UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

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VACCINES AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE

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MEETING

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WEDNESDAY,  MARCH 7, 2001

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The meeting was held at 9:30 a.m. in the Versailles Room of the Bethesda Holiday Inn, 8120 Wisconsin Avenue, Bethesda, Maryland, DR. ROBERT DAUM, Acting Chair, presiding.

PRESENT:

STEVE KOHL, M.D.

KWANG SIK KIM, M.D.

ROBERT S. DAUM, M.D.

DAVID STEPHENS, M.D.

PAMELA DIAZ, M.D.

BARBARA LOE FISHER

JUDITH D. GOLDBERG, D., S.c.D

WALTER L. FAGGETT, M.D.

DIANE GRIFFIN, M.D.

NANCY CHERRY

Executive Secretary

TEMPORARY VOTING MEMBERS::

WILLIAM BRITT, M.D.

CLAIRE S. BROOME, M.D.

THOMAS FLEMING, PhD.

MELINDA WHARTON, M.D., PhD.

INVITED PARTICIPANTS:

MICHAEL GERBER, M.D.

DOLORES LIBERA

PAMELA MCINNES, D.D.S., Msc

FDA REPRESENTATIVES PRESENT:

DR. ROLF TAFFS

DR. KAREN MIDTHUN

DR. LESLIE BALL

MANUFACTURER REPRESENTATIVES:

DR. CLARE KAHN

FLORENCE JAUMIN

DR. MONCEF SLAOUI

DR. JOHAN VANHOOF

DR. BARBARA HOWE

DR. ACHIM KAUFHOLD

DR. BRIGITTE CHEUVART

DR. MICHEL DUCHENE

DR. DAVID WHEATON

PUBLIC PRESENT:

DR. MARGARET REYNOLDS

I-N-D-E-X

AGENDA ITEM PAGE

Call to Order/Welcome 4

Dr. Robert Daum, Acting Chair

Introduction of Committee 4

Conflict of Interest Statement 5

Nancy Cherry

Dr. Rolf Taffs 9

Dr. Clare Kahn 14

Dr. Barbara Howe 20

Dr. Achim Kaufhold 39

Dr. Leslie Ball 83

Open Public Hearing 135

Dr. Rolf Taffs 140

Committee Discussion 146

Committee Voting 158

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

(9:36 a.m.)

CHAIRMAN DAUM: Good morning and welcome to the VRBPAC meeting. We will begin with asking the Committee members, and those seated at the table, to introduce themselves. Please, Dr. Ball, we will start with you, and we will go right around the table.

MS. LIBERA: Leslie Ball, FDA, CBER.

DR. TAFFS: Rolf Taffs, FDA CBER.

DR. KOHL: Steve Kohl, Oregon Health Science University.

DR. STEPHENS: I'm David Stephens, Emory University.

DR. GRIFFIN: Diane Griffin, Johns Hopkins.

DR. DIAZ: Pamela Diaz, Chicago Department of Health.

DR. GOLDBERG: Judith Goldberg, New York University.

MS. LOE FISHER: Barbara Loe Fisher, National Vaccine Information Center.

CHAIRMAN DAUM: Dr. Fleming?

DR. FLEMING: Thomas Fleming, University of Washington, Seattle.

DR. WHARTON: Melinda Wharton, Centers for Disease Control.

DR. BROOME: Claire Broome, Centers for Disease Control.

DR. GERBER: Michael Gerber, Children's Medical Center, Cincinnati.

MS. LIBERA: Dolores Libera, Allergy and Asthma Network, Mothers of Asthmatics.

DR. MCINNES: Pamela McInnes, National Institute of Allergy and Infectious Diseases, NIH.

CHAIRMAN DAUM: And I'm Robert Daum from the University of Chicago. Thank you, we will now turn the floor over to Ms. Cherry for the conflict of interest statement.

MS. CHERRY: Before I say that, could I ask any of you who are carrying cell phones, and I know that that probably applies to everybody in the room, to please turn them off during the meeting.

We have, the room seems pretty crowded today, and that would be very disruptive.

Now I will read the statement. The following statement addresses conflict of interest issues associated with the open session of the Vaccines and Related Biological Products Advisory Committee meeting on March 7th, 2001.

The topic before the Committee today is a discussion of the safety and immunogenicity data pertaining to a combination DTPa-HepB-IPV vaccine. Committee members Dr. Snyder and Manley will be unable to attend this meeting. Dr. Katz is expected to join us tomorrow.

The Director of the Center for Biologics Evaluation and Research has appointed Dr. Britt, who will be here later this morning, and Drs. Broome, Fleming, and Wharton, as temporary voting members for this discussion.

To determine if any conflict of interest existed the Agency reviewed the submitted data, and all financial interests reported by the meeting participants. As a result of this review the following disclosures are made regarding today's discussions.

Drs. Goldberg and Fleming have been granted waivers in accordance with 18 USC 208b3, so that they can participate fully in the discussions.

In addition, in accordance with the Food and Drug Administration Modernization Act of 1997, Section 505, Drs. Goldberg, Kohl, Stephens and Fleming, have been granted waivers which permit them to participate fully in the Committee discussions.

Drs. Broome, Daum, Goldberg, Griffin, Kohl, Snyder, Stephens, and Ms. Libera, have associations with firms that could be, or appear to be, affected by the Committee discussions.

However, in accordance with 18 USC 208 in section 2365.502 of the Standards of Conduct, it has been determined that none of these associations is sufficient to warrant the need for a waiver, a written appearance determination, or an exclusion.

In the event that the discussions involve specific products or firms not on the agenda, and for which FDA's participants have a financial interest, participants are reminded of the need to exclude themselves from the discussions. Their recusals will be noted for the public record.

In the interest of fairness we ask that any other individuals who may wish to participate in this meeting state their name and affiliations, and any current or previous financial involvements with any firm whose products they wish to comment on.

Copies of all waivers addressed in this announcement are available by written request through the Freedom of Information Act.

CHAIRMAN DAUM: Thank you very much, Nancy. Ladies and gentlemen, we are reminded of our frailty in our short existence on this planet, by events, sad events that have occurred since we met last.

One of our Committee members, Ms. Barbara Loe Fisher has had the untimely and unfortunate passing of her spouse. Ms. Fisher, I wish to tell you, on behalf of myself, and on behalf of the Committee, that your loss is in our thoughts. To the extent that we can, we share your pain, and we hope that you heal in peace and in reflection.

MS. LOE FISHER: Thank you, Dr. Daum. I want to thank the Committee and you, and Dr. Greenberg, and the FDA staff for extending your condolences to me personally and as a Committee in the past few weeks. It meant a lot to me.

And I would also like to thank anyone in this room who gives blood, especially platelet. My husband died of a sever autoimmune blood disorder, and the giving of blood meant that it extended the period of time that he had to spend with us, and in many cases it saves people's lives.

CHAIRMAN DAUM: It would be remiss if I didn't point out that there is also joy in this human existence of ours. Dr. Snyder is not with us during this meeting because he is off to attend to the birth of a grandchild. So that, as always, we mix the sorrow with the joy.

And now to the business of the Committee this morning. We are going to begin an open session to consider some issues related to Infanrix HepB-IPV from SmithKline Beecham Biologics.

We are going to begin, please, by calling on Dr. Rolf Taffs from the FDA, to introduce the topic to us.

While you are setting up, Dr. Taffs, I'm just going to take a second here. I'm remiss, I did not announce the open public Hearing that we are going to have.

There will be another opportunity later, and there are several individuals who have declared a possible interest to speak later. But does anyone want to speak now?

(No response.)

CHAIRMAN DAUM: Good. In that case, Dr. Taffs, I apologize to you, and turn the floor over to you.

DR. TAFFS: Thank you. It is my responsibility and my pleasure this morning to welcome the members of this Advisory Committee and all others present to the important topic of consideration of this combination vaccine, Infanrix DTPa-HepB-IPV. I promise to keep my introductory comments brief.

If I could have the next slide, please? The DTPa-HepB-IPV combination vaccine that is the subject of today's meeting, is comprised of the following components.

DTPa as in Infanrix-DTPa, a licensed vaccine, incorporating diphtheria and tetanus antigens produced under license by Chiron Behring. The hepatitis B surface antigen, as in Engerix-B, also a licensed vaccine, and IPV, that has not been previously licensed in the United States.

Next slide, please. I would like to update those present on certain matters, that during the last 11 months, a number of significant updates have taken place regarding recommendations for the sourcing of materials of bovine origin that are used in the manufacture of vaccines.

These include a letter to manufacturers of biological products on recommendations regarding bovine spongiform encephalopathy from April 19, 2000, as well as a joint meeting of the Transmissible Spongiform Encephatolopathies Advisory Committee, and the Vaccines and Related Biological Products Advisory Committee that met on July 27th of 2000.

The letter to manufacturers reiterated recommendations that were made in letters issued in 1993 and 1996 from CBER, and appraised manufacturers of the need to be informed of the listing of countries potentially affected by BSE in cattle that is maintained by the USDA.

Next slide, please. These documents were followed by a publication from the Public Health Service on recommendations for the use of vaccines manufactured with bovine-derived materials in morbidity and mortality weekly reports in December 22nd of the year 2000.

And the posting of a webpage by CBER titled Current List of Vaccines Using Bovine-Derived Materials From Countries on the USDA's BSE List, or from unknown countries. And the web address is given in this slide.

Included on the web site, in the section of vaccines that use bovine-derived materials from countries on the USDA's list, is a SmithKline Beecham Biologicals DTP vaccine, Infanrix.

The manufacturer has committed to implementing changes that when completed may lead to the removal of this vaccine from the listing.

Now, based on the proposed initial marketing of the Infanrix DTPa-HepB-IPV because it contains the same components as Infanrix DTPa, it will also be placed on the list, until the changes indicated by the manufacturer have been completed.

Next slide, please. So proceeding with the purpose of this meeting this morning, CBER is requesting that the Committee assembled here today consider a series of questions and discussions points, and make their recommendations regarding this vaccine.

The following questions pertain to efficacy. The FDA is asking for the Committee's vote on this question. Are the available data adequate to support the efficacy of DTPa-HepB-IPV vaccine, when given to infants in a primary series at 2, 4, and 6 months of age?

If the data are not adequate to address efficacy, what additional information should be requested?

Next slide, please. Discussion point number 2. Please discuss whether available clinical data are adequate to demonstrate the safety of the DTPa-HepB-IPV combination vaccine, when given to infants in a primary series at 2, 4, 6 months of age. Please comment on the increased rates of fever.

If the data are not adequate to demonstrate safety what additional information should be requested?

Next slide, please. Discussion point 3. Please discuss the data submitted in support of the concurrent administration of other routinely recommended childhood immunizations with the DTPa-HepB-IPV vaccine in infants, that is, haemophilus influenza type b vaccine, and 7-valent pneumococcal conjugate vaccine, Prevnar.

Next please. The final discussion point, number 4, please identify any issues that should be addressed in post-licensure studies, specifically, please include a discussion of the safety and immunogenicity of concurrent administration of other routinely recommended vaccines, for example, Prevnar, the safety and immunogenicity of fourth and fifth dose of Infanrix DTPa, following a primary series of DTPa-HepB-IPV.

The safety and immunogenicity of DTPa-HepB-IPV following a complete or partial primary series of Infanrix or other DTPa vaccine. And, finally, the safety of a primary series of DTPa-HepB-IPV following a birth dose of Hepatitis B vaccine.

I think very much, and I now turn the floor back to the Chair.

CHAIRMAN DAUM: Thank you, Dr. Taffs. It is now time to hear from the sponsor of this proposed product. And I've been given to believe that there are three speakers, Drs. Kahn, Howe, and Kaufhold, and that to remind you, before you start, that there are 50 minutes allotted for this part of the presentation.

I see Dr. Kahn up there, so I think we have the right information.

DR. KAHN: Good morning. If everyone can hear me?

Good morning, members of the Committee, FDA, ladies and gentleman. GlaxoSmith Kline is pleased to be here today to present the candidate infant vaccine, Infanrix DTPa-HepB-IPV.

The agenda, my name is Clare Kahn, I should say at the outset, and I'm vice president for U.S. regulatory affairs, responsible for vaccines. So following my introduction Dr. Barbara Howe, who is vice president and director of clinical R&D, North America, responsible for vaccines, will provide an overview of the clinical data with an emphasis on immunogenicity, and following that, Dr. Achim Kaufhold, head of pediatrics vaccine development unit at SB Biologicals in Rixensart, Belgium, will provide a corresponding overview of this clinical safety, and then I will make final conclusions.

The product is a liquid combination of diphtheria and tetanus toxoids, three acellular pertussis antigens, that is PT, SHA, and potactin, Hepatitis B recombinant, and inactivated poliovirus vaccine types 1, 2, and 3.

