Okay. And the second question I had had to do with adverse events. You said, I think, on slides 107 and 108
that in the U.S. Efficacy Studies, there were no reports of whole arm swelling
or autoimmune disorders. Were there
reports of those events in other efficacy trials not conducted in the U.S. and
do you want to comment?
DR.
KUYKENS: Yes. So we can look at two sets of data. We have the three Canadian trials that were mentioned by Dr.
Decker. In those Canadian trials, there
were no reports of autoimmune disorder, either. There were three reports of whole arm swelling. Those events, slide one, were two in Adacel,
the number of recipients of Adacel was 449 and the total in that study, one in
Td. They were all in females between 23
and 32 years of age. The latency was
zero, so basically the whole arm swelling occurred immediately, lasted for two
to three days and in two of the three cases no action was taken, and in one
case the person took ibuprofin over-the-counter.
In
addition, I think, we can comment on the post-marketing surveillance because we
have now used more than 800,000 doses of Adacel, mainly in Canada, and more
than 5 million doses of Adacel combined IPV in Europe and there has been no
reports of whole arm swelling from any post-marketing surveillance.
CHAIR
OVERTURF: Dr. Word?
DR.
WORD: Oh, hi, I think it was in Dr.
Johnson's initial presentation, now, the question I had before, I don't recall
you having a limit in terms of when you could have received a prior tetanus and
I think you alluded to the fact that you had some data that people had gotten
that is as close as 18 months before.
Could you just expound on that?
Because that was one of the questions earlier how close, particularly
for practitioners.
DR.
DECKER: Yes, in fact, although it was
not submitted to the BLA, a study was just completed by our Canadian colleagues
led by Dr. Scott Halperin, whom I would like to ask to come to the podium right
now, to investigate this question precisely and he'll tell you about the
results of the study.
DR.
HALPERIN: Can I have the slide on,
please? Yes, we did a study which was a
study on the Province of Prince Edward Island where we immunized the entire
cohort from grade 3 to 12, except for the cohort who had received Adacel the
previous year. Next slide.
And
our question was what is a safe interval?
From the pre-licensure trials in Canada, one of the exclusion criteria
had been that one couldn't enter the trial if they had received a dose of
Adacel or a Td containing vaccine within the previous five years. But we knew that most severe adverse events
from the literature, such as Arthus reactions, really occur after multiple
injections within a very short time period.
In
Canada we had concerns that we needed to do catch-up, we had it similar in the
U.S., high rates of pertussis in adolescents and adults and we would need to do
catch-up, which would be shorter intervals than five years. Next slide.
So
the objective of this study was a comparison of the reactogenicity of Adacel
after intervals of 2 to 9 years compared to 10 or more years since a previous
Td or adult formulation Td containing vaccine.
Next slide.
This
was an open-label non-randomized Phase III/IV province-wide study in the
Province of Prince Edward Island. A
single dose of Adacel was given to all participants and adverse events were
collected via diary or a web entry system and diaries were collected for day
zero to 3, days 4 to 14 and days 15 to 28 after immunization. Next slide.
These
cohorts are the years since the last Td for Td containing vaccines. You have cohorts at two years, three years,
four years up to the control of 10 years.
And we define two years as being from 18 months to two and a half years,
three years being from two and a half to three and a half, etcetera. Whereas, the 10 year control was from nine
and a half years and beyond. These were
the appropriate grades, so the two year interval was grade 11, three year grade
12 and then the four year interval was grade 3 after receiving their preschool
immunization.
The
nominal ages of those cohorts are estimated to be here. And here is the prior vaccine history. The prior vaccine history varies by the
cohort, so that the two and three year cohorts were the high school adolescents
and they would have received five doses of whole cell DTP back when they were
up to the preschool. And then they
would have received a single dose of the adult formulation PD two or three
years before.
The
other intervals coming down beyond that would have received a mixture of the
whole cell vaccine and acellular vaccine and as they got towards -- the 10 year
control would have been back up to just the whole cell alone. Next slide.
This
is the demographics of these, again, cohorts, and as you can see, the total
eligible in Prince Edward Island, the cohort is, approximately, 2,000 per birth
cohort and the number immunized range from about 25 percent to as high as 50
percent of the eligible cohort.
And
the diaries that were returned where we do have safety data ranges from about
74 percent in the oldest groups up to as high as 90, in the low 90 percents, in
some of the younger groups. The mean
ages are listed there and they approximate what we would have expected based on
their school age, and slightly over 50 percent were females. Next slide.
These
are the data. Looking first at any
erythema. What you can see is compared
to the 10-year interval, their only difference is, and what our hypothesis was
is we were using a non-inferiority from the 10 year age group with 10 percent
for the injection site reactions and 5 percent for fever.
And
what you can see is there were four cohorts that did not meet the
non-inferiority criterion and those were all five cohorts who had received the
Tdap vaccine at preschool. Those who
were receiving a sixth Td-containing vaccine were non-inferior to the control
group. That's for any erythema at the
injection site.
The
next slide is what was defined as moderate or severe erythema being greater
than or equal to 10 millimeters and what you can see is that, again, in this
stage none of the groups -- all of them met the non-inferiority criteria. And the next slide for severe, which is
greater than or equal to 50 millimeters, there were very low rates and, again,
all groups were non-inferior to the 10 year group.
The
next slide is swelling day zero to 3 and this is any swelling. And what you can see again is, again, only
the groups that had had their most recent immunization had been with the Tdap
preschool were non-inferior with marginal increases over the 10 year age
group. I am not going to show you the
moderate and severe, but they do just tend to drop down just like the erythema
and they all met the non-inferiority criteria.
The
next slide is pain and pain, as any pain, was up around 80 percent and there
were no differences within any of the groups and they all met the
non-inferiority criteria compared to the 10 year age group. And I will show you the moderate pain, which
drops down substantially, and moderate we defined as causing interference with
usual activities. And as you can see,
all the groups were similar and all met the non-inferiority criteria. And severe pain was substantially lower than
these and I won't show you those data.
The
final data slide that I'll show you is the next slide, which is any fever, and
that was fever greater than or equal to 38 degrees centigrade. The rates were very low for all groups and
they were all similar to the 10 year criteria.
And for moderate and severe fever of higher grades, those bars virtually
disappear. Next slide.
So
in conclusion, what we concluded from the study was that the Adacel, the Tdap,
was well-tolerated by adolescents who were immunized after intervals of 2 to 10
years or more since a previous diphtheria-tetanus or
diphtheria-tetanus-pertussis vaccine.
Severe
adverse events, including Arthus reactions, were not observed during the study
and that there was a modest increase in injection site events with increasing
intervals since the prior immunization, but that Adacel can be safely
administered at intervals of greater than or equal to two years since a prior
Td or Td-containing vaccine.
CHAIR
OVERTURF: Are there any questions from
the Committee? Yes, Dr. Markovitz?
DR.
MARKOVITZ: Yes, just a comment and then
two questions. One is I want to
compliment you guys on having these data available. Also, I have never seen anybody quite as prepared for a question
as this one, so congratulations.
I
have two other questions on a totally different front. One is in fairness to your colleagues at
GSK, I want to also point out that similar to their results displayed today and
similar to the Menactra trials, the ethnic makeup again does not reflect modern
America, and I think this isn't just a political-correctness point, but rather
a vaccine efficacy point, and I'm wondering if you guys do have a program in
place, so that future Committees will see a more diverse group of people in the
trial. And then I have another question
after you answer that.
