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 15^th. 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 102^nd 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 As a result of this review and based on the FDA Draft Guidance on Disclosure of Conflict of Interest for Special Government Employees participating in an FDA product-specific Advisory Committee meeting, the following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.)