All component antigens are produced by SmithKline Beecham Biologicals in Rixensart, Belgium, with the exception of DT adsorbed, this is manufactured by Chiron Vaccines in Germany, and shipped for further manufacturer to SB Biologicals, and included in the combination.

The generic name, spelled it all out, is diphtheria and tetanus toxoids acellular pertussis hepatitis B recombinant inactivated polio virus vaccine. And the trade names provides good clarity for the physician in that it not only spells out the component antigens in the vaccine, but its relationship to our DTPa vaccine, which is currently marketed, which is Infanrix.

The vaccine is indicated for immunization against diphtheria, tetanus, pertussis, all known sub-types of hepatitis B virus, and poliomyelitis caused by polio virus types 1, 2, and 3.

As a three dose vaccination series in infants and children, from 6 weeks to 7 years of age, prior to the 7th birthday. And just to clarify this, we are talking about immunization prior to the 7th birthday, intended to allow for catch-up for the primary series.

An indication for a fourth dose, following the primary series not being sought at this time, and so booster doses are still required according to the recommended immunization schedule.

The basis for licensure, the components of the vaccine, as I shall review shortly, are included individually, or in combination, in products licensed in the U.S. and/or in many world-wide markets.

And the development of the candidate was based on CBER's guidance for industry for evaluation of combination vaccines for preventable diseases, which was published in April of '97, in which one would show the combination vaccine is not inferior to separately administered U.S.-licensed vaccines, with respect to immunogenicity, as a surrogate for efficacy, and in regards to safety.

And a word about the components, now. The DTPa components are identical in terms of manufacturing composition to those in our currently licensed DTPa vaccine, which is Infanrix.

And just to remind you that Infanrix is licensed in the USA in January of '97, licensed in 69 countries, with over 31 million doses distributed world-wide. In fact that is more than 50 million

doses if one counts DTPa in combination.

The hepatitis B component is similar to our licensed engerix-B, that was licensed nearly 12 years ago in 1989, apparently licensed in 145 countries, with more than 500 million doses of that vaccine distributed as a monovalent vaccine.

So now the IPV component, and GSK does not have a U.S. licensed IPV vaccine, but this component is an enhanced potency IPV inactivated trivalent polio vaccine similar to the Aventis Pasteur vaccine, IPOL, similar in that the manufacturing process is similar, it is CFR and WHO compliant. And the same cell line were used for the manufacturing process in that very cells.

It also contains the same three strains, types 1, 2, 3, and the same antigen content as IPOL, so that would be Mahoney strain, 40 antigen units. And if you want, it is ADU and the Saukett strain, 32 DU.

Now, our IPV vaccine has been in clinical development since 1989, with 78 trials conducted in more than 26,000 infants and children, either as IPV alone, or in combinations.

It was first licensed in France in '96, and licensed outside the U.S. in quite a variety of combinations shown here, DTPa-IPV in six countries, DTP-IPV, and mixed with Hib before administration in 36 countries.

And shown in yellow here is our candidate combination licensed as such in 17 countries, and licensed with mixing with Hib before administration in 19 countries.

And for this combination, for the IPV, over 8 million doses of IPV equivalents have been distributed to date.

So this is the vaccine composition. As I mentioned, the DTPa, the hepatitis B and the polio components are the same, and in the same content as in the separately licensed vaccines of the U.S.

We point out that there is an aluminum adjuvant, .7 migs of aluminum, as an aluminum source, this is lower than one would have if one would have the separate vaccines. And there is phenoxyethanol as a preservative in common with Infanrix. And there is no detectable thimerosal in the final product.

So manufacturing changes have been made during the process of clinical development. There are in fact three lots, first, second, and third lot series. Third lot series actually being the launch material that we propose.

For the pertussis component there have been 2 successive purification scale-ups, all of which have been approved and in use for the currently licensed Infanrix.

In going from the first to the second lot during development we added one additional purification step for hepatitis B, which triggered the clinical bridging trial in addition to the usual technical bridging.

So for the launch material we have this final PA scale-up a minor volume increase in the hepatitis B purification, and the introduction of new working seeds for the IPV. The technical bridge was sufficient to bridge to the launch material.

So with that let me just say that regarding the status of the BLA review, all the BLA questions, including the complete response letter, have been responded to, and we are now in active discussion on those responses with the Agency.

And a pre-approval inspection has also been satisfactorily completed. So it is now time to move onto the clinical presentation, and may I introduce Dr. Barbara Howe, to talk about the clinical immunogenicity. Thank you.

DR. HOWE: Good morning everyone. Can I be heard okay?

So in the next few minutes what I would like to do is to, first of all, overview the contents of the file in support of the Infanrix HepB-IPV and then this will be followed by a review of the pivotal and major supportive studies which had immunogenicity as their primary objective.

A total of 12 clinical trials, in which infants received one or more doses of Infanrix HepB-IPV were conducted in ten countries. Three in North America, 2 in the U.S.

And these evaluated five different primary immunization schedules, and involved 11 different production lots of vaccine. In total more than 7,000 infants received more than 20,000 of Infanrix HepB-IPV in these 12 trials.

Now, the three studies that are highlighted in yellow on this slide, studies 011, 15, and 44, are the pivotal trials, which will be the focus of the presentations which follow.

There are two additional U.S. studies which employed related combination vaccines, and these provided supportive data for the file.

In study DTPa-HepB-030, a combination DTPa vaccine, which is similar to Infanrix HepB-IPV, with the exception of the IPV component, provided support for a schedule change in the hepatitis B component from the license 016 to 246 as part of the combination.

Then we have study 003, another U.S. study. And in this study Infanrix HepB-IPV was used to reconstitute GlaxoSmith Kline's Hib vaccine, and which was administered a three dose primary series, following a birth dose of HepB, and this provided supportive safety data for use of Infanrix HepB-IPV in this manner.

If we focus now on the six trials from which the most important data for the U.S. file are derived, in accordance with the FDA guidance for industry, for the evaluation of combination vaccines, and in support of the proposed indication, the following critical objectives were included.

First of all from an immunogenicity point of view, comparison to U.S. licensed separate administration vaccines was provided in study 015, a U.S. study. And this study also had as an objective an evaluation of the immunogenicity and safety of Infanrix HepB-IPV, co-administered with U.S.-licensed Hib vaccine.

For lot consistency study 044 provided data on three production lots of vaccine, and from the point of view of the schedule change for HepB, DTPa-HepB-030, again, provided immunogenicity data from 246, the hepatitis B component in the combination given at 246, the licensed 0, 1, 6 months of age.

From the point of view of safety an evaluation of common, that is solicited adverse events, following Infanrix HepB-IPV as compared to U.S.-licensed separate administration products was provided in two studies, study 015 in the U.S., and study 011 in Germany.

And the latter study, which involved more than 5,000 infants, and had safety as its primary objective, also provided an evaluation of less common events, that is, those that occurred at about a rate of 1 in 100.

And then, finally, study 003 provided safety data following a birth dose of HepB. It is important to state up front that all of the pivotal studies in the file were analyzed as equivalents, or non-inferiority trials.

And the objective of equivalence trials are to show that two treatments are similar, not necessarily identical, to rule out superiority of the separate components by a pre-specified amount, which is felt to be clinically important.

As such the difference must be felt to be important clinically in order to justify use of the combination vaccine.

Practically speaking, then, what one does is to first of all pre-specify a clinically relevant difference, here shown as delta, and this sets the limit for non-inferiority.

The difference between treatment groups is then calculated and in this example, we have the separate minus the combined vaccine, and 90 percent confidence intervals are built around the absolute difference.

If the upper limit of the confidence interval exceeds the pre-specified limit then we consider that non-inferiority is not shown. However if the upper limit of the 90 percent confidence level is within this limit, then non-inferiority is demonstrated.

Now, in the case of equivalence trials, both upper and lower limits are pre-specified, and if the upper or the lower limit of the 90 percent confidence interval on the treatment exceeds the pre-specified limits and equivalence is not shown, if both upper and lower limits are within the pre-specified limits equivalence is considered to be demonstrated.

A few words about the end points in the immunogenicity trials, so serum samples were -- measurement of the humoral antibody were generally obtained prior to vaccination, and one month after the third dose of vaccine.

For those products, for the antigens and combinations that are already part of U.S.-licensed products, such as DTPa and hepatitis B, the assays that were employed were similar to those used and approved by FDA under the existing license application.

This slide first summarizes the parameters for which a correlate of protection has been established, all of these were considered to be co-primary endpoints in the trial.

So seroprotection rates for anti-diphtheria and anti-tetanus were assessed via an ELISA with seroprotection defined as a titer greater to .1 international units per ML, anti-HBS was assessed via commercial RIA, with seroprotect cutoff of ten million international units per ML, and polio was assayed using a cell culture neutralization assay WHO protocol, and seroprotection was defined as any detectable neutralizing antibody.

The clinical limit defining non-inferiority for all of these parameters -- if you would go back, please -- was ten percent. Next slide.

Now, for the response for pertussis, for which a serologic correlate has not been established, the co-primary endpoints took into account both because response rates to the pertussis, as well as the geometric mean antibody titers.

And here vaccine response was defined as appearance of antibody in initially seronegative subjects and at least maintenance of antibody in initially seropositive subjects.

Again, the clinical limits defining non-inferiority for vaccine response were set at ten percent, and for the geometric mean titers a maximum of 1.5.

Okay. So if we move now to review of the primary immunogenicity studies, and we start with study 015, this study was conducted in order to rule out important differences between the immune response to each antigen in the combined vaccine, as compared to separately administered U.S.-licensed products, and also had co-administration with U.S.-licensed Hib vaccine.

This was an open study in which 400 subjects were enrolled, and randomized equally into one of four groups. Group one received three doses of Infanrix HepB-IPV, co-administered with U.S.-licensed Hib, this is Adventis' Hib, given at 2, 4, and 6 months of age.

Group two received two doses of Infanrix HepB-IPV co-administered with Hib, at 2 and 4 months of age. And then at six months of age they received a combination DTPa-HepB co-administered with Hib, and oral polio. So this was our sequential IPV OPV arm.

Group 3 received three separate injections. That is the combination DTPa-HepB, co-administered with Hib, and this is U.S.-licensed IPV manufactured by Adventis, and this was at 2, 4, and 6 months of age. So this is our separate injection U.S.-licensed IPV arm.

And group 4 received standard of care, separate administrations, this is GlaxoSmith Kline's DTPa Infanrix, our hepatitis B, Engerix-B, Hib, and Lederle's oral polio.

I just want to emphasize that at the time that the trial was performed, actually, this was the standard of care, that is oral polio was the standard of care.

For the purposes of the remainder of the presentation I'm going to primarily focus on the comparison of group 1, three doses of the Infanrix HepB-IPV, to separate administrations in group 4.

This slide then summarizes the immune response to diphtheria, tetanus and Hep-B, with seroprotection rates shown as the height of the bars, and geometric mean titers listed at the top.

You can see that for all three antigens, diphtheria, tetanus and Hep-B, high seroprotection rates, 99 to 100 percent were achieved in both groups, with geometric mean titers that were higher following the combination, than following separate administration.

Here, then, the response rates for the three pertussis antigens. Again we see high vaccine response rates that is greater or equal to 91 percent correlates of the group. This is a combined vaccine versus separate administration, with GMTs to PT and Pertactin, which were higher following the combination, than following separate administration, and GMT to FHA was somewhat higher following the separate administration, than following the combination.

Here are the results for polio. You see high seroprotection rates to all three polio serotypes. Of course there was a further relevant control group for polio in this study, namely the U.S.-licensed IPV.

And so this slide compares three doses of, or one month after the third dose of the combination, as compared to U.S.-licensed IPV.

If we look, then, at the comparison of the geometric mean titers, first looking at that, comparing the combination versus oral polio, what you see is that the GMTs to polio 1 and 2 are higher following oral polio, as compared to the combination.

But the GMT to polio 3 is higher following the combination than following oral polio. However if we look at a comparison of geometric mean titers comparing the combination to U.S.-licensed separate injection IPV, you see that for all three polio serotypes the GMTs were higher following the combination, than following separate injections.

That was the descriptive analysis. But what is important, of course, is the non-inferiority testing. So this slide shows non-inferiority testing for seroprotection and vaccine response rates to each of the contained antigens.

And the absolute difference is taking the rates for the separate injection, or separate administration, minus that for the combined vaccine are shown above the horizontal bars.

And then we have the 90 percent intervals plotted horizontally. What you can see is that for all parameters, other than FHA, the upper limit of the 90 percent confidence interval is within the pre-specified limit at 10 percent. For FHA the upper limit of the confidence interval marginally exceeded this limit.

You will recall that I said that for -- since there is no correlate protection for pertussis, that geometric mean titers for the three pertussis antigens were also taken into account as co-primary endpoints, and this slide shows the non-inferiority testing for the ratio of GMTs.