DR.
DECKER: Well, I have the same answer
you heard this morning and that you heard a few months ago for Menactra, which
is that we really tried. You saw how
many sites we had. We seek minority
center sites, minority investigators, but it's hard to get them and so we keep
pushing. All we can do is push. Ultimately, there has to be the desire to
participate in a study.
We
are all united in the desire to have the studies exactly balanced with the
country's population. That's all I can
say. We're going to keep trying. I can't promise you it will get better. This is as good as we have been able to do
so far, but we're going to keep trying.
You
asked also the implicit question of the impact on immunogenicity and I can tell
you that we did do analyses of the immunogenicity by racial subgroup and,
indeed, the minority groups by and large responded better than the majority
group, so there is no signal there that suggests that we have got a hidden
problem in actually protecting the minority recipients of the product.
DR.
MARKOVITZ: Thank you. One other question on a totally different
front, the fimbriae antibody. Could you
summarize? Because that's different in
your product than the other, can you summarize what the data are that suggest
that that is an important measure?
DR.
DECKER: Yes. As was mentioned by Dr. Kuykens, there was a Household Contact
Study that was conducted nested within the Sweden I Efficacy Trial by the
Swedish investigators. Slide on,
please. And they intended -- it was one
of their intents at that stage. The
hope has always been to describe protective levels of antibody to
pertussis. We have never achieved that
hope and I suspect we never will, in part because there are so many different
antigens that could be at play.
We
have seen licensed around the world one component, two component, three
component, four component and five component vaccines and, although their
immunogenicity results might differ markedly, each and every one of those has
been shown to be efficacious for the prevention of pertussis. And although many people believe that they
differ in their efficacy, it's still a true statement that in populations that
have systematically received each of those vaccines, pertussis has been
eradicated or virtually eradicated, even the one component when used
systematically. So they all achieve
their public health goal.
Nonetheless,
the question remains, what is the correlation, if any, between antibody levels
and protection? So this study was
intended directly to look at that and they modeled, arbitrarily assigned, a
binary division point high or low for the antibody levels for PT, FHA,
pertactin and FIM. What they found was
that FHA was not predictive of protection, but that PT, pertactin and FIM were.
If
you had high pertactin or, I'm sorry, here we go. If you had high FIM, this one, if you have high FIM, even if
everything else was low, you were well-protected. If you had high pertactin, even if everything else was low, you
were well-protected. Now, if you had
both high FIM and high pertactin, you're even better protected. And all these differences were statistically
significant.
DR.
MARKOVITZ: What is the immunogen there,
Mike?
DR.
DECKER: I'm sorry?
DR.
MARKOVITZ: Michael, what is the
immunogen there?
DR.
DECKER: What was the vaccine?
DR.
MARKOVITZ: Yes, what's the vaccine?
DR.
DECKER: The vaccine. Well, it included all the vaccines that were
used in the Sweden I trial, so it was a candidate 2 component of vaccine from
GSK, it was Daptacel and it was the former Connaught whole cell vaccine
previously used in the United States.
DR.
MARKOVITZ: Thanks, that's very
helpful. One other question just for my
interest. The issue of CMI was raised,
Cell-Mediated Immunity, this morning.
Obviously, there are no special data to address that here, but do you
have a feeling whether CMI is actually important or just based on --
DR.
DECKER: Yes, I have a feeling. For what my feelings are worth, my feeling
and I venture to say the feeling of a lot of my colleagues in the room is that
CMI probably is important. We're all
doing studies that look into that, but I don't think anybody has nailed a scalp
to the wall yet to really nail down what the story is.
CHAIR
OVERTURF: Yes, Dr. Stephens?
DR.
STEPHENS: I'm particularly interested
in the older adult group for a lot of personal reasons, the 49 to 64 group and
the next subgroup down. Can you give us
a breakdown of the immunogenicity and safety data in that group? I'm particularly interested in other
illnesses or just a comparison of those two groups versus the adult group as a
whole.
DR.
DECKER: Let me first just comment on
the safety at the risk of encroaching on Dr. Kuykens' turf, that I don't
believe we got any evidence of material safety differences among those age
subgroups and he can step in if I'm wrong.
As
far as immunogenicity, slide on please, here are diphtheria and tetanus. Thank you.
Here are diphtheria and tetanus post-immunization seroprotection levels
by age category, and what you see is that they are really quite
consistent. There is a little bit of a
decline in the diphtheria. There is
really no decline in the tetanus by age group.
Slide on, please.
Here
are the results for pertussis and what you see is that for the two antigens
that are least likely to be encountered anywhere else in nature, PT and FIM,
there is a strong correlation with age in the post-immunization sera GMTs. For the antigens one commonly encounters in
other bugs, particularly FHA, there is no correlation.
And
so I conclude from that that what this is really showing us is that the longer
you are, the further out you are from your last immunization with a
pertussis-containing vaccine, then the less you respond to a booster. It will be very interesting to see what
happens if Tdap systematically replaces Td for the 10 year immunization cycle
and whether we see a shifting in this pattern then amongst the older adults.
CHAIR
OVERTURF: Yes, Dr. Hetherington?
DR.
HETHERINGTON: Yes. Two questions on data collection. One is with regard to limb circumference as
a reaction. Were the limb measurements
done by the subject and, if so, did they have standard instructions and how
much of that data, particularly in the adolescents, was missing? And similarly for the data on prior
immunization history, how much of that was by parental or patient report and
how much of it was confirmed by looking at medical records?
DR.
KUYKENS: I would first like to answer
the question on safety for Dr. Stephens.
Just like for immunogenicity, we did analyze the safety data in adults
by age groups and there were no differences in the older adults, 49 to 64,
compared to the younger adults.
DR.
STEPHENS: Just to follow-up, those were
all healthy individuals. Is that
correct?
DR.
KUYKENS: Yes.
DR.
STEPHENS: How about other concomitant
illnesses or medications?
DR.
KUYKENS: We didn't specifically study
those sub-populations yet. Now, to your
question, slide on, please.
So
the way this was done was the subjects were given a measuring tape and were
asked to measure their limb circumference at the midpoint between the shoulder
and the elbow as a baseline. So that
gave you the baseline data. And then
they were asked to measure that once a day for 14 days after vaccination.
Now,
it's clear that you get variability in there that is inevitable depending on
how hard you pull the tape measure and also if you go a little higher or a
little lower on the limb, you're going to expect some variability. So for us the main interest was do we pick
up any signals of serious swelling?
That is why we decided -- it's a different approach maybe than we heard
this morning, but that's why we decided to have every participant measure this
every day for two weeks.
The
difference, I think I showed you the difference in the control group, Td versus
the Adacel group, where I think it was 1.25 versus 1.35 centimeters, so there
was 1 millimeter difference between the two groups. And for adults, if I can get the data for adults on limb
circumference. I think for adults it
was 2 millimeters, 1.5 versus 1.3.
So
I think we can conclude that between the control arm and the Adacel arm, we
really didn't see a difference in limb circumference.
CHAIR
OVERTURF: I assume, because you didn't
present it, that you don't have preliminary data perhaps with the new
quadravalent or the old polysaccharide vaccine with meningococcal, that you
don't have any concomitant data with this vaccine.
DR.
DECKER: No. That study was just begun.
For simple practical reasons, it's too hard to do a study with two
unlicensed vaccines. Now that Menactra
is licensed, the study has started.