Here we take the ratio of GMTs, they have calculated in the 90 percent confidence intervals built around the ratio. You can see that for all three pertussis antigens the upper limit of the 90 percent confidence interval was within the pre-specified limit of 1.5.

What I would like to do is sort of quickly walk you through the reverse cumulative distribution curves, because they are important to look at as well. And what you are going to see is a series of slides that shows the combined vaccine, the results following the combined vaccine in black, and that following separate administration in red.

And what you are going to see is a similar pattern, that is, a similar shape for the curves themselves. But generally with that, the curve for the combined vaccine to the right of that is separate administration indicative of the higher titers.

So these are the curves for anti-diphtheria, anti-tetanus, anti-PT, FHA, pertactin, and anti-HBS.

Now, on the polio slides we have the curve for the combination vaccine in black. Still that oral polio in red, and also we have the curve for IPV. And what you can see for polio 1 is that the curve following the combined vaccine falls largely between that of oral polio, and an activated IPV separate injection.

The same pattern is seen for polio 2. And for polio 3 the curve following three doses of the combined vaccine is to the right for both OPV and IPV.

Now, study 015, as I had mentioned, also afforded the opportunity to evaluate the response to co-administered U.S.-licensed Hib. And here are the results for anti-PRP, one month after the third dose.

You can see that the proportion who achieved a titer greater than .15, as well as greater than equal to 1, as well as the GMC, were comparable between the two groups. This is the combined vaccine co-administered with Hib, and this is Hib given as a separate injection with other routine administered separate vaccines.

So from study 015 we can conclude that Infanrix HepB-IPV is at least as immunogenic as U.S.-licensed separately administered vaccines, including oral polio, with respect to the response rates to all of the antigens.

It is also at least as immunogenic as U.S.-licensed IPV with respect to the response rates to polio 1, 2, and 3. And there does not appear to be any negative impact on the immunogenicity to the co-administered Hib vaccine.

We move to the next study, study 044, which studied clinical consistency with regard to immunogenicity of the three production lots of Infanrix HepB-IPV.

And this was a U.S. study in which a total of 484 subjects were enrolled in randomized equally into one of four groups. Groups 1 through 3 received one of three production lots of Infanrix HepB-IPV, lots A, B, and C, co-administered, again, with U.S.-licensed Hib vaccine.

Group 4 received Infanrix HepB-IPV from another lot series co-administered with Hib vaccine, and this was done in order to asses a manufacturing change.

For the purpose of this presentation I'm going to focus now on the lot consistency data. This slide shows the immunogenicity results for diphtheria, tetanus and hep-B. You can see that high rates of seroprotection were achieved in all three lot groups, for all three antigens.

Here are the results for the pertussis. Vaccine response rates were high, greater than equal to 91 percent for each pertussis antigen, regardless of the lot used.

This was with the exception to the response to Pertactin, for which one lot achieved a somewhat lower response, that is 84 percent.

Here are the results for the three polio serotypes, essentially one hundred percent of all subjects in all three lots achieved detectable neutralizing antibody to polio.

Again, that was the descriptive results, here are now the equivalence testing results. The lots were shown to be statistically equivalent with respect to diphtheria, tetanus, and Hepatitis B. You can see that the upper and lower limits of the 90 percent confidence intervals were within the pre-specified limits.

Similarly the three lots were shown to be statistically equivalent for all three polio serotypes. However, although the absolute difference between the lots did not exceed the limit, the 90 percent confidence interval on the difference between lots exceeded the limit for FHA and for Pertactin, for two of the three lot comparisons.

This slide then shows the equivalence testing for geometric mean titers in this study. And what you can see is that the 90 percent confidence interval in the GMT ratios was within the pre-specified limits for all three pertussis antigens, with the exception of a marginal exceeding of the lower limit for one of the three lot comparisons for Pertactin.

I'm just going to show you the reverse cumulative curves for the pertussis antigens from this study, then. And what you will see is that the distribution of titers in all three lots is remarkably similar for anti-PT, anti-FHA, and here is anti-PRN.

Now, importantly, the same three lots were evaluated for lot consistency when extemporaneously mixed with GlaxoSmith Kline's Hib vaccine, and these were studied in two additional studies, study 027, which is a U.S. study.

The vaccine was administered on a 2, 4, 6 month schedule, and study 048, which was done in Germany, on a 3, 4, 5 month schedule. And data from both of these studies were provided to you in your pre-read materials.

I'm just going to show the results from study 027. This is the design of study 027. Again, these are the identical three lots, lots A, C, and B, from the study 044 of Infanrix HepB-IPV, extemporaneously mixed with Hib vaccine, and given to approximately 360 infants per group, 2, 4, and 6 months of age.

The identical criteria for equivalents were applied in this study. And what you see is that for all three pertussis antigens, the 90 percent confidence interval on the lot comparisons for vaccine response rate for all three pertussis antigens were met, they fell within the pre-specified criteria.

And consistency was also demonstrated with respect to the geometric mean antibody titers in this study.

So from study 044 the pre-specified limits for equivalence were exceeded for two out of the nine valencies. And both of these were pertussis antigens.

One possible explanation for the lack of consistency in this study was the observation that there was an imbalance in the twin groups in the pre-existing, that is maternal antibody, across the lot groups.

It has previously been recognized that infants with high pre-existing titers are more likely to have a lower response to pertussis antigens, particularly FHA, and Pertactin.

Importantly, though, the same three lots were evaluated into additional studies mixed with Hib, and in these two additional studies they were shown to be statistically equivalent for all nine antigens, including FHA and Pertactin.

So from these studies we conclude that equivalence has been demonstrated for all parameters.

The last study I would like to review is study DTPa-HepB-030, this was conducted in support of the schedule change for the hepatitis B component. As I mentioned previously, the combination of the vaccine is similar to Infanrix HepB-IPV with the exception of the IPV.

So this was an open randomized study conducted in the U.S. Group 1 received the combination DTPa-HepB co-administered with Hib, and oral polio, at 2, 4, and 6 months of age.

And group 2 received co-administered Infanrix, Hib, oral polio, at 2, 4, 6. And then our Hep-B and Engenrix-B was given at birth, 1, and 6 months of age.

Here are the results. It shows the seroprotection rates, 99 and 100 percent. This is for the combined vaccine given at 2, 4, 6. This is for Engerix monovalent 016, with a GMT of 1,000 in those who received the combination on a 2, 4, 6 month schedule, as compared to 3,700 in those who received the monovalent vaccine.

If we look at the non-inferiority testing on the seroprotection rates, you can see that the upper limit of the 90 percent confidence interval was below the specified limit of ten percent, and the primary objective of the trial was, therefore, met.

Now, in order to put the GMT result into perspective, we reviewed data in the published literature in the two U.S.-licensed monovalent Hep-B vaccines, Engerix and Recombivax.

And you can see results plotted from the literature. This is Engerix-B in red, Recombivax two and a half and five in yellow. And these data have been plotted, then, against the results from the study I just showed you, DTPa-HepB-030 in green, and multiple studies involving Infanrix HepB-IPV given according to a 2, 4, 6 month schedule.

And what you can see is that the results achieved with these combinations on a 2, 4, 6 month schedule, are in line with that published in the literature for the monovalent Hep-B vaccines.

So from this study we conclude that the combination given at 2, 4, and 6 months of age is at least as immunogenic as monovalent Hep-B given at 0, 1, and 6 months of age, with respect to the seroprotection rate to Hep-B.

The GMT on a 2, 4, 6 month schedule was lower as compared to 0, 1, 6, as one would expect, given the fact that the interval between the second and the third dose was shorter. This is a schedule effect.

The lower GMT is not thought to be clinically relevant. However, given the fact that the GMT is in line with that previously reported following the administration of the two U.S.-licensed monovalent vaccines, which have been shown to provide long-term protection against disease.

Additionally the GMT was more than 100 times greater than the seroprotective cutoff. And individuals with titers greater than equal to ten should continue to be protected from both symptomatic and chronic infection on the basis of immunologic memory, given the absence of detectable antibody.

So the overall conclusions on immunogenicity are that Infanrix HepB-IPV is at least as immunogenic as separately administered vaccines in head to head trials involving Infanrix, Engerix-B, oral polio, and IPV.

And although I didn't show data, I think it is important to mention that we also looked at a comparison of antibody titers following Infanrix HepB-IPV to historical data following the immunogenicity achieved in two efficacy trials for Infanrix that were provided the basis for licensure for Infanrix, and the titers were comparable.

Additionally, Infanrix HepB-IPV has demonstrated lot to lot consistency. There is no negative impact on the co-administered Hib, and hepatitis B, as part of the combination given on a 2, 4, 6 month schedule is at least as immunogenic as monovalent 0, 1, 6, in terms of seroprotection for hepatitis B.

I would like to turn the podium over now to my colleague Dr. Achim Kaufhold, who is in charge of the pediatric vaccine development unit in our central headquarters in Belgium, and he is going to provide you with an overview of the clinical safety for this product.

DR. KAUFHOLD: Good morning, everybody. Before I come to the summary of key data obtained in the clinical trial program, I would like to emphasize that we can build on a large experience with individual components of the DTPa-HepB-IPV vaccine.

First, individual components have been studied extensively. Second, individual components administered simultaneously in separate injections are in wide use. And third, individual components contained in similar combinations are currently in wide use.

Indeed, GlaxoSmith Kline has licensed, and is currently marketing a variety of DTPa combination vaccines in many countries around the world. A DTPa vaccine, Infanrix, a DTPa-HepB combination, a DTPa-IPV-Hib combination, DTPa-IPV vaccine.

The DTPa-HepB-IPV combination we are discussing today, as well as hexavalent DTPa-HepB-Hib vaccine were simultaneously licensed in October 2000 in all 15 European member states, and in a few other countries.

In most European countries the larger hexavalent combination is preferred over the DTPa-HepB-IPV combination vaccine, and has been launched thus far in two countries, in Germany and in Switzerland.

Today almost 50 million doses of these DTPa based combination vaccines have been commercially distributed, and all of these combinations are well tolerated in clinical practice.

The extensive clinical trial experience, and the post-marketing surveillance have not raised any signal of concern with regards to safety.

In the next 20 minutes I would like to give an overview of the safety and reactogenicity of DTPa-HepB-IPV when co-administered with commercially available Hib vaccines.

My presentation will focus on the comparison to separately U.S.-licensed vaccines. I will share with you data of common AEs that were obtained in the pivotal studies 011 and 012.

The occurrence of less common AEs was specifically addressed in the last safety study, 011. Safety following a birth dose of hepatitis B was evaluated in study 003. And finally, I will briefly comment on the serious adverse events and death that contained in the clinical trials contained in the BLA.

A few words regarding the methodology applied that in general were standardized across all trials for solicited local and general AEs all infants were followed for four days after each dose. That means on the day of vaccination and the subsequent three days.

The parents were asked to complete diary cards. In the two U.S. study, 011 and 044, additional telephone calls were made between day 1 and day 3 post-vaccination, in order to encourage parents to complete the diary cards, and to check on the status of the child.

This active surveillance allowed an unbiased assessment of the frequency, severity, and duration of local symptoms, pain, redness and swelling, and general signs and symptoms.

Next. In addition all other AEs, whether or not considered related to the candidate, or the comparator vaccine, were recorded as unsolicited AEs. The follow-up period for 30 days following each dose.

Prior to analysis all unsolicited symptoms were classified according to the WHO body system and preferred term. Special attention was paid to promptly gather all information of serious AEs.

The follow up period for throughout the vaccination course, up to 30 days after the last dose was administered. Overall, in the 12 clinical trials contained in the BLA, a total of 7,028 subjects received at least one dose of vaccine, so that all together almost 21,000 doses of DTPa-HepB-IPV were administered.

As you can see here, compliance for reactogenicity reporting was very high in all studies. Symptom sheets were completed for more than 99 percent of subjects enrolled in the trials.

All data that I will present are based on the analysis of the according to protocol cohort. But I would like to point out that the results obtained from the ATP analysis are virtually identical with the conclusions drawn from the ITT analysis.

You are already familiar with the design of the U.S. 015. This was an open randomized trial with four groups of 100 subjects each.

I will limit this presentation to the comparison of group one, the combined group, three doses of DTPa-HepB-IPV co-administered with Hib, to group four, that received -- in which infants received separate injections of U.S.-licensed vaccines, DTPa, Infanrix, HepB, Generix-B, Hib from Aventis Pasteur, and Lederle's oral polio vaccine.

And this was the standard of care at the time the trial was conducted in the U.S.

Infants of group one received two injections that were given intramuscularly into opposite limbs. While infants of group four received three injections, along with oral polio vaccine.

In the following I will compare the local symptoms only for the DTPa-HepB-IPV group one, and the DTPa injection sites. At the DTPa based injection was generally thought to be more reactogenicity than the reactogenicity elicited by the other vaccines.

But please keep in mind that the additional HepB and Hib injections would also contribute to the overall reactogenicity profile.

Having said this, you will appreciate that the incidence of pain was very similar for dose 1, dose 2 and dose 3, for both the DTPa-HepB-IPV and the DTPa injection site.

This is true for any pain, as well as for pain that was judged to be graded 3 in intensity. So clinically more relevant pain.

For redness at the injection site the incidence appears a little bit higher for the DTPa-HepB-IPV as compared to the DTPa injection site. There was no increase by dose, and the incidence of redness above 20 millimeters was very low in both groups.

For swelling we see a very similar picture. A slightly higher incidence for the DTPa-HepB-IPV, as compared to the DTPa injection site, a slight increase from dose 1 to dose 2, but no further increase after dose 3.

If you compare the incidence of solicited general symptoms between the combined group, and the separate injection control group, over the four day follow-up period, over the full three dose vaccination course, you can see that the figures are virtually identical for all symptoms other than fever, greater or equal than 100.4 degree fahrenheit.

Fever was 41 percent in the combined group, versus 29.6 percent in the separate administration control group, although as you can see here, the 95 percent confidence intervals overlapped.

Importantly there was no difference in the incidence of clinically more relevant symptoms rated 3, and this includes a low rate of fever above 103.2 degree fahrenheit.

Now I come to the large German safety study 011 that was initially designed as an uncontrolled safety study, in which infants were randomized to receive the candidate vaccine, along with one of four different Hib vaccines at 3, 4, and 5 months of age.

After enrollment of almost 1,600 children, the study protocol was amended. The amended design allowed for the introduction of a control group, group 5, of U.S.-licensed vaccines, namely DTPa Infanrix, Hib from Aventis Pasteur, and Wyeth-Lederle's OPV.

This design was implemented upon consultation with the FDA, and was in line with the guidelines for the evaluation of the combination vaccines that were published in April '97.

There was an imbalance between group in the sense that the control group did not receive the hepatitis B vaccine. This was necessary, as German physicians and parents do not accept more than two injections at the same visit. And this illustrates, very practically, the need for pediatric combination vaccines.

Regarding the comparison between groups for systemic reactogenicity, however, the design implied the bias in favor of the separate administration control group.

The study was analyzed as a non-inferiority trial. The primary endpoint was the proportion of subjects reporting at least solicited symptom graded 3, a clinically relevant symptom.

And non-inferiority was demonstrated if the upper limit of the 90 percent confidence interval for the difference between the pool that had the IPV group, and the control group was below the up priority clinical limit of 7.5 percent.

The percentage of subjects with any grade 3 solicited symptom was 16.2 percent for the pooled candidate vaccine group, and numerically higher, 20.3 percent, for the control group.

The absolute difference was 4.1 percent, and the upper limit of the 90 percent confidence interval for the difference between groups, was below the pre-specified clinical limit, 7.5 percent, for non-inferiority.

Thus the primary objective of this trial was met.

Let's now look again at the incidence of local symptoms by dose. Again, as seen for study 015, also in this large comparative trial the incidence of pain was similar between both DTPa-HepB-IPV and DTPa injection sites.

Any redness appears to occur slightly more frequent at the DTPa-HepB-IPV injection site, as compared to the DTPa injection site. There was a slight increase from dose 1 to dose 2, but no further increase after dose 3. And redness greater than 20 millimeters was, again, equally low in both groups.

For swelling the picture looks very similar. And, importantly, the incidence of more pronounced local reaction, injection site reactions, were equally low for both vaccines.

When looking at general symptoms please keep in mind that the separate injection control group received one systemic antigen less, the hepatitis B antigen. Thus, as already mentioned, the comparison is biased in favor of the control group.

For the percentage of subjects for the solicited general symptoms there were two differences between groups, unusual crying was observed more frequently in infants receiving separate administration of vaccines, while the infants in the candidate vaccine group had a higher rate of low grade fever, 40.6 percent versus 27 percent.

Again, as already observed in study 015, the incidence of clinically more relevant grade 3 symptoms was low in both groups for all symptoms, including high fever. Restlessness and unusual crying occurred more frequently in the separate administration control group, and these differences were statistically significant.

Regarding unsolicited symptoms, an important secondary objective of this large safety trial, the rates were similar between DTPa-HepB-IPV plus Hib, versus DTPa plus Hib plus OPV recipients, for all unsolicited AEs, for unsolicited AEs considered related, or possibly related, and for less common AEs. There were no unexpected AEs.

And you can find a comparison of the rates of unsolicited symptoms occurring at a frequency above one percent in your briefing document.

Let me summarize, now, the key findings of study 011. The candidate vaccine was at least as safe as separately administered U.S.-licensed vaccines, with respect to the percentage of subjects with any grade 3 solicited symptoms.

There were similar rates of solicited symptoms with the exception of unusual crying, restlessness, that occurred more frequently in the separate versus the combined group, and low grade fever that occurred more frequently in the combined group versus the separate administration control group. And there were similar rates of unsolicited symptoms.

Now, one of the questions, question number 2A, that is to be addressed by the panel is the following. There were higher rates of fever above 100.4 degree fahrenheit in DTPa-HepB-IPV plus Hib recipients in studies 011 and 015, as compared to the control vaccine recipients. What is the clinical relevance of this finding?

We have looked into this very carefully and did a variety of comparative analysis between groups. Indeed, there was no difference between groups in the duration of fever. In the vast majority of infants fever lasted for one or two days.

In more than 98.5 percent of children the fever episode resolved during the four day follow-up periods. There was no difference in the use of anti-pyretics across groups in both studies.

There was no difference between groups in the number of sepsis work-ups within seven days post-vaccination. There was no difference between groups in the incidence of febrile seizures occurring within seven days post-vaccination.

Indeed there was only one case, in study 011, that occurred after dose 1, in the DTPa-HepB-IPV plus Hib vaccine recipient. A diagnosis of an underlying convulsive disorder was made, and the investigator stated that the event was not related to vaccination.

If you look at hospitalizations with any fever within seven days post-vaccination, there were 11 cases among 4,695 equals .23 percent DTPa-HepB-IPV recipients, and 3 cases among 776 equals .39 percent control vaccine recipients.

Thus there is strong evidence that the higher incidence of low grade fever did not result in clinically relevant consequences.

The safety of the candidate vaccine following the administration of a birth dose of hepatitis B is of practical relevance. This question -- next slide, please -- was addressed in a randomized trial conducted in the U.S.

In study 003 one group of infants received a dose of hepatitis B at or shortly after birth, while the comparator group did not receive a hepatitis B dose at birth. And then three doses of the combination vaccine were given at 2, 4, and 6 months of age.

The combination vaccine was the identical liquid DTPa-HepB-IPV combination under consideration today, but it was used to reconstitute revitalized POP tetanus conjugate prior to injection.

The primary end point was the percentage of subjects reporting any grade 3 solicited symptom during the eight day follow-up period after any of the three doses of the combination vaccine.

This occurred in 23.2 percent of subjects that had not received a hepatitis B dose at birth, and in 20.2 percent, 20.6 percent of subjects that had received hepatitis B at birth.

Non-inferiority was shown as the upper limit of the 90 percent confidence interval for the difference between groups was below the priority find clinical image for non-inferiority.

The percentage -- next slide, please -- the percentage of subjects with solicited symptoms observed over the 8 day follow-up period actually tended to be higher for the group that had not received hepatitis B at birth.

There was no difference between groups when we look, again, at the percentage of infants with clinically more relevant symptoms graded 3 in intensity.

Let me now summarize the findings regarding serious AEs and death. In 12 clinical trials 182 subjects reported 199 SAEs, and this translates into 2.1 percent among DTPa-HepB-IPV vaccinees, versus 1.8 percent among comparator vaccine recipients. Eight SAEs were considered possibly, or definitely related to study vaccines.

In brief there were three SAEs considered by the investigator to be related to vaccination, all occurred in study 011. Two of the three cases involved symptoms that were related to the Hib injection sites, while the third case was associated with high fever.

There were five SAEs considered possibly related to vaccination. Four of these cases involved fever, and in three of these cases an alternative cause of fever was diagnosed, possible influenza, possible viral infection, and possible gastroenteritis, or bronchitis.

In the 12 clinical trials contained in the BLA, six unrelated deaths were reported. Five deaths in 7,028 DTPa-HepB-IPV vaccinees, and one death in 1,764 comparator vaccine recipients.

Here the causes of and relationships to vaccination are listed for the six deaths. All cases were considered unrelated, or probably not related to vaccination.

In study 011 there was one case of sudden infant death syndrome in the candidate vaccine group, and one case of SIDS occurred in the control group. The overall incidence of SIDS was .2 per 1000 infants in the German safety study 011, and this must be seen against an expected backdrop rate in Germany of more than 1 case per 1,000 live births. A rate that is very similar in the U.S.

It is worth mentioning that in the 12 clinical trials with 7,000 DTPa-HepB-IPV vaccinees, no cases were reported of hypotonic hyporesponsiveness encephalopathy, or anaphylaxis.

Ladies and gentlemen, with respect to safety and reactogenicity let me conclude. In 12 clinical trials, 7,028 subjects received almost 21,000 doses of DTPa-HepB-IPV that was an active follow-up with standardized methods across all trials.

Rates of common solicited AEs, as well as less common AEs were similar to separately administered U.S.-licensed vaccines. Rates of low grade fever were higher, but did not result in clinically relevant consequences.

No unusual pattern or symptom complex were identified for any of the SAEs reported in any of the clinical trials. Three doses of DTPa-HepB-IPV when mixed with Hib, following a dose of HepB were well tolerated.

So the combination of antigens does not place infants at an increased risk of clinically relevant AEs.

Thank you very much, and at this point I would like to hand over to Dr. Clare Kahn.

DR. KAHN: I have some overall conclusions to make pertinent to the consideration of the questions.

Concerning the adequacy of efficacy data for all antigens we show that the combination was at least as immunogenicity as separately administered U.S.-licensed vaccines, and with special regard to hepatitis B, the 2, 4 and 6 schedule in the combination was at least as immunogenic as 016 schedule, in terms of seroprotection for hepatitis B.

Regarding the adequacy of the safety data, GSK has extensive clinical and post-marketing experience with individual antigens, alone or in combination, the safety of the product has been demonstrated in more than 7,000 infants, even as a three dose primary series, and this safety profile was generally similar to separately administered U.S.-licensed vaccines.

Especial attention has been given to fever, and the rates of low grade fever are higher with this combination than the separate vaccines. This is not so for grade 3 fever.

And, importantly, this difference did not result in clinically relevant sequealling. Regarding the co-administration with U.S.-licensed vaccines, the data show that there is no interaction upon co-administration of Infanrix HepB-IPV with U.S.-licensed Hib vaccine.

And we are planning a co-administration study of Prevnar as a post-approval commitment.

We saw safety data for three doses of the combination product, in fact mixed with Hib, following a birth dose of hepatitis B. And under these circumstances the vaccine was well tolerated, and when comparing those who received a birth dose of HepB to those who did not, there was no increase in any grade 3 solicited symptoms, this was the primary endpoint of this study, or for the solicited symptoms specific rates of adverse events.

Regarding boosters after the combination, we've experienced in hand with the administration of fourth dose boosters following administration of Infanrix HepB-IPV in the primary series.

But before I describe the scope of this data, let me make the following clarifications. As noted in my introduction, the focus of the current BLA, and this current presentation, is the indication for the use of the combination administered at 2, 4, and 6 months of age, with the recommended schedule thereafter.

But in addition to that we do have some data, and these were submitted to the FDA at their request, they are in the form of synopsis. And these are three studies in which the fourth dose of the series was administered as Infanrix, shown here in the green box, following three doses of the combination.

And here we have safety data in 327 subjects, and immunogenicity in 152. And such data would be from the future supplement to put this data and describe them in the label.

And, furthermore, we have six studies in which all four doses, 2, 4, 6, and 12 to 18 months of age, the administration of the full combination. And here we have safety in 816 and immuno in 303.

So these data are somewhat supportive, perhaps, of the fourth dose of Infanrix.

Now, the data here for the three doses of combo with the fourth dose of Infanrix were highlighted in FDA's briefing document. And we are happy to address questions on that, should you wish to see that.

But, again, these were only submitted as synopsis officially in the BLA.

Now, the safety and efficacy of Infanrix HepB-IPV in infancy received one or more doses of the DTPa vaccine in the primary series has not been studied.

But in keeping with ACIP recommendations that interchangeability of acellular DTB vaccines in the primary series is not recommended, we suggest that since DTPa in the combination is identical to Infanrix, we suggest that Infanrix DTPa-HepB-IPV may be used to complete the primary series in infants who received one or two doses of Infanrix.