CHAIR
OVERTURF: Are there any -- yes, Dr.
LaRussa?
DR.
LARUSSA: You may have mentioned this
and I missed it. On Slides 41 and 42
you presented the percentage of individuals who had diphtheria and tetanus
titers above 0.1 international units.
Did you mention how many were above 1?
And I think you said the GMTs were equal, but what were the GMTs?
DR.
DECKER: I didn't mention it, but I
would be happy to. Could I see the
slide on, please? Here is a slide that
is completely analogous to the one that I did show you, but the cutoff that is
being presented is 1.0. And you see
again essentially identical results between Adacel and Td vaccine for both pres
and post. This is for adolescents and
adults. Here you see, slide on please,
the analogous information for tetanus with the same result. The Adacel and the Td comparator are,
essentially, identical whatever your cut points are.
DR.
LARUSSA: And what were the heights of
the GMTs?
DR.
DECKER: Slide on, please. Here are the GMCs and you see that there is
no meaningful difference between Adacel and Td vaccine for tetanus or for
diphtheria, for adolescents or for adults.
Within each of those sub-analyzes they are the same. Slide one, please. And in fact, there is non-inferiority of the 95 percent
confidence intervals of the ratios of the GMCs. I can show you long-term data on that also if you would like to
see over five years.
DR.
LARUSSA: Sure.
DR.
DECKER: Could I have that, please? Slide on, please. Let me explain the slide a little bit. Diphtheria going across, tetanus going across, adults going down,
adolescents going down. These are data,
as I mentioned, from the Canadian population that we have been following for
nearly eight years now. These are data
through five years, which was the last time that we obtained serum samples from
them.
And
there is a bar for every study group, pre, one month post, one year post, three
years post, five years post. And what
you see here is for any measure, for any age interval, there is essentially
identical results between the Adacel recipients in blue and the Td recipients
in the brown or tan color, whether you're talking about adults or adolescents,
diphtheria or tetanus. Next slide,
please.
Now,
this slide is organized a little bit differently, because it's PT, FHA,
pertactin and FIM. These are GMCs. The data that are graphed right now are the
data as originally published from the Sweden I cohort by the Swedish
investigators showing the post-immunization, actually the pre-immunization, one
month post, six months post and two years post-immunization results. Now, bear in mind that these are the
antibody levels that were associated with 85 percent efficacy against classic
pertussis. Next slide, please.
Now,
superimposed are the Adacel antibody levels.
The post-Adacel antibody levels in the Canadian cohort at one year,
three years and five years out. And
perhaps the most interesting here is the PT, because there is nothing else that
cross-reacts with that. FIM has very
few cross-reacting, so that's of interest, too. And what you see is that the antibody levels are markedly
well-maintained. Of course, there is a
steep decline in the first year. After
that, very, very flat lines.
As
I mentioned before, these data have not been submitted to the BLA and have not
been reviewed by the FDA. These are the
Canadian data from the Canadian Licensure and Development Program. We're continuing to follow this
population. We'll have the eight year
bleeds next year.
CHAIR
OVERTURF: Yes, Dr. Royal?
DR.
ROYAL: You mentioned that in your
minority population that there seem to be a more robust immune response to the
vaccinations. Did you see a difference
in adverse events in the group?
DR.
KUYKENS: No, we didn't see any pattern
or difference in adverse events by ethnicity at all.
CHAIR
OVERTURF: Any further questions? Before we have the FDA presentation, I think
we'll take a 15 minute break, reconvene at 2:40.
(Whereupon,
at 2:25 p.m. a recess until 2:41 p.m.)
DR.
KUYKENS: Dr. Mink asked me to make one
--
CHAIR
OVERTURF: There was one comment.
DR.
KUYKENS: One clarifying comment.
CHAIR
OVERTURF: Okay.
DR.
KUYKENS: I think it was mentioned, but
just to make this very clear, the data presented by Dr. Halperin, the study was
concluded two months ago, so those were not part of the BLA, but were presented
at ACIP a few weeks ago, so just to make clear for the record those were not
part of the BLA. Thank you.
CHAIR
OVERTURF: At this time, we'll go ahead
and hear the FDA presentation, which will be made by ChrisAnna Mink.
DR.
MINK: Can you hear me now? Yes.
Can you hear me now? Thanks. I'm Chris Mink from the Office of Vaccines
at the FDA and I will be presenting the Aventis Pasteur tetanus toxoid, reduced
diphtheria toxoid and acellular pertussis vaccine, Tdap, Adacel. I will try to make my presentation
non-inferior to the ones you have heard previously.
You
have seen the composition a few times today, if I can work this, mostly to note
that there is reduced diphtheria and reduced pertussis toxoid in the Adacel
preparation compared to the Daptacel, DTaP, the acellular pertussis vaccine
licensed for the first four doses in the United States and that which was
evaluated in Sweden I Efficacy Trial.
In my talk, the terms Adacel and Tdap will be used interchangeably.
An
additional vaccine evaluated in the clinical trials was the Td vaccine, which
was produced by Aventis Pasteur, Inc., a U.S.-licensed product. Adacel is indicated for the active
immunization for the prevention of diphtheria, tetanus and pertussis in
adolescents and adults ages 11 through 64 years as a booster.
The
dosing schedule is one dose administered intramuscularly. The trials in the BLA included two pivotal
trials, Td506, the comparative study about which you heard earlier, which
embedded in that was a serology bridge for efficacy, which was a laboratory
based study.
Also,
Td505, a lot consistency trial, and two non-pivotal trials evaluating
concomitant administration of the Tdap vaccine, one with influenza, Td502, and
with hepatitis B in adolescents, Td501.
Additionally, three abbreviated study reports on the historical trials
performed in Canada were provided to the BLA giving a total safety database of
6,803 Tdap recipients.
Let's
begin with the Pivotal Trial 506. This
was a Phase III randomized, observer-blinded, controlled trial comparing Tdap,
Adacel, with Td in adolescents and adults 11 through 64 years of age. Of note, the inclusion criteria was no
diphtheria- tetanus-pertussis-containing vaccines in the five previous
years. Enrollment was stratified within
age group with Tdap to Td randomized 3:2 for 11 to 17 years of age and 3:1 for
18 to 64 years of age. Each participant
received one 0.5 mL dose of Tdap or Td.
The
monitoring in this pivotal trial included immunogenicity and this was performed
on a randomly selected subset within each age strata. Serum was obtained pre-vaccination and post-vaccination at 35
plus or minus seven days.
And
for safety monitoring, immediate adverse events, AEs, will be abbreviated in
the talk, within 30 minutes were captured.
Solicited systemic and local adverse events were captured on diary cards
for 14 days after immunization and serious adverse events and new-onset medical
conditions were monitored through a six month safety phone check.
The
objectives in Td506 included Tdap versus Td for a comparison of safety to assess
the immune responses to diphtheria, which I will abbreviate as dip, and
tetanus, which I will abbreviate as tet.
Additionally, the objective of Tdap versus DTaP, Daptacel, was performed
to compare the immune responses to the pertussis antigens. These assessments were performed separately
for the adolescent age group and the adult age group.
The
total enrollment, as shown on this slide, in this trial of 4,480 individuals,
and you can see the randomization is reflected in about 3:2 for the adolescents
and 3:1 for the adult population. You
heard the demographic characteristics in the AP presentation and, of note, they
were similar for the Tdap and Td groups.
The
populations for analysis included intent-to-treat for safety, ITTS. Those were all randomized individuals that
had received a dose of study vaccine, Tdap or Td. The ITTI immunogenicity population were all those randomized,
vaccinated and bled and the Per Protocol Immunogenicity, the PPI, was the ITTI
subset who had no major protocol violations.
I
will present the results for safety for the ITTS and the results for
immunogenicity primarily for the PPI.
With that in mind, some of the numbers of enrollees on my slides may not
be the same as those you saw on the Aventis presentation.
For
the endpoints for diphtheria and tetanus immune responses, the Tdap compared to
Td were evaluated for the percent of subjects achieving the response would be
considered non-inferior if the lower limit of the two-sided 95 percent
confidence interval of the difference, abbreviated as delta, in rate was
greater than -10 percent.
The
responses evaluated included seroprotective levels defined as 0.1 international
units per mL and booster responses.
These were defined as a 4-fold rise if the pre-vaccination level was
below the cutoff and a 2-fold rise if the level was above the cutoff. The cutoffs established, based upon
historical trials, were 2.56 for diphtheria and 2.7 international units for
tetanus.
I
apologize for the busyness of the slide, but all the data for the adolescents
are shown here. As you can see for the
0.1 international unit level pre-vac for the adolescents were similar between
the groups. The pre-specified endpoint
for analysis is shown in bold and was not inferior with both groups, 99.8
percent, achieving this seroprotective level.
Additionally,
values for seroprotection at 1.0 international units is shown with pre-vac
being low and equal for the two groups, and post-vac also being equal between
the two groups at 98.7 and 98.4. Although
not pre-specified, non-inferiority was also demonstrated for this comparison.
For
tetanus, similar findings were shown and that the pre-specified endpoint,
percent of subjects above 0.1, was non-inferior between the groups. Pre-titers were high. Pre-titers at 1.0 level were about 40
percent, 44 percent, in each group. And
again, although not pre-specified, the majority of subjects, over 99 percent,
achieved greater than 1 international unit post-vaccination in the adolescents.
This
slide shows similar results for the adults as you just saw for
adolescents. Again, the pre-specified
endpoints are shown in both. For the
pre-titers, they were equal between the groups and also post at 0.1, about 94
to 95 percent of both groups achieving the seroprotective level and the results
were non-inferior.
The
pre-1.0 level, there were low percentages similar to the adolescents in both
groups and about 78 to 79 percent of both adolescent, adult, Td and Tdap
achieved this level. Non-inferiority
was demonstrated. The pre-titers for
tetanus were high and the percent of individuals who had achieved the 0.1
percentage was virtually 100 percent in both groups and non-inferiority was
demonstrated. This is also true at the
1.0 level.
For
tetanus and diphtheria booster responses, the adolescents and adults are both
shown on this slide. As you can see,
there are no differences between the adolescent groups for diphtheria or
tetanus with non-inferiority being demonstrated with the 95 percent confidence
intervals, as shown. And additionally
for the adults, there were no differences observed between the groups for
diphtheria or tetanus with non-inferiority being demonstrated.
An
additional endpoint for evaluation in the Td506 was for pertussis immune
responses for the efficacy bridge. In
this comparison, Tdap versus DTaP. And
as you recall from the earlier presentation, that DTaP had, approximately, 85
percent efficacy demonstrated against Bordetella
pertussis infection with 21 days of paroxysmal cough observed in the Sweden
I trial.
For
our comparisons, we looked at geometric mean concentrations, GMCs, for each of
the pertussis antigens, PT, FHA, pertactin as well as fimbriae. These comparisons would be considered
non-inferior if the lower limit of the two-sided 95 percent confidence interval
of the GMC ratio, Tdap over DTaP, was greater than 0.67.
For
the serology bridge to efficacy, the DTaP samples from Sweden I included 80
pairs from the original 181 pairs.
These 80 pairs had sufficient volume available to perform the testing
and were not selected randomly. The
samples were obtained from the infants pre- and post-one month after the third
dose in infants who were immunized at 2, 4 and 6 months of age.
The
laboratory evaluation for these DTaP samples included being assayed
concurrently with Tdap samples from the adolescents in Td505 based on timing of
the availability of samples from Td505.
The assays performed were indirect to ELISA performed in 2002 at APL.
The
DTaP antibody values generated in this comparison, generated in this
evaluation, were used for comparisons with antibodies from adolescents and
adults in Td506. Because Td506 crossed
the age span of 11 to 64 years of age, it was considered the primary comparison
for the efficacy bridge.
This
slide shows the results for the Tdap and DTaP geometric mean
concentrations. On this column you can
see for each antigen the results from the 80 paired samples from infants who
had received the DTaP. These results
are lower than those observed, assayed simultaneously with the 505, at 338 to
86, 265 to 39, 1804 to 341 and 367 to 108.
Additionally,
the infant serum, as compared to the adolescents in the planned predefined
comparison with Td506, shows lower response in the infants compared to these
adolescents, as well as to the adults, in Td506. Also of note, in the 1,000 infants evaluated, serum evaluated, in
505 the results were similar for the adolescents in 506.
As
I mentioned, however, the efficacy bridge of primary interest was the
comparison of adolescents and adults in 506 for the geometric mean
concentration ratios. This shows the
Tdap to the DTaP with the 95 percent confidence intervals. All of these ratios and their confidence
intervals are shown for adolescents, as well as for adults, with each of these
values, including the lower limit of the confidence interval, exceeding the
0.67 criteria that was predefined, thus demonstrating non-inferiority of the
responses to Tdap compared to the responses following DTaP.
An
additional co-primary endpoint was an evaluation of booster responses to the
pertussis antigens. For this
evaluation, the comparison of Tdap compared to the historical limits
established for Tdap were booster responses for the percent of subjects that
achieved the booster response compared to the acceptable rate for each antigen,
as determined in historical studies.
This comparison would be considered non-inferior if the lower limit of
the 95 percent confidence interval was above the acceptable rate, so
approximately 80 percent for each antigen.
The
results are shown on this slide. These
are the predefined acceptable rates, the lowest one at 77.6 for FHA, but again
all of them approximately 80 percent, the highest being for pertactin at about
86 percent.
These
are the percent of individuals that achieved the booster responses for
adolescents and the percent of individuals in adults that achieved these. And as you can see, the lower limits for
each of these 95 percent confidence intervals all exceeded the predefined
acceptable rate.
The
safety endpoint in Td506 was the comparison of Tdap versus Td. Safety comparisons were performed and
predefined for erythema, swelling, pain and fever from day zero to 14. The rates of these events would be
considered non-inferior if the upper limit of the two-sided 95 percent
confidence interval on the difference was less than 10 percent.
For
the predefined endpoints in adolescents, non-inferiority was demonstrated for
erythema, for swelling and for fever and the intensity for all of the groups. However, for pain, the upper limit of the 95
percent confidence interval was 10.7, slightly exceeding the 10 percent. Similar results are shown here for adults. For erythema, swelling and pain, as well as
fever, non-inferiority was demonstrated.
Additional
safety evaluations included the events for immediate adverse events, those
within 30 minutes, and there were no differences between the two study groups
in adolescents or adults. For any local
adverse events, which included the monitoring of pain, swelling, erythema and
axillary node swelling, these were the most common events reported occurring in
the majority of the adolescent as well as the adult populations, but there was
non-inferiority demonstrated between the groups for comparison.