In final conclusion, then, here is the current immunization schedule published in MMWR for 2001. And we've highlighted the three component vaccines that form the combination.

This is hepatitis B vaccine here in the first year of life in the yellow, and into the second year. Three doses of the primary series of DTPa, and the first doses of IPV.

And as you will see it is possible to have as many as five injections in a single visit, or perhaps elect to defer doses.

So here would be the proposed schedule, looking at the inclusion of DTPa-HepB-IPV combination at 2, 4, and 6 months of age, which is a lot less busy looking.

And the advantages of such combinations are clear. Here you are targeting five diseases with one single injection, and in the primary course for those antigens, for those five diseases, you are reducing -- not yet for that one -- you are reducing those injections from -- not from 9 to 3, so just 3.

And in the first year, for the overall primary course, you are reducing injections from 15 to 9.

And, furthermore, for such a combination vaccine there is the potential for pharmacoepidemiologic or pharmacoeconomic benefit. And in fact outcomes modeling studies have been conducted by Alan Meyerhoff and presented at meetings last year.

And I know he is in the audience if there is any interest in that aspect of these combinations.

So this formally concludes GSK's presentation for the day, and thank you for your attention.

CHAIRMAN DAUM: Thank you very much, SmithKline presenters, Dr. Kahn, et al. We now will entertain comments from the Committee regarding the sponsor's presentation. Questions? Ms. Fisher.

MS. LOE FISHER: How long did you monitor children for persistence of antibodies to all antigens in the combination vaccine versus the separate injection controls to confirm long-term immunity?

And how long did you monitor children which had acute reactions, particularly the more serious reactions, for development of autoimmune neurological or behavioral disorders following the 30 day acute observation period?

DR. KAHN: Dr. Barbara Howe.

DR. HOWE: So with respect to persistence of immunity we followed infants, after the three dose primary series up until the time of the booster in a number of the trials.

We have data with us in the context of persistence and boosting data. In the U.S. studies that included up to a mean age of 14 months, that is in study 015, we followed the children out until mean age of 14 months and administered a booster dose of, actually, separate injection DTPa and Hib. So Infanrix and U.S.-licensed Hib vaccine.

And in study 044, which was the consistency study, we followed children out to a mean age of 16 months, and administered booster doses there. And I do have data to show that persistence was comparable in those who received the combination vaccine at 2, 4, 6, out to the mean age of 14 months as to those who had received separate administration of the U.S.-licensed products out to the mean age of 14 months.

MS. LOE FISHER: For hepatitis B too?

DR. HOWE: Yes.

MS. LOE FISHER: And then the reactions?

DR. HOWE: In terms of the reactogenicity and the safety data children were followed up until 30 days after the last dose of vaccine.

Some of these children would have gone on to be included in booster trials as well, but not all of the children.

MS. LOE FISHER: So you don't know what happened to those children after 30 days?

DR. HOWE: Unless they were subsequently in booster trials.

CHAIRMAN DAUM: Dr. Stephens, please.

DR. STEPHENS: Two questions. One relates to the demographics in terms of race, ethnicity, sex of the infants used in the study, and any differences that you saw based on those parameters.

DR. HOWE: So your question was about demographics. And for the majority of the studies in the file more than 95 percent of the infants were caucasian, with the exception of the two U.S. trials, which provided much more heterogeneity in terms of ethnicity.

I believe that demographics for study 015, 044 and 011 are all in the FDA briefing document. In study 015 a little less than half of the children were caucasian, 34 percent hispanic, and 10 percent afro-american. And there were assorted other, I think middle-eastern, Samoan.

And in study 044 about 85 percent of children were caucasian.

DR. STEPHENS: The question was actually different than that. It was about differences in rates of reactions among ethnic groups --

DR. HOWE: I'm sorry, we do not have reactogenicity analyzed by ethnicity.

DR. STEPHENS: Or immunogenicity?

DR. HOWE: Or immunogenicity, right.

CHAIRMAN DAUM: Dr. Gerber do you want to clarify this? I will put you in line here, one second. Dr. Goldberg, Dr. Kohl, then Dr. Gerber.

DR. GOLDBERG: Okay, I have two questions. One relates to, it is in your briefing document, on the lot to lot consistency trial, when you looked at FHA and PRN, where you weren't able to show equivalence crudely, you did an adjustment where you removed the subjects with high baseline titers.

DR. HOWE: Yes.

DR. GOLDBERG: Did you do analysis within strata by baseline titer, and do you have the distribution of baseline titers, and what might the overall impact of that removal be?

You brought the difference down, but not completely. And I'm a little concerned about that. Do you have any more information to bear on that?

DR. HOWE: Yes. I think if I could have the maternal antibody folder? So to take this in a couple of parts, first I will just answer what was the distribution of the pre-existing antibody titer across the various lot groups.

So this shows the distribution of pertussis titers by antigen, first of all, anti-PT, and what you see plotted here is the distribution of titers. This is, I don't know if you can see it, but 10, 20, 40, and 80 for each of the three lots, with a color coding similar to what you had seen when I showed you the immunogenicity.

You can see the pre-existing antibody titers for anti-PT were actually relatively low. This is typical. And was equally distributed across the three lot groups.

If we see, then, the results for anti-FHA, anti- pre-existing antibody titers to anti-FHA were higher, but again, they were relatively equally distributed at these higher titers. Again, this is greater than equal to 40, this is greater than equal to 80.

If we look at the results for anti-pertactin, again, higher levels of pre-existing antibody for pertactin similar to anti-FHA. If we look at the higher titers, though, this is greater than equal to 40. And then, particularly greater than equal to 80, this is for lot A, B, and C.

Here are the proportion who had the titer greater than equal to 80 at baseline for lots A, B, and C. And lot C was the one that had the lowest response. So you can see the proportion who had a titer greater than equal to 80, with lot C, was 7.1, lot B 0.9, and lot A 2.8.

So this is what I'm talking about, an imbalance in the pre-existing titers.

DR. GOLDBERG: And then did you look at the response within those strata?

CHAIRMAN DAUM: You need to speak right into the microphone, Dr. Goldberg, please.

DR. HOWE: We didn't look within the strata. I can ask our biometrician to explain exactly what the definition of high maternal antibody was, and what was done in the reanalysis.

DR. GOLDBERG: Okay.

CHAIRMAN DAUM: Could you tell us who you are, please?

DR. CHEUVART: Yes, my name is Brigitte Cheuvart, I'm a statistician.

CHAIRMAN DAUM: Right into the microphone, and you are all set. Thank you.

DR. CHEUVART: Thank you. So in terms of vaccine response we had the issue that we were dealing with vaccine response rate which were quite high, around -- very close to one hundred percent.

Therefore it was difficult to apply a stratified analysis, because the stratified analysis are really based on Asantotic methodology. And we felt that in the context of grades very close to one hundred percent, it would be preferable to do an analysis where we would have excluded subject with high pre-vaccination titer.

Can you show, maybe, the slides with respect to the reanalysis? It is in the folder of all statistics. It is, yes, the next one, please.

So this is illustrating the relationship that we had between the post-vaccination titer, and the pre-vaccination titer, for one of the pertussis antigen. And we had the same pattern for the three pertussis antigen.

So you see that there is really a strong relationship between pre-vaccination titer, and post-vaccination titer. Below you see here the slope with respect to that -- with respect to a regression, for the three pertussin antigen.

And you see that the confidence above 40 slope is excluding minus 1, as well as 1.

MS. LOE FISHER: I'm sorry, does that exclude -- that excludes the patients, the subjects with the high titers at baseline, or is that all the patients?

DR. CHEUVART: This is fully including all the subjects. With respect to the GMT analysis, what we did, we applied an ANCOVA model to adjust for the possible imbalance with respect to pre-vaccination titer.

For vaccine response, since there were not satisfactory method, exact method dealing with rates very close to one hundred percent, we did supportive analysis, which excluded subject with very high titer.

And how did we select the subject to be excluded? We examined the relationship between the post-vaccination titer over the pre-vaccination titer, with respect to the pre-vaccination titer.

And what you see is subject with pre-vaccination titer above specific value will have little problem. It will be very difficult for those subjects to have a vaccine response. The vaccine response being defined by post-vaccination titer above the pre-vaccination titer.

CHAIRMAN DAUM: Thank you very much. I think we are really going to move on at this point. It is such intense scrutiny on pertussis, it sure would be nice to know what the protective correlate is and what to interpret here, but I think we will move on.

Dr. Kohl please, then Dr. Gerber, and Dr. Faggett.

DR. KOHL: Before we get to the clinical relevance of the results I would like to ask the manufacturer to verify that, indeed, they set up a priori definitions of non-equivalency.

And although it has been stated several times that all the results were equivalent in terms of serological results, my understanding of both the reading and the presentation this morning was, in looking at the GMT of both hepatitis B, given at a different schedule, and it was done to test whether they were equivalent at those schedules, and also looking at the FHA results in the only data that I think were presented, there was non-equivalency of the GMTs.

DR. HOWE: So with respect to the co-primary endpoints that were mentioned, seroprotection rates to each of the contained antigens, as well as vaccine response rates to the three pertussis antigens, as well as geometric mean titers to the three pertussis antigens, were a priori defined as primary endpoints, co-primary endpoints.

For all of the other antigens, other than pertussis, the geometric mean titers were secondary antigens. And with the exception of hepatitis B in a couple of the studies, actually, there were not pre-defined criteria for non-inferiority for HepB.

When there was, there was still a secondary endpoint. I just want to be clear that the limits for non-inferiority, and for equivalence, particularly for the pertussis antigens are the same as was used in the context of licensure of Infanrix itself, in order to bridge from efficacy trials, for instance, to a U.S. population.

So, for instance, for immunogenicity bridging for the pertussis antigens there is precedent for those, for those pre-specified criteria.

Does that answer your question?

DR. KOHL: Thank you. Could you just say yes or no? With the FHA levels and the hepatitis B levels by schedule not equivalent?

DR. HOWE: Well, for HepB the endpoint was, in the DTPa-HepB-030 studies, the primary endpoint was seroprotection rates. So the non-inferiority testing was on seroprotection rates to HepB, not to the GMTs.

DR. KOHL: So it wasn't tested there, and it was non-equivalent for FHA.

DR. HOWE: And for FHA you are right. In the 015 study the vaccine response rate marginally exceeded, or the difference in vaccine response rates marginally exceeded the pre-specified limit.

CHAIRMAN DAUM: Dr. Gerber please. Thank you.

DR. GERBER: With respect to the increased incidence of fever in the combination group, I understand that you are talking about temperatures of 100.4 or greater, but less than 103.2.

That is a fairly large range. And what I'm wondering is, what is the distribution of those temperatures, for most of these temperatures of 101, 102, 103, do you have that information?

DR. KAUFHOLD: In the two comparative trials, 015 and 011, we have indeed made this breakdown. In the upper part of the slide you see the results, the breakdown for the study 015.

And in this trial any fever, as well as fever above 38.6 degrees centigrade, and fever above 95 percent degrees centigrade, there was no statistical difference between groups.

However, the trial was not designed to detect such difference, the sample size was much too small.

Now, if you look at study 011 you see in green highlighted those temperature categories for which there was a statistical difference. So for any fever that is defined as fever greater than 38 degrees centigrade, and fever greater equal than 38.5 degrees centigrade, there was no statistical difference for higher grade fever above 39.5 degrees centigrade.

And in this trial there were only two cases of children who had fever above 40.5 degrees centigrade. One was in the group that received the candidate vaccine, whereas the other case was in the group that received separate administrations of licensed vaccines.

CHAIRMAN DAUM: Dr. Faggett, then Dr. Fleming.

DR. FAGGETT: My question is adequacy of safety data. You mentioned that safety was demonstrated in 7,000 infants at three dose primary series.

One of the earlier speakers mentioned 5,000 infants, 015 and 011 study, and 1,600 children were mentioned in the German safety study. My question is, what is the total number of children in the safety studies, and is that ongoing, and what is your endpoint in terms of how many you plan to study?

DR. KAUFHOLD: So the total, altogether 7,028 children received at least one dose of vaccine. And as I showed in the main presentation there were only very few subject excluded both from the ITT analysis and from the ATP analysis.

DR. FAGGETT: So how many -- is this ongoing, what is your endpoint, in terms of how many children --

DR. KAUFHOLD: I'm not sure if I understand the question.

CHAIRMAN DAUM: The question is, are there ongoing trials conducting safety data that you are conducting right now, right?

DR. KAUFHOLD: Yes.

DR. FAGGETT: Seven thousand sounds kind of small to me, I mean it is --

CHAIRMAN DAUM: And the answer is?

DR. KAUFHOLD: There are no ongoing trials.

DR. FAGGETT: Okay, thank you.

CHAIRMAN DAUM: Dr. Fleming is next, and wanted to see the last slide that you showed, Dr. Kaufhold. If you could put that back up, please?

DR. FLEMING: Great, I have a number of issues, and I would like to reserve my questions to the end just to avoid overlap. And I did want to, since this slide was put up, it does get at the heart of the issues.

My interpretation of this data are that there is much more strength of evidence here about an increase in fever than your interpretation. I think when you had presented the data on 015 you noted the estimates for the fever greater than 38, that the -- relating to whether the confidence intervals are overlapping. In fact confidence intervals can overlap. That is not the way you assess whether there is a statistically significant evidence of an increase.

Your upper limit of the confidence interval for the difference does, in fact, reflect what is on the margin of statistical significance on the 015 trial. You are estimating an 11 percent higher rate.

The lower limit, which you would be using in a non-inferiority sense clearly is not satisfying in non-inferiority criteria, in fact, it is on the edge of being statistically significantly greater.

You have in 011 clear cut evidence of a statistically significant greater rate of fever. The estimate is 13. -- the difference is 13.7. The lower limit of the confidence interval is close to zero.

And in addition to that you have certain trends that, granted, is under power for the fever greater than 38.6, but you have consistent trends in the two.

These data are improperly interpreted as not providing statistically significant evidence of an increase in fever. Clearly there is, and it is consistently seen in these two studies, as it is seen in the 044 trial.

CHAIRMAN DAUM: Thank you, Dr. Fleming. Dr. Ball next, then Ms. Fisher.

DR. BALL: I wanted to comment that some of the questions that you are addressing now, as well as what Dr. Gerber addressed, which is with regard to what degree of fever are found in my slides, and I will be discussing that later.

And I don't know if you have the information in front of you, but it may be easier for people to see that slide, because I know I can't see that slide.

But if you have my briefing, or my slides, slide number 31 addresses the incidence of fever in study 011, and it breaks it down to fever greater than 38.6 degrees, and 39.5 degrees.

And as you can see here with the asterisk the difference is for the groups, for fever greater than 38 degrees, and greater than 38.6 degrees, were statistically significantly different.

Study 015 was addressed in slide 35, with the same information, fever greater than 38 degrees, fever greater than 38.6 degrees, and fever greater than 39.5.

And as Dr. Fleming pointed out, fever with greater than 38 degrees in this study was on the margin of being statistically significant. But the trends were the same in both studies.

CHAIRMAN DAUM: Thank you. I know that you are planning to return to this topic in some depth, and the Committee members will have a chance to reflect on this issue further after the FDA presentation, as well.

Ms. Fisher, please.

MS. LOE FISHER: I'm interested in the -- getting more information about the two seizure cases. One was, I think, in the adverse event category of febrile seizure, which was then determined to be caused by an underlying seizure disorder, the other was a death that had the cause of death listed as an underlying seizure disorder.

Was this the same patient, and what determination was made that the seizure, was this the first time that the seizure had occurred following the vaccination, had there been pre-existing seizures?

And what was the determination, how did you determine that they were not connected to the vaccine? And I have the same question on the deaths. Because you had five deaths in the combination group and only one death in the controls.

That seems pretty significant to me, and what determination was made that those deaths were not, indeed, in some way connected with the combination vaccine?

DR. KAUFHOLD: You are right, there were five deaths in the group that received the combination vaccines. That includes all trials that are contained in the BLA, and one death in the comparative vaccine.

If you now look at the denominator you can, and the denominators between those two groups are, obviously, very different. So if you compare the percentages the figures are virtually identical.

Perhaps we can have another look at the slide that lists all the deaths, perhaps that went too fast.

Altogether there were three cases of sudden infant death syndrome, the next one please, three cases of sudden infant death syndrome. I highlighted in my presentation, in the comparative study 011 there was one case, in the group that has received the candidate vaccine and one case in the group that received separately administered licensed vaccines.

Then there was one case of neuroblastoma, and one case of congenital immunodeficiency. And if you will read the narratives, we -- one can support only the conclusion of the investigator that stated that these cases are certainly unrelated to vaccination.

With regard to your question regarding convulsive disorder, yes, there were altogether two febrile convulsive disorders in study 011. And one occurred after four days post-vaccination, and the other case occurred more than two weeks post-vaccination.

The case with the febrile seizure is the same, that was diagnosed to have an underlying convulsive disorder, and this child died later on.

MS. LOE FISHER: So it was the same patient?

DR. KAUFHOLD: It was the same patient.

CHAIRMAN DAUM: Dr. Diaz, then Dr. Broome, and then I think we are going to take a break.

DR. DIAZ: Thank you. I have just a couple of questions. The first in regards to immunogenicity.

Do you have -- how did the anti-PRN data vary lot-to-lot consistency for the original Infanrix? Did you see the same kinds of differences in the immunogenicity lot-to-lot?

DR. HOWE: I have to go back to look at the exact definition of lot consistency at the time that Infanrix was licensed, to be quite honest.

And I don't think that the same criteria were applied. Maybe another way -- I mean, I can certainly share with you how this data compare with anti-PRN results, or other antigens, results for other antigens.

With respect to the efficacy trials that data I have with me. I don't know if that helps to answer your question. But I can say that the criteria for consistency were not -- those same criteria were not applied to Infanrix in the context of that licensure, because that was years ago. These were subsequently developed.

DR. DIAZ: And in the studies today, that are being presented, were the same -- it may be implied, but I don't recall seeing it in your data. Were the same lots used to prepare the combination vaccines that were used for the control lots in the studies?

DR. HOWE: In terms of the -- no, these were commercial lots of, for instance, it would be a commercial lot of purchased Infanrix, or commercial lot of Engerix-B.

In terms of, for instance, the Lederle OPV could have been multiple lots.

DR. DIAZ: And how were those lots chosen?

DR. HOWE: They were just chosen as to what was available commercially, on the market. In terms of the Infanrix and the Engerix-B there was, in general, a single lot used throughout the course of the trial. That was true for the Hib vaccine, as well.

But these were commercial products that we would purchase.

DR. DIAZ: So from study site to study site the lot may have varied in terms of the control group?

DR. HOWE: No, no. The lot was the same for Infanrix, for Engerix-B, and for Hib in the trials. The lot would have been provided to the site, but it was a commercial lot, I'm sorry.

And then for oral polio, in the trials we did allow the sites to purchase their own. So that is the only one for which we used various lots.

CHAIRMAN DAUM: Thank you, Dr. Howe. Dr. Broome, please.

DR. DIAZ: Just one other question if I could, please.

CHAIRMAN DAUM: If it is very brief.

DR. DIAZ: You've looked at children post-vaccination up to four days, and then at 30 days, correct? And I recognize that in the recommendations from the FDA to the manufacturers they recommend following children up to seven days, initially.

And I was just curious why you chose four days as your cutoff.

DR. HOWE: So for the detailed reactogenicity analysis the period of solicitation was four days.

DR. DIAZ: For safety?

DR. HOWE: For safety, yes. And then for -- but, however, for unsolicited symptoms the period for follow-up was 30 days after each vaccine dose. And then for serious adverse events they were followed throughout the entire course of the trial, for up to 30 days after the last dose.

DR. DIAZ: I was just curious if there was a reason.

DR. HOWE: Well, four days, I think, is more typical of inactivated products. For instance, in some later trials we may have had an eight day period of solicitation, but these trials were all designed for four days.

DR. DIAZ: I just noticed that the industry guidelines recommended seven days.

CHAIRMAN DAUM: We are going to move on now. Please, Dr. Broome?

DR. BROOME: I'm still interested in this issue with the possible lack of lot consistency with the pertussis antigens.

The reverse cumulative distributions you are showing are all for post-vaccination, they do not include pre-titers. And in the reverse cumulative distribution, in study 44, there seems to be a slight but consistent left shift for lot C.

So I wondered if you could show me the reverse cumulative distribution for study 027, in terms of whether that was seen in that, you know, other larger study.

(Unmiked answer.)

DR. BROOME: It is a fairly slight left shift, but I thought that was somewhat interesting for the anti-PRN. And it wouldn't, you know, it is independent of the high pre-existing titer. So it looked like an observation worth noting.

CHAIRMAN DAUM: I don't suspect the person trying to bring the slide up has too much anxiety at this moment.

DR. BALL: Dr. Daum, can I just interject? This was one issue that we looked at, and I think they are having a difficult time finding the slide. But the backup slide which unfortunately I didn't bring today, shows that those lots were basically superimposable.

There wasn't that difference in that outlier, the lot, in study 027.

CHAIRMAN DAUM: Can we accept that?

DR. BROOME: Sure.

CHAIRMAN DAUM: Here we have the slide. Take the anxiety off for a moment, distract it.

DR. HOWE: These are the three lots, then, in red, yellow, and black, lots A, B, and C. And these are for anti-PT. But if you could just go to anti-FHA? And what we really want to see is the anti-PRN.

Those are very superimposable, anti-FHA, and here is anti-PRN.

CHAIRMAN DAUM: Thank you very much. Thank you for the sponsor's presentation. We will revisit some of these issues, I'm sure, when we hear from the FDA, and have Committee discussion.

We will take a 15 minute break and reassemble at 11:35.

(Whereupon, the above-entitled matter went off the record at 11:24 a.m. and went back on the record at 11:44 a.m.)

CHAIRMAN DAUM: I'd like to get started so that those of us like lunch can get there.

Before we move on to the FDA's presentation on this issue, I would like to ask a favor, or make a request of our audience members today. A number of people have complained to me that there is sufficient amount of buzzing and talking there that they have actually been distracted from being able to hear what is going on in the meeting.

And I would like to request that people minimize, or eliminate that kind of conversation, and maybe step outside for a moment if they need to have a conversation while the meeting is going on. Thank you.

There is one more announcement, we will turn the floor over to Nancy.

MS. CHERRY: Yes. I understand -- I know that there is a binder with briefing materials that is out on the table, or that was out on the table. I understand that all of the sponsor's briefing materials have all been given out.

And now the binder has disappeared. So if you look around and you see your neighbor with that binder, would you kind of -- since we asked you not to talk, but at least jab that person in the elbow and hint that they take it back to the table out there, and give it to Dennise and Rosanna. Thank you. The binder has a copy of the briefing materials.

CHAIRMAN DAUM: I think we will call on Dr. Ball at this point.

DR. BALL: Good morning. I will be presenting the FDA's clinical review of GlaxoSmith Kline's DTPa-HepB-IPV combination vaccine.

My intent is not to present all the material that was presented this morning, nor present everything that was in the briefing document from the FDA, but to highlight some issues for your consideration.

First I will discuss the proposed indication and provide an overview of this combination, and the FDA's approach to combination vaccines. Next I will discuss the clinical studies submitted in the license application to support efficacy and safety of this combination vaccine.

I will present the available data on concomitant vaccines, and as was noted, this will consist of data with concomitant Hib vaccine. Prevnar was not licensed, nor was it commercially available at the time the studies were conducted, and at the time the BLA was filed.

In addition I will discuss some limited data on the fourth dose of Infanrix following a primary series of the DTPa-HepB-IPV vaccine. Finally I will present the questions and discussion points for the Committee.

The proposed indication, as was mentioned earlier today, for this combination is a three dose primary series, given at 4 to 8 week intervals, with the customary age of administration, 2, 4, and 6 months of age.

This slide presents the current recommended childhood immunization schedule to illustrate how this combination would fit in the existing schedule.

The combination under discussion today contains the components that are in light yellow, namely DTPa, HepB, and IPV. The proposed schedule, as was mentioned, would fit under this time frame, 2, 4, and 6 months of age.

So what would this vaccine mean in terms of injections administered to infants during the primary series? Under the current recommended childhood immunization schedule an infant would typically receive four to five injections per visit, depending on the formulation used, as illustrated here.

With this new combination vaccine, if it is used in the primary series, and if it would receive up to three injections per visit in the primary series, namely that of the combination Hib and the pneumococcal conjugate vaccine.

Next slide. As we heard, earlier today, the hepatitis B vaccine consists of two vaccines that are currently licensed in the U.S., namely Infanrix, DTPa and hepatitis B, Engerix-B, as well as the IPV component that is not currently licensed in the U.S.

In the FDA approach to the licensure of combination vaccines, there are two regulations that I wanted to mention.

First a new license is required when already licensed products are combined, or when unlicensed components are added to a licensed vaccine. Secondly, products may be combined if each component makes a contribution to the claimed effects, and combining does not decrease the purity, potency, safety, or effectiveness of the individual components.

In addition the FDA's approach to combination vaccines is outlined in the 1997 guidance document for industry, which states: Clinical studies of combination vaccines should be designed to rule out clinically meaningful differences.

The approach taken for licensure of this combination has been through the evaluation of immunogenicity of each component in the combination, rather than clinical end point efficacy studies.