Any
systemic adverse events included monitoring of fever, chills, headache, nausea,
vomiting, body ache, lethargy, rash and sore or swollen joints. These also occurred commonly and SEAs
occurred in less than 1 percent of both the adolescent study groups and 1.9
percent of both the adult study groups.
For
safety there were no anaphylaxis events captured for immediate adverse
events. The solicited systemic AE
events were similar in the Tdap and Td groups and, of note, sore and swollen
joints were reported by, approximately, 11.5 percent of both Tdap and Td groups
in adolescents and 9.1 percent of Tdap and 7 percent of the Td groups in the
adults. Unsolicited AEs reported in the
first 30 days after vaccination, there was no pattern of events observed upon
our review.
There
was a trend for higher rate of local adverse events in Tdap and Td vaccinees in
the younger adolescents, 11 to 14 years of age. This was exploratory analysis and no statistical comparisons were
planned or performed.
For
SAEs, a total of 83 events were reported in 63 participants with a rate of 1.5
percent in both Tdap and Td groups over the entire six month safety
period. There were no deaths reported
in this study. As discussed earlier by
AP, there were two neuropathic events that occurred in adults that were
considered to have a plausible association with vaccine administration.
One
occurred one day post-Tdap in a 26 year-old female who was hospitalized for a
migraine and unilateral facial paralysis who was noted to be hypertensive at
the time of vaccination. A second event
occurred 12 days post-Tdap in a 49 year-old female who was hospitalized for
dysasthesias in her neck and left arm.
She was evaluated for myocardial infarction and diagnosed with nerve
compression.
To
summarize, all but one of the safety and immunogenicity endpoints were met for
both adolescents and adults. For
safety, non-inferiority was demonstrated for the rates of adverse events after
Adacel as compared to the rates after Td, except for pain of any intensity in
adolescents at the 10.7 percent upper limit.
The
immunogenicity results for dip and tet show that non-inferiority was
demonstrated for both of these antigens following Adacel as compared to Td on
the basis of seroprotective rates and booster response rates. And for the pertussis immunogenicity,
non-inferiority was demonstrated for the immune responses to the pertussis
antigens following Adacel as compared to the immune responses following three
doses of Daptacel in the infants from the Sweden I trial.
Additionally,
booster responses to each of the pertussis antigens was demonstrated. Although not included in this submission,
Td506 has a follow-on study that includes evaluation of immunogenicity, which
is planned at 1, 3, 5 and, ideally, 10 years.
For
the next pivotal trial, we will discuss briefly the lot consistency study,
Td505. This was a Phase III,
randomized, double-blind trial to assess the lot consistency of three
consecutively produced lots of Tdap as measured by safety and immunogenicity
when given as a booster dose to adolescents 11 to 17 years of age.
This
study required documentation of previous immunizations for study enrollment and
99.9 percent of participants did have documentation as provided by records of
five previous doses. Each participant
received one 0.5 mL IM dose of one of the three lots of Tdap, and assessments
for safety and immunogenicity were performed similar to Td506 with the
exception of no six month safety check.
For
immunogenicity, consistency was demonstrated based upon equivalence testing for
dip and tet for two-sided 95 percent confidence intervals of the difference in
seroprotection rates and booster rates between any two lots were within the
interval of -10 and 10 percent. For the
pertussis antigens, two-sided 90 percent confidence interval for the ratio GMCs
for any two lots within the interval of .067 and 1.5. Subsequent to the design of this trial, we have moved to 95
percent confidence intervals and those comparisons were also performed.
Approximately,
1,811 adolescents were enrolled equally into each of the three lots and the
demographic characteristics were similar for participants in each of the
lots. As a result, the lot consistency
was demonstrated with immunogenicity showing similar results for each of the
three lots for dip, tet and the pertussis antigen. Additionally, these responses in adolescents in 505 were similar
to those observed in Td506.
For
safety, erythema, swelling, pain and fever from day zero to 14 for
"any" and "moderate and severe" intensity were evaluated by
equivalency testing. Although not a
customarily evaluated parameter for lot consistency, additional safety testing
was performed in this trial, because the study contributed a large number of
adolescents to the safety database.
The
results show that the rates of adverse events for those predefined parameters
were similar between the three lots and similar to the adolescents in
Td506. No anaphylaxis events were
observed. There were four SAEs, three
of which were appendicitis hospitalizations that were not, apparently,
vaccine-related and there was one death, a suicide, as mentioned earlier.
To
summarize, consistency of manufacturing of the three production lots was
demonstrated. The study contributed,
approximately, 1,800 adolescents to the overall safety database for the
BLA. And as mentioned, serum samples
from this trial were assayed at the same time as the Sweden I samples providing
additional support for the serologic bridge to the Sweden I for the adolescent
age group.
For
Td502, this was an open-label, randomized, controlled trial of the safety and
immunogenicity of Tdap and influenza vaccines when given concurrently or
separately in adults 19 to 64 years of age.
Group
A was Tdap and flu given concurrently, which I will abbreviate as
Tdap+flu. And Group B was flu followed
four to six weeks later by Tdap, which is abbreviated as flu, Tdap. The assessments were performed similarly to
Td506. However, there was no active
monitoring after the influenza vaccine when administered alone.
For
the endpoints for dip and tet, they were similar as defined for 506. For the pertussis antigens, the GMC ratio of
Group A, concomitant, over Group B would be considered non-inferior if the
lower limit of the two-sided 90 percent confidence interval was greater than
0.67.
The
influenza strains included, the three types included in the vaccine, the
A/H3N2, A/H1N1 and Type B. The
responses would be considered non-inferior if the upper limit of the two-sided
95 percent confidence interval of the difference, B minus A, was less than 10
percent.
Seroprotection
rates were defined as the hemagglutination HAI titers were greater than or
equal to 1:40 and seroconversion was defined as greater than or equal to a
4-fold rise.
A
total of 720 adults were enrolled in this study equally to Group A and Group
B. 24 individuals discontinued from the
study and 21 of those were from Group B, those who received the flu vaccine
first and then four to six weeks later received the Tdap vaccine. The difference in discontinuation rate is
likely due to the difference in the vaccine study visits. Again, the demographics between the two
study groups were similar and 69 percent gave a reported history of five
previous DTaP.
The
results for the dip, tet and pertussis immune responses are shown on this
slide. For diphtheria as well as
tetanus, at the 0.1 international units per mL, non-inferiority between the
groups was demonstrated.
For
pertussis, the geometric mean concentrations post-vaccination are shown for
concomitant versus separate administration.
Non-inferiority was demonstrated for PT, FHA and FIM. However, the lower limit of the confidence
ratio for pertactin was at 0.61, lower than the predefined 0.67. You will also note that, generally, the
responses in Group B, the separate administration, were higher than those
observed in Group A.
This
slide shows the immune responses to the influenza antigens. For both seroprotection, HAI titers greater
than 1:40 and seroconversions, the results between the groups for percentages
who achieved those levels were similar and non-inferiority was
demonstrated. However, you will note
for Group A, concomitant administration, the results for the percent of
subjects achieving seroprotection rate was slightly higher than those obtained
in Group B.
The
safety results show that non-inferiority of the adverse event rates for
concomitant compared to separate administration was demonstrated for erythema,
swelling and fever, but not for pain, of "any" or "moderate and
severe" intensity. At least one
local adverse event was frequent, occurring in 69 percent of concomitant
administration and about 64 percent of separate administration.