In other words, efficacy is inferred from immunogenicity. The objectives of the clinical studies of the combination have been based in first demonstrating non-inferiority of the combination, compared with separately administered U.S.-licensed vaccines, namely Infanrix, Engerix B, oral polio, and in study 015, IPV.

Note that polio vaccine was the standard of care at the time of studies to support licensure were conducted.

In addition, for those components having a generally accepted immune correlate of protection, namely D and T, hepatitis B and IPV antigens, the clinical studies have sought to demonstrate that the immune response to the combination exceeds these correlates.

The objectives of the clinical studies in support of licensure have been to demonstrate the immunogenicity and safety of DTPa-HepB-IPV, to evaluate the immunogenicity when vaccine is given concomitantly under the recommended schedule, immunization schedule, and to demonstrate that the vaccine can be manufactured consistently, and to demonstrate that clinical bridging between the two sequential lots following a manufacturing change.

You have heard, earlier today, about the clinical studies submitted in support of licensure. I will be concentrating on the three pivotal studies that are in this slide namely study 011, which was the large-scale safety trial conducted in Germany under a 3, 4, 5 month immunization schedule.

Study 015 evaluated the immunogenicity as safety on the schedule of 2, 4, and 6 months of age. Study 044 examined DTPa-HepB-IPV for lot consistency and manufacturing bridging from the first production lot to the second lot series.

The total number of subjects receiving the combination in the pivotal trials was over 5,000. In addition to the pivotal trials Dr. Howe discussed data from supportive studies not conducted under USIND that were submitted to the license application.

These studies used the same procedure for evaluating safety immunogenicity generally speaking, as the pivotal trials, but utilized different schedules at times and comparators that were not U.S.-licensed vaccines.

The total data base of subjects receiving the combination in the pivotal and supportive trials was approximately 7,000, with 764 of these subjects receiving the combination at the 2, 4, 6 month schedule.

Additional data were provided through studies of related DTPa Infanrix combination that were not licensed in the U.S. These Infanrix-based combinations were DTPa-HepB-IPV Infanrix with Hib, as was mentioned earlier today and the combination DTPa-HepB vaccines.

These studies provided additional data on lot consistency, the safety of the primary series following a birth dose of hepatitis B vaccine, and data on the change and schedule of the administration for hepatitis B combination for the hepatitis B component in a combination.

This slide presents the demographics of the clinical studies as DTPa-HepB-IPV that was submitted in the license application, with specific data on the pivotal trials, and total data for both the pivotal and supportive studies.

As highlighted in blue the majority of infants studied in the clinical studies were caucasian. The population was diverse in a pivotal study conducted in the U.S.

Now I will move on to examine the studies evaluating the immunogenicity of the combination vaccine. The primary immunogenicity endpoint included the percent of subjects achieving immune response correlated with protection for the D and T, Hib and polio components.

For the pertussis components the immunogenicity endpoints evaluated were the percent of infants showing response to PT, FHA, and Pertactin. In addition geometric mean titers were evaluated.

In assessing the immune response the statistical approach used for evaluating the combination vaccine compared with a separate administration of U.S.-licensed vaccine, was for testing for non-inferiority.

For non-inferiority testing a one sided equivalence test was used with an alpha of five percent. To evaluate manufacturing consistency a two-sided equivalence test was used.

AS was mentioned earlier today, pre-specified limits for defining non-inferiority were maximum difference of ten percent for seroprotection vaccine response rates to D and T, pertussis, hepatitis B and polio antigens.

For GMTs the pre-specified limits for non-inferiority were maximum ratio of 1.5 on the GMTs for the pertussis components, and 2.0 for the hepatitis B component. And hepatitis B GMTs -- I'm sorry, go back for a second. Hepatitis B GMTs were considered a secondary endpoint.

Now we will discuss the specific clinical studies. The objective of study 015 was to evaluate immunogenicity and safety of a primary series of the combination compared with separately administered U.S.-licensed vaccines.

The study was conducted in the U.S. on a 2, 4, 6 month schedule. This slide depicts the study groups to which the infants were randomized. In the study I will concentrate on group one which received the combination with Hib vaccine, and group 4, which received the -- I'm sorry, separately administered Infanrix, Engerix-B, Hib, and OPV.

Group 2, as was mentioned earlier, evaluated the combination vaccine given in a sequential schedule, which is no longer the recommended schedule in the U.S.

In addition group 3 examined the combination DTPa, hepatitis B, which is no longer licensed in the U.S., and is no longer under consideration today.

This data presented, in terms of the immune response for the two eligible groups, as I mentioned, group 1 and group 4. And the difference of immune response was seen with a 90 percent confidence interval on the difference.

Note the statistical methodology was non-inferiority, a one-sided equivalent testing, for sero response and vaccine response. The upper bound of the 90 percent confidence interval should not exceed 10 percent.

Dr. Howe earlier presented the immune response data for all the antigens contained in the combination, and noted that all pre-specified immunologic endpoints for demonstrating non-inferiority of a combination, compared to the separately administered vaccines were met, with the exception of the percent responders to FHA.

This slide presents the vaccine response to pertussis antigens, to each of the pertussis antigens, and highlighted in blue is FHA, which exceeded the pre-specified limit of ten percent.

I think it should be noted that variability of immune response to FHA has been noted previously, specifically in studies used to support licensure for Infanrix DTPa.

In the German household contact study multiple lots of Infanrix were used showing various immune responses to FHA, but efficacy did not appear to differ among these lots.

The second pivotal study of immunogenicity was study 044, which evaluated lot consistency in manufacturing bridge. This study was conducted in the U.S. on a 2, 4, 6 month schedule.

This slide depicts the study groups in study 044, which evaluated lot consistency in groups 1 through 3, which consisted of three lots of the second lot series in the combination and mixed with Hib.

It should be noted that as compared with the previous presentation by the manufacturer, we've labeled lot C, and lot C are different on the lot that was labeled lot C by GSK we have labeled lot B.

The study also compared pooled lots from the first lot series, I'm sorry, from the second lot series to group four, which contained one lot of the first lot series.

I think it is also important to note that in this study there was no separate administration control arm.

This slide depicts the immune response data for lot consistency. We have the vaccine response rates here, and the GMTs here. And in the middle columns here are the groups 1 through 3, and here are the maximum 90 percent confidence interval limits on the pair wise differences between the three groups.

And for the GMT the maximum 90 percent confidence interval limit on the pair-wise ratio. As was noted earlier today by Dr. Howe, all pre-specified immune endpoints were demonstrating equivalence, that is lot consistency of the second series of DTPa-HepB-IPV were met with the exception of the percent responders to FHA and pertactin, as well as the GMTs to pertactin.

This slide presents the immune response data for the manufacturing bridge from the first to the second lot series. All pre-specified immunologic endpoints were demonstrating non-inferiority were met, with the exception of the percent responders to pertactin.

Here are the upper limit of the 90 percent confidence interval was 12.3 where pre-specified limit was 10 percent.

Now I will present information on the immune response to the hepatitis B component in the combination vaccine. Engerix B, GlaxoSmith Kline's hepatitis B monovalent vaccine is currently licensed under 0, 1, and 6 months schedule.

For the proposed indication the schedule is 2, 4, and 6 months. Several studies in the license application evaluated the immune response of the combination on a 2, 4, 6 month schedule. And these data are presented here.

The observed hepatitis B immune response in infants receiving the combination was significantly greater than the 10 international units per mil, the level considered protective against hepatitis B disease.

In these studies 99 to 100 percent of infants achieved levels considered seroprotective with the GMTs ranging from about 1,400 to close to 1,700.

Note that none of the infants in these studies received a birth dose of hepatitis B. So it is important to note that no data were submitted as part of the license application that directly compared the hepatitis B immune response of the combination vaccine given at 2, 4, and 6 months of age to the immune response of Engerix-B administered at birth, 1, month, and 6 months of age.

Supportive data for the change in schedule for the hepatitis B were submitted from study DTPa-HepB-030, which evaluated SmithKline Beecham's DTPa-HepB combination that is not licensed in the U.S., and the data were presented on the next slide.

So the DTPa-HepB-030 compared the hepatitis B immune response to the hepatitis B DTPa combination, given at 2, 4, 6 months of age, to hepatitis B given at 0, 1, and 6 months of age.

The immunogenicity of the DTPa hepatitis B combination on a 2, 4, 6 month schedule, compared with the standard 0, 1, 6 month schedule, met the pre-specified criteria for non-inferiority with respect to seroprotection, with 99 percent of the subjects given the vaccine on a 2, 4, 6 month schedule, having host vaccination levels above the level considered seroprotective.

The hepatitis immune response to GMTs were lower when the hepatitis B antigen was given on a more compressed schedule of 2, 4, and 6 months of age. However, the hepatitis B immune response of the combination was well above the level considered protective.

Now I will move on to the studies evaluating the safety of DTPa-HepB-IPV vaccine.

The objectives of these pivotal studies was to compare the rates of adverse events following administration of the combination with the separately administered U.S.-licensed vaccines.

Study 011 was a large scale safety study with the objective being to evaluate common and less common adverse events. The study was amended after initial enrollment as was mentioned earlier today, to include a control arm that received a separately administered U.S.-licensed vaccines. The study was conducted in Germany on a 3, 4, 5 month schedule.

It should be noted here that there was no sera drawn to evaluate immunogenicity in this study.

This slide depicts the study arms in study 011. Groups 1 through 4 received the combination vaccine with Hib vaccine from various manufacturers. And as was mentioned, the original intent was to evaluate the safety with these four different Hib vaccines.

Infants in group 5 received separately administered vaccines, Infanrix, Hib, and OPV. As was noted earlier today, group 5 did not receive hepatitis B during the study period.

Also, as was mentioned earlier, the arms of the groups receiving the combination was significantly higher, 4,696 compared with the group receiving separate injections, 776.

This slide depicts the incidence of local reactions in the groups receiving the combinations, compared with the separately administered vaccines, by looking at the site of injection at the DTPa hepatitis B IPV compared with the Infanrix given alone site.

And I'm -- with the vaccines but not in combination. This was measured in three days, following the vaccination for each dose, and for any dose of vaccine. The two columns in the middle present the data on the incidence of redness and swelling in the pooled groups receiving the combination, compared with the groups receiving separate vaccines.

Instead of P-values the last column presents the difference between the groups, and the confidence interval on the difference. The difference is statistically significant if the lower bound on the 90 percent confidence interval is greater than zero.

In this study increased incidence of redness and swelling was observed for groups receiving the combination, compared with the infants receiving separately administered Infanrix.

Following doses 2, 3, and for any dose the difference between the combination and Infanrix were statistically significant. Of note grade 3 local symptoms defined as swelling or redness greater than 20 millimeters did not appear increased in the combination recipients.

This slide presents the incidence of fever greater than 38 degrees after each dose, and after any dose. An increased incidence of fever greater than 38 degrees centigrade was observed in the combination with recipients with a difference between the combination in a separately administered vaccine, statistically significant after each dose, and after any dose of the vaccine when compared with the separately administered vaccines.

For example, following dose one, 25 percent of infants receiving the combination experienced fever greater than 38 degrees centigrade, compared with 13 percent in the group receiving separately administered vaccines.

And for any dose the incidence of fever was 43 percent versus 26 percent in the separately administered vaccines.

To determine whether this increased rate of fever was for low grade fever or higher fever, we further evaluated the incidence of fever in addition to 38 degrees we looked at fever greater than 38.6 degrees or 101.5 degrees fahrenheit, and fever greater than 39.5 centigrade, or 103.2 degrees fahrenheit.

The incidence of fever greater than 38.6 degrees also increased with a difference of 4.7 percent, reaching statistical significance. The incidence of grade 3 fever, greater than 39.5 degrees was not significantly different in the groups receiving the combination, as compared with the control.

I will move on now to study 015, which I discussed earlier, with respect to immunogenicity. This slide reviews the study groups and the data I will present will concentrate, again, on groups one and four.

Note that in the study groups one and two received two injections, and group three and four received three injections, generally, each visit.

This slide presents the incidence of local swelling in the three days following vaccination, similar to the pattern observed in study 011, where the combination was associated with increased redness and swelling, compared with a separate DTPa site.

The incidence of redness and swelling was increased in the group receiving the combination, compared with the group receiving separately administered U.S.-licensed vaccines. Although this difference did not reach statistically significance.

The incidence of redness and swelling greater than 20 millimeters was higher in the group receiving the combination. However, again, this difference did not reach statistical significance.

I think it should be noted that this study was not powered for safety but for immunogenicity, so therefore the finding of no statistical significance may be due to the relatively small sample size.

This slide presents the incidence of fever following each dose and after any dose. As was seen in study 011, the incidence of fever greater than 38 degrees was increased in the group receiving the combination, compared with the separately administered control arm, although this difference did not reach statistical significance.

Again, this finding of non-significance may be due to the small sample size.