And
solicited systemic AE rates were higher for concomitant administration. Those data are not shown. No anaphylaxis events were reported. There were two SEAs, one in each group,
reported that were not vaccine-related and there were no deaths reported.
To
summarize this trial, not all of the endpoints were met. As noted, safety, the pain was more frequent
with concomitant administration. For
immunogenicity for the pertussis responses, non-inferiority of the GMCs for
concomitant versus separate administration was noted for three of the four
antigens, PT, FHA and FIM, but not for pertactin.
However,
robust rises in antibody responses were observed for both groups. However, the responses for concomitant
administration were lower. Clinical
significance of the failed endpoints are not clear and should be considered in
the context of risks and benefits of concomitant immunization.
Study
501 was an open-label, randomized, controlled trial of safety and the immune
responses of Tdap and hepatitis B when given concomitantly or separately in
adolescents 11 to 14 years of age. Each
participant received one dose of Tdap vaccine and a two dose regimen of
hepatitis B vaccine given about four months apart with each dose being 1 mL per
dose.
Group
A was Tdap plus Hep B #1 concurrently, abbreviated Tdap+Hep B, and the Group B
was Tdap followed by hepatitis B four to six weeks later, abbreviated as Tdap,
Hep B.
The
dip, tet and pertussis comparisons were performed similar to Td502. For hepatitis B, the seroprotection rates
greater than 10 milli-international units per mL, as measured by the Abbott RIA
kit, would be considered non-inferior if the upper limit of the two-sided 95
percent confidence interval for the difference, B minus A, was less than 10
percent.
The
safety monitoring following Tdap was performed similar to the other trials and
there was no active monitoring after administration of the hepatitis B vaccine
alone. Erythema, swelling, pain and
fever would be considered non-inferior if the rates of the events in A versus B
with the upper limit of the 95 percent confidence interval on the difference, A
minus B, was less than 10 percent.
A
total of 410 adolescents were enrolled, approximately equal in both groups of
concomitant and separate administration.
Again, the demographics were comparable for the two study groups and 89
percent of these adolescents gave a history of previous five DTP-containing
vaccines.
The
results for dip, tet and pertussis are shown on this slide. It looks very similar, I'm sure, with almost
100 percent of all of the individuals in both groups having greater than 0.1
percent for diphtheria and tetanus, and non-inferiority was demonstrated for
both antigens between both groups. For
the pertussis geometric mean concentrations, the results for the concomitant
compared to the separate administration were not different and non-inferiority
was demonstrated.
For
hepatitis B, the simplest slide I have shown all day, you can see that for
Group A, concomitant, and Group B, approximately, 96 to 97 percent of both
groups achieved seroprotective levels with non-inferiority between the two
groups.
The
safety results show that the endpoints were met for fever and "any"
pain, but not for "any" erythema or swelling at "any" and
"moderate and severe" intensity.
Local adverse events were common in both groups with concomitant
immunization group reporting about 88 percent, at least one or more AE, and
about 87 percent for the separate administration group.
Solicited
systemic adverse events after Tdap were generally higher in the concomitant
group. Sore and swollen joints were
frequent in both concomitant at 22.5 percent and separate at 18 percent, and
these rates appeared higher than other trials.
No anaphylaxis events were reported.
There were two SAEs, one in each group reported, that were not
apparently vaccine-related, and no deaths were reported.
To
summarize, all of the immunogenicity, but not all of the safety endpoints,
primarily those for local AEs, were met.
The clinical significance of the failed safety endpoints is not clear
and, again, should be considered in the context of risks and benefits of
concomitant administration.
As
mentioned earlier, in this trial we also looked at safety events of interest
across trials including whole limb swelling.
There were no occurrences reported in the four core trials. Though in the historical trials, Dr. Kuykens
already mentioned those events.
There
were three seizures events in the trials, one in a 15 year-old male 135 days
after Tdap and one in a 17 year-old 133 days after Td and both of those individuals
had known seizure disorders.
Additionally, I have a 51 year-old female about 22 days post-Tdap, and
during her evaluations was identified as substance abuse.
We
also looked for diabetes and autoimmune disorders. There was one new-onset insulin-dependent diabetes mellitus,
IDDM, identified in an 11 year-old 23 days after Tdap and his sibling was also
diagnosed with IDDM. And there was one
non-insulin-dependent diabetes mellitus identified in a 56 year-old 13 days
after Tdap who was identified as a coincidental finding with a suprasellar mass
at the time of an accidental trauma.
Additionally, there was an IDDM in an 11 year-old 105 days following
Td. No other autoimmune disorders were
identified in these trials, including the six month follow-up in Td506.
For
pregnancy, which was primarily monitored in 506 because of the six month
follow-up, there were 30 women with 31 pregnancies and we have data available
for 29. 19 of the 29 resulted in
healthy full-term infants. There were
five spontaneous abortions with four in the Tdap group and one in the Td group,
one planned abortion. Four premature
infants were delivered who were described as otherwise healthy and no
congenital abnormalities identified.
These events are not remarkably different from the expected background
rates in the population.
Additional
exploratory analyses were performed looking at any associations of local
adverse events with age, gender, ethnicity, day of the week. No, I'm sorry, a few other things. Primarily for age at immunization, there did
appear to be a trend for higher rates of local AEs for younger adolescents, the
11 to 13 not yet turned 14 group, compared to the older adolescents, those
greater than or equal to 14 through 17 years of age.
Additionally,
in the exploratory analyses, there were associations of local adverse events
with gender with a trend for higher rates of local AEs in females than in
males, and this was observed in both the adolescent and adult populations.
To
summarize, the data submitted to the BLA show a similar safety profile of
Adacel as compared to the U.S.-licensed Td.
Non-inferiority of the immune responses to dip and tet as compared to
the U.S.-licensed Td was also demonstrated.
The
data submitted support non-inferiority of the immune responses to the pertussis
antigens following Adacel as compared to those observed after three doses of
Daptacel in infants in Sweden I.
Booster responses to all of the vaccine antigens was demonstrated and
consistency of manufacture of Adacel was also demonstrated. Additionally, data to assess concomitant use
of Tdap with influenza and with hepatitis B vaccine have been provided.
I
would like to thank my colleagues who have been of great help and tolerated my
irritability, including Dr. Douglas Pratt, Ms. Martha Monser, Dr. Bruce Meade
and Dr. Henry Hsu, our biostatistician, as well as my DVRPA colleagues for
their helpful input. Let's go
home. I would be happy to take
questions.
CHAIR
OVERTURF: We'll open this up for
questions. I just have one question
regarding pregnancy. As we embark on
adolescent immunizations in which pregnancy is a real possibility, what is the
likely labeling going to be regarding pregnancy notification?
DR.
MINK: The company has the option of
providing data to us to assess what pregnancy category goes onto the
label. Without data and without
toxicology studies, vaccines indicated for women of child-bearing age usually
get a Pregnancy C category. I don't
know if the company would like to comment further.
DR.
KUYKENS: I would like to make two
comments. First, we did submit
reproductive toxicology data so, in fact, the labeling statement may be B or C,
because we will have animal reproductive tox data available.