The incidence of fever was further evaluated in terms of the degree of fever greater than 38.6 degrees, or greater than 39.5 degrees. The observed incidence of fever greater than 38.6 degrees was increased in the combination, compared to the control, although this did not reach statistical significance.

DR. FLEMING: A clarification. You keep saying did not reach statistical significance. Can you go back to that previous slide?

DR. BALL: Okay.

DR. FLEMING: Confidence interval zero to 24.

DR. BALL: I'm sorry, as I pointed out earlier today, this was really right there in terms of showing a statistical significance, right on the borderline, I mentioned that earlier, sorry.

This slide compares the incidence of fever in study 011 to that of study 015. Recall that the vaccination schedule study 011 was on a 3, 4, 5 month schedule, and study 015 it was 2, 4, 6 month schedule.

The incidence of fever greater than or equal to 38 degrees was fairly similar between the two groups, especially in the groups -- in the incidence of fever greater than 38 degrees centigrade.

The sample sizes for the two safety studies comparing the combination, and the separately administered vaccines were not powered to look at rare events.

I want to emphasize that, specifically events that occurred in the rate of one in several thousand. However, the rates of these events were looked at to see if there were any unexpected findings.

For this purpose the groups receiving the combination vaccine, and the groups receiving the separately administered vaccines, here labeled control, were pooled between studies 011 and 015, and the difference in the incidence was calculated.

Note that the sample sizes of the pooled combination was much higher than that of the control, and thus the absolute number may appear larger in the combination group.

We are here focusing more on the incidence. As was mentioned earlier today, there were no cases of anaphylaxis, hypotonic hyporesponsive episodes, in addition there was no cases observed in the combination recipients for invasive bacterial disease.

Rates of hospitalization, death, and withdrawals due to adverse events were not different, were not significantly different among the groups receiving the combination, as compared to the control.

And, again, recognizing the limitations of this type of comparison, given the sample size, we looked at the incidence of seizures in the groups. For seizures over the full vaccination course, namely during the primary series, 2, 4, 6 months, and one month, to one month following the third dose, the absolute number of events appears higher in the combination vaccines, but there was no difference in the incidence of the seizures when the subjects receiving the combination were compared with the control.

In addition there was no difference observed in the incidence of febrile seizures.

To further evaluate whether the increased rate of fever observed in recipients of the combination translated into increased hospitalizations, or increased evaluations for sepsis, or increased febrile seizures, we looked at the incidence of these events within seven days of vaccination.

The rate of hospitalizations, hospitalizations for fever and febrile seizures observed in the pooled groups receiving the combination compared with the separately administered vaccines was not different. Although, again, I stress the small sample sizes.

Now we will discuss data submitted to the license that addresses the safety of the primary series of the combination following a birth dose of hepatitis B.

With regard to studies filed with the license application there were no comparative trials examining the use of the combination with and without a birth dose of hepatitis B.

The application included the supportive study DTPa-HepB-IPV 030 in which all infants received a birth dose of the hepatitis B. Assessment of safety data from this study was further hampered by the inclusion of the combination vaccine that contained wholesale pertussis as comparator to the combination vaccine.

The manufacturer submitted data from a related Infanrix based combination from study DTPa-HepB-IPV Hib, study 003, to provide supportive data. This study compared the primary series of this combination at 2, 4, and 6 months of age following a birth dose of hepatitis B with the primary series of this combination given without a birth dose.

In this study the rate of grade 3 fever, greater than 39 was somewhat higher in the group receiving a birth dose. The rate of local reactions appeared higher in the group that did not receive the birth dose.

Not shown here were data that were presented previously by the manufacturer on the incidence of any fever greater than 38 degrees centigrade.

Of note the rate of any fever for any dose defined as greater than 38 degrees was similar in the groups with and without a birth dose of hepatitis B.

Now I will present available data on concurrent administrations given in the primary series.

Several studies in the license application evaluated the concomitant administration of Hib vaccine with the DTPa-HepB-IPV combination. Study 015 in the U.S. looked at one type of Hib, and supportive study 012 evaluated the immune response from four different Hib vaccines.

Study 011 different Hib vaccines were used but only safety was assessed.

This slide presents the observed immune response to the Hib component from studies 015 and 012. The level achieving anti-PRP responses greater than or equal to 0.15 micrograms per Ml were 99 to one hundred percent for all groups, and 88 to 95 percent achieving anti-PRP responses greater than or equal to one. The anti-PRP GMTs were between 5 and 7.

As was mentioned earlier there were no data submitted with the license application on concurrent administration of the combination with Prevnar. It should be noted that Prevnar, again, was not licensed, nor was it commercially available at the time these studies were conducted.

Although there are no data on the concomitant administration of Prevnar with this combination, there was some data included in your briefing materials that suggested that concurrent administration of Prevnar with two different acellular pertussis vaccines, namely a cell amune, and an Infanrix based combination vaccine, DTPa-IPV vaccine showed a diminished immune response to Pertactin.

Now I will review data submitted to the license application on a fourth dose of Infanrix following the combination.

As was mentioned for proposed study for the combination it is a three dose primary series. Children receiving the primary series would then need a booster of DTPa at 15 to 18 months of age.

The manufacturer has indicated that at this time they are not seeking licensure for a fourth consecutive dose of DTPa-HepB-IPV. And these data were not reviewed, formally, as part of this file.

Note that a fourth consecutive dose of this combination would mean an extra dose of IPV, and an extra dose of hepatitis B vaccine. In addition if a birth dose of hepatitis B vaccine is administered it would mean two extra doses of hepatitis B vaccine.

These studies conducted data on a fourth dose of Infanrix following a primary series of the combination. Study 015B was the booster phase to study 015 presented earlier.

Study 028 and study 061, specifically 061 was the booster phase to study 044 that was addressed earlier. Some of these studies, as was mentioned earlier today, evaluated fourth consecutive dose of the combination.

The numbers presented here are just for the Infanrix booster following a primary series. Study 015 received a combination plus Hib in the primary series include four received separately administered vaccines.

In study 015B all children were boosted with Infanrix. In this small study the safety and immunogenicity of Infanrix as a target booster following a primary series of the DTPa-HepB-IPV combination was comparable to the safety and immunogenicity following a primary series of separately administered Infanrix, hepatitis B, and oral polio vaccine.

To summarize the data submitted in support of licensure, all pre-specified immunologic endpoints for demonstrating non-inferiority of the DTPa-HepB-IPV were met, with the exception of the percent responders to FHA.

To summarize the data submitted in support of safety, there was an increase incidence of fever greater than 38 degrees centigrade in infants receiving the combination compared with the separately administered vaccines.

The incidence of fever greater than 39.5 degrees was not significantly increased. An increased incidence of redness and swelling was observed in infants receiving the combination compared with the separately administered vaccines, but only in the larger study was this difference statistically significant.

Next slide. I would like to acknowledge the individuals that contributed to the clinical review, especially Theresa Fin, and the others listed here, as well as the CBER Review Committee evaluating the product.

I'm going to move on here to present the questions. The first question pertains to efficacy or immunogenicity, are the available data adequate to support the efficacy of the DTPa-HepB-IPV vaccine, when given to infants in a primary series at 2, 4, and 6 months of age. If the data are not adequate to address efficacy what additional information should be requested.

The following questions pertain to safety. Are the available data adequate to demonstrate the safety of the DTPa-HepB-IPV vaccine combination when given in a primary series at 2, 4, and 6 months of age. Please comment on the increased rates of fever. If these data are not adequate to demonstrate safety, what additional information should be requested.

The discussion point number 3, please discuss data submitted in support of concurrent administration of other routinely recommended childhood immunizations with the combination in infants, namely Hib vaccine, and the 7-valent pneumococcal conjugate vaccine, Prevnar.

Discussion point number 4, please identify any issues that should be addressed in post-licensure studies of this combination, specifically, please include a discussion on the safety and immunogenicity of concurrent administration of other routinely recommended vaccines, namely Prevnar, the safety and immunogenicity of a fourth and fifth dose of Infanrix, following a primary series of this combination, the safety and the immunogenicity of the combination following a complete or partial series of Infanrix, or other DTPa vaccine, and finally the safety of a primary series of the combination following a birth dose of hepatitis B vaccine.

I think I will end here, and I will be happy to answer any questions.

CHAIRMAN DAUM: Okay, thank you very much, Dr. Ball. I think I'm going to ask the Committee for questions and comments about the sort of the meat of Dr. Ball's presentation. And we will deal with the questions after lunch.

So let's take comments. I see Ms. Fisher first. Why don't you go ahead and start?

MS. LOE FISHER: May I ask a question?

CHAIRMAN DAUM: Yes, please.

MS. LOE FISHER: Earlier when I asked the manufacturer about seizures in this study, it was my understanding that there was one febrile seizure, and it was judged to be due -- the child had an underlying seizure disorder and resulted in the death.

You mentioned, it went by so fast, but seven seizures, five of which were afebrile. Now, what is it, one seizure, seven seizures, how many seizures?

DR. BALL: I think it should be clarified. I think what was referred to was the two seizures that occurred within the seven day time frame after vaccination.

The first slide that I presented, I'm sorry, I can't pull that out for you right at the moment, referred to seizures that occurred during the whole vaccination course.

It could have occurred six weeks later, you know, three weeks later after the vaccination.

MS. LOE FISHER: I really think we should have more information about the seizure picture, particularly the afebrile seizures.

DR. BALL: I'm sorry, what more information would you like?

MS. LOE FISHER: How soon after did these occur, was it the first time that it occurred in the child, did the child have a pre-existing seizure history, some more information about seizures.

And I have one more question, and then I won't ask another question.

CHAIRMAN DAUM: Well, before you go on to another question, is this information available?

DR. BALL: I think it is available, but I think the manufacturer could probably clarify or expand on the information that I have at the tip of my fingers, which is that seizures were evaluated over the full study course, and that was the first slide on the serious AEs that I presented.

In addition seizures were presented, also, within seven days of vaccination. There were two episodes of seizures within the seven day time frame. And I think that perhaps the manufacturer would want to clarify further regarding the timing after vaccination, and whether or not there was an underlying condition.

I think that infants -- my understanding was that pre-existing conditions, pre-existing seizure disorders would have kept the children out of this study.

MS. LOE FISHER: Just one other one. Nearly 5,000 of the 7,000 children came from Germany, which unlike the U.S. has a generally homogenous population with respect to genetic diversity.

And also the German children began their vaccinations at 12 weeks, rather than 8 weeks. Can you comment on the possible significance of this, when we apply this vaccine to the U.S. population?

DR. BALL: Certainly. I think that that was something that we looked at very closely, and with regard to the timing of immunization I think that the manufacturer may be able to bring up a slide.

It is in my briefing material that was presented to you that looked at the timing of each dose, and the overlap between the different doses.

And there was significant overlap, particularly for the second, and somewhat the third dose. The timing, certainly for the third dose was delayed between the infants in Germany versus the infants in the U.S.

So the question that we could readily answer is whether or not the incidence of fever, which I think we've sort of identified as one of the key focal points, did the incidence of fever differ whether the vaccines were given at 2, 4, and 6 months of age, versus 3, 4, and 5 months of age.

I think where this becomes clinically relevant, particularly to parents, and physicians who care for infants, is whether or not that fever that would occur maybe in a 6 week old to a 2 month old, would translate to more hospitalizations, sepsis workups and so on, than perhaps if the immunization is given at 3 months of age.

And I did show a slide that compared the rate of fever between the two schedules, 2, 4, and 6, and 3, 4 and 5, and the rate of any fever was remarkably similar between the two groups.

MS. LOE FISHER: It also could have an effect on death, and seizures, etcetera. I mean, the 8 weeks versus the 12 weeks starting.

DR. BALL: Do you mean in terms of the occurrence of febrile seizures?

MS. LOE FISHER: Or afebrile. In other words, the one month difference is going to have an impact, could potentially have an impact, both on immunogenicity as well as reactions.

Just because 5,000, almost 5,000 of the 7,000 children came from Germany, and had the schedule, and were not genetically diverse like we are, I think is an important point to --

DR. BALL: I acknowledge that point, and I think that we looked at that as well.

MS. LOE FISHER: Thank you.

CHAIRMAN DAUM: Other comments? I would like to ask a question that is along the similar kind of lines, and maybe we know, and maybe we don't.

But I'm trying to gauge, in my mind, the impact of the fever excess in the combination group. And I saw some data on hospitalizations this morning, and they were reassuring.

But you mentioned septic workup. I don't know what is the standard of care practice in Germany, where most of these children were. But in the U.S. we tend to do probably an excess, but we do a lot of septic workups in very young infants who are febrile.

We hospitalize them, and I get a sense that there wasn't an excess of hospitalizations. But what did German pediatricians do? I mean, do they react the same way we do?

DR. BALL: I think I will defer to the manufacturer to answer that question.

CHAIRMAN DAUM