The
second point is the general question of maternal immunization. As a company we are very interested in
supporting the concept of maternal immunization and, in fact, we are talking to
a number of investigators who are interested as well in studying this product
in maternal immunization. Later this
year there is going to be an important conference on the maternal immunization
concept, but I think the Committee will appreciate that maternal immunization
is not just a medical or scientific question, but there are other aspects that
are non-scientific that come into play.
CHAIR
OVERTURF: Dr. Royal?
DR.
ROYAL: I couldn't help but notice that
you didn't include the neurologic complications under the category of
autoimmune, but they were referred to as neuritis. You would expect that someone who has had facial palsy and
headache, perhaps they do have some inflammation in the nervous system response
before that aseptic meningitis can do that.
You can also see that with multiple sclerosis and sarcoid, which are
autoimmune disorders.
And
the other patient who was said to have nerve compression, I would more likely
think of some sort of, again, inflammatory disorder, perhaps mild
Guillain-Barre or some other sort of irritability as opposed to the pain that
you get with compression.
Again,
this is an age group where you're going to start to see those sorts of
idiopathic autoimmune disorders appear.
The sort of meningeal inflammation that could explain both cases could
occur secondary to an immunization. So
I think it's important that as cases like that occur, they be evaluated
carefully and that over time, patients be watched very closely. Six months is not necessarily long enough to
try to keep track of those sorts of things occurring.
DR.
MINK: I agree. A close evaluation is very important for all
of the unusual or anything that sticks out as a safety event, though one
individual did have hypertension at the time, which it's hard to know
that. There are so many possible
factors.
DR.
ROYAL: Yes.
DR.
MINK: It's even hard to know.
DR.
ROYAL: Hypertension really should not
be a cause of facial palsy, per se.
DR.
MINK: I'm sorry, she had migraines and
hypertension.
DR.
ROYAL: Yes, unless there is high
pressure inside the head, which can occur with a lot of inflammation.
DR.
MINK: Right.
DR.
ROYAL: From aseptic meningitis.
CHAIR
OVERTURF: Dr. Karron?
DR.
KARRON: I was actually just curious and
I don't know whether you can answer this, Chris, or perhaps somebody from the
company. With the increased rates of
either reported local pain or swelling with concomitant immunization, I assume
that this was one shot in each arm, and I'm curious to know which one it
was. Was it more pain in influenza,
more pain for the acellular pertussis Td or was it --
DR.
MINK: The local was monitored only
after the Tdap. The systemic,
obviously, you can't sort out, but the local was measured and monitored at the
Tdap side.
DR.
KARRON: Okay. So you gave both, but you only looked at the reactions to the
one?
DR.
MINK: Right.
DR.
KARRON: Okay.
DR.
MINK: Right.
CHAIR
OVERTURF: One of my concerns about the
issue of adding antigens, if you will, and using non-inferiority particularly
in safety is you clearly are going to see an increase in reactions as you
increase the number of immunogens you're using or you very well might likely.
So
one of the, I wouldn't call it a flaw, but concerns about non-inferiority data
for safety is there needs to be -- I don't understand how is it going to be
defined as to what's the upper limit of those?
What is an acceptable upper limit of increased reactions in
non-inferiority as you go to vaccines that have increased number of antigens?
This
is going to happen with a number of combination vaccines probably in the
future. That is maybe a general
question for the FDA, but you got stuck with it.
DR.
MINK: The non-inferiority can only be
done on pre-specified endpoints where you have an idea of what the rate is and
what you consider an acceptable rate of increase. So particularly for this file, examples, erythema, swelling, pain
and fever were chosen as the predefined to base sample-size calculations to do
those non-inferiority comparisons.
But
also, a huge safety database -- well, I shouldn't -- a larger safety database
was included to look for additional events, solicited systemic events,
etcetera, and we always have a never ending discussion of how big is big
enough, because most things you're not going to find the rare events until they
are out and licensed in a large population.
For
some of the other events that are more common that rare, you try and get
studies big enough to help you see if there is a significant increase, and
significance seems to vary by product like it's a risk/benefit ratio. Is that increase in adverse events
outweighed by the benefits? Is that a
good general answer?
CHAIR
OVERTURF: Dr. Stephens?
DR.
STEPHENS: Two quick questions. One is a follow-up to my question to the
company about breaking out the adult groups and the older and younger. Did you look specifically at that breakout
in your analysis?
DR.
MINK: The substrata was an exploratory
analysis. Again, the same thing for
powering the study to be reasonable to perform the study.
DR.
STEPHENS: Right.
DR.
MINK: But we did look at substrata and
exploratory analysis. And the safety
profiles and immunogenicity profiles generally were similar, except as I have
reported, there seemed to be a trend for higher rates of reactions in the
younger adolescents. But it occurred
with Td and Tdap.
DR.
STEPHENS: The second question is a more
general one and goes back to a question Dr. Markovitz asked earlier about, and
this is kind of a comment from the FDA on the role of fimbriae in this
particular vaccine, the question of efficacy was addressed in the Sweden
study. But my question more is about
effectiveness and what your opinion or what the FDA opinion is on the issue of
fimbriae.
DR.
MINK: Thanks. I think the FDA opinion is that any vaccine that comes to us and
has demonstrated safety and efficacy will get a licensing that it has safety
and efficacy. The number of -- we have
not taken a position on the number of components being better or worse, more or
good, just if that product demonstrates safety and efficacy.
CHAIR
OVERTURF: That was a fairly safe
answer.
DR.
MINK: And very atypical of me, by the
way.
CHAIR
OVERTURF: Dr. Royal?
DR.
ROYAL: I would just like to again
emphasize my point in the context of Dr. Overturf's comments that with more of
reactogenic vaccine some of these issues with inflammatory neuritis that I
mentioned, it wouldn't be surprising to see so. So I just again would like to encourage that to not be taken too
lightly.
CHAIR
OVERTURF: Any further questions? Dr. LaRussa?
DR.
LARUSSA: I would just like to go back
to, I'm not sure you quite answered Dr. Overturf's question. It seems to me that if new antigens get
presented sequentially, you could continually meet the non-inferiority criteria
compared to the last one and end up with vaccines that have 100 percent
reactogenicity rates. So at some point,
we have to start thinking about what are acceptable absolute numbers or maybe
looking at the categories a little bit more closely, so we look at the moderate
and severe at least and have acceptable ranges for those.
CHAIR
OVERTURF: Are there further
questions? We'll have an opportunity in
the discussion on the questions that we'll have in a moment to do that. But I would like to proceed, because I know
that some Members have to leave early and I would like to get on to vote on the
questions. Before we do that, we need
to again address the issue of 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. I have not received any requests, at this
time. Is there anyone in the room who
would like to address the Committee?
Okay. Thank you.
CHAIR
OVERTURF: The good news is you don't
have to hear me read the statement again.
I think I'll turn back to Dr. Mink, who I think has the questions
outlined.
DR.
MINK: The new questions.
CHAIR
OVERTURF: The new questions. The slightly modified questions.
DR.
MINK: Question 1, "Are the
available data adequate to support the effectiveness of Adacel in individuals
11 through 64 years of age?" And
this one we are asking for a vote.
No.
2, "Are the available data adequate to support the safety of Adacel when
administered to individuals 11 to 64 years of age?" And again, this one we are asking for a
vote.
And
discussion item is: "Please, identify any issues which should be
addressed, including post-licensure studies."
CHAIR
OVERTURF: Because of the need to
maintain a quorum, I'm going to do this in reverse than what we did from this
morning. I'll ask for the vote first
and then get on the record lastly any discussion items that require further
study during any post-licensure period.
So the first question was "Are the available data adequate to
support the effectiveness of Adacel in individuals 11 to 64 years of
age?" And we'll start with Dr.
Wharton, at this point. Dr. Wharton?
DR.
WHARTON: Based on demonstrated efficacy
in infants in the available literature as well as the immunogenicity data
presented, I would say yes.
CHAIR
OVERTURF: Dr. Markovitz?
DR.
MARKOVITZ: Yes.
CHAIR
OVERTURF: Any comments, Dr.
Hetherington?
DR.
HETHERINGTON: No, I believe that the
answer is going to be positive for this question.
CHAIR
OVERTURF: Dr. Royal?
DR.
ROYAL: I would say yes.
CHAIR
OVERTURF: Dr. Farley?
DR.
FARLEY: Yes.
CHAIR
OVERTURF: Dr. McInnes?
DR.
MCINNES: Yes.
CHAIR
OVERTURF: Your face. Everybody is giving me trouble. Ms. Province?
MS.
PROVINCE: Yes.
CHAIR
OVERTURF: And I will vote yes, Dr.
Overturf. Dr. LaRussa?
DR.
LARUSSA: Yes.
CHAIR
OVERTURF: Dr. Wood?
DR.
WORD: Word.
CHAIR
OVERTURF: Word.
DR.
WORD: Yes.
CHAIR
OVERTURF: Dr. Word, I'm sorry.
DR.
WORD: Yes.
CHAIR
OVERTURF: Dr. Geller?
DR.
GELLIN: Gellin, yes. Careful.
CHAIR
OVERTURF: It's a late afternoon. You can change your spelling slightly. Dr. Self?
DR.
SELF: I vote yes.
CHAIR
OVERTURF: Dr. Murphy?
DR.
MURPHY: Yes.
CHAIR OVERTURF: Dr. Stephens?
DR.
STEPHENS: Yes.
CHAIR
OVERTURF: Dr. Karron?
DR.
KARRON: Yes.
CHAIR
OVERTURF: You could spare me this by
announcing your own name. But I do need
to -- we have to have it on the record and so I have to call your name. I'm sorry.
The
second question was "Are the available data adequate to support the safety
of Adacel when administered to individuals 11 to 64 years of age?" I just wanted to make sure it was the same
as what was written up there. And we'll
start with Dr. Karron.
DR.
KARRON: I vote yes.
CHAIR
OVERTURF: Dr. Stephens?
DR.
STEPHENS: Yes.
CHAIR
OVERTURF: Dr. Murphy?
DR.
MURPHY: Yes, yes.
CHAIR
OVERTURF: Dr. Self?
DR.
SELF: Yes.
CHAIR
OVERTURF: Dr. Gellin?
DR.
GELLIN: Yes.
CHAIR
OVERTURF: Dr. Word?
DR.
WORD: Yes.
CHAIR
OVERTURF: Dr. LaRussa?
DR.
LARUSSA: Yes.
CHAIR
OVERTURF: Dr. Overturf, yes. Ms. Province?
MS.
PROVINCE: Yes.
CHAIR
OVERTURF: Dr. McInnes?
DR.
MCINNES: Yes.
CHAIR
OVERTURF: Dr. Farley?
DR.
FARLEY: Yes.
CHAIR
OVERTURF: Dr. Royal?
DR.
ROYAL: I would vote yes with the caveat
that more follow-up needs to be done, more looking into the possibility for the
development of neurologic complications with the vaccine.
CHAIR
OVERTURF: Dr. Hetherington, do you have
any comments?
DR.
HETHERINGTON: I have no additional
comments.
CHAIR
OVERTURF: Okay. Dr. Markovitz?
DR.
MARKOVITZ: At the risk of being dull, I
vote yes also.
CHAIR
OVERTURF: Dr. Wharton?
DR.
WHARTON: Yes.
CHAIR
OVERTURF: The last business of the day
is to open it up to discussion regarding what further needs to be done and what
recommendations we would make the FDA for post-licensure of this particular
vaccine. Dr. LaRussa?
DR.
LARUSSA: So continued follow-up on
young adults who are getting this vaccine who have been boosted with DTaP, who
have been primarily immunized with DTaP.
CHAIR
OVERTURF: I would actually add that the
same questions that we brought up this morning, in that we need to see the differences
in priming with whole cell versus DTaP and also, obviously, there is some
preliminary data which was very useful, I thought, this time on the intervals
following different vaccines, but additional data like that also would be very
useful. Any other comments? Dr. Stephens?
DR.
STEPHENS: I certainly would like to see
more data on the older adult populations, especially with concurrent
medications, concurrent illness issues.
And also, we haven't heard about, for example, the live attenuated influenza
vaccine as a concomitant vaccine or examples of the kind of data I would like
to see.
CHAIR
OVERTURF: Yes, I think there's a number
of adult vaccines like pneumococcal vaccine which was also left out. And of course, now, there is meningococcal
vaccine, which we had mentioned earlier, which also needs to be looked at a
little more critically. Yes, Dr.
Hetherington?
DR.
HETHERINGTON: To add to or repeat the
question from this morning, there are a lot of patients that a preexisting
antibody would be useful to know among those patients or subjects who have low
or no preexisting antibody, what's their response rate compared to the other
patients.
CHAIR
OVERTURF: Yes, Dr. Murphy?
DR.
MURPHY: Just as an addendum to that,
people who don't have a primary series or are not known to have had a primary
series, the 7 to 10 year-olds and unvaccinated people, people who may have had
DT vaccine for their initial immunization.
CHAIR
OVERTURF: Any further questions,
recommendations? I'll also -- Dr. Gellin?
DR.
GELLIN: I may have missed this, but
this is for a single administration once in life between the ages of 11 and
64? Is that what's on the table?
CHAIR
OVERTURF: I think so, yes. I think that's the --
DR.
GELLIN: So obviously, it raises a
question of well, if you are 11, what happens at some period later? And how that's going to be managed over
time.
CHAIR
OVERTURF: Well, I think we mentioned
this morning that for both of these vaccines, there's going to be great
interest in the future to see whether this vaccine can really safely and
effectively substitute for the current DT regimens, the 10 year booster
doses. And so I think clearly this needs to be something that's
incorporated in the plans for further and continued evaluation of these
vaccines. Yes, Dr. Hetherington?
DR.
HETHERINGTON: Some way to measure the
overall health and public health impact of this vaccine as it gets introduced
into the general public, I think, would be useful to see if the epidemiology
truly changes.
CHAIR
OVERTURF: Of course, that can be done
as a single-dose vaccine first in adolescents and then secondly to see whether
the addition of immunization of populations which traditionally have not been
considered at high risk for pertussis, but may be. It seems to me we saw some slides this morning in which there
were some grandparents in there and being at that age group, we do occasionally
see small children who might be susceptible.
So that population will need to be looked at further as well.
Were
there other questions or comments that we thought the FDA should know
about? I think most of what we said for
the vaccines this morning are going to apply to the vaccines this afternoon and
it will probably become a general plan for both of these vaccines to be looked
at in the same way in the future.
I
have no other comments. Are there any
comments from the Committee or is there anybody who wants to comment from the
audience? Any comments from industry? No?
I think we can adjourn the meeting.
Thank you very much.
(Whereupon,
the meeting was concluded at 3:36 p.m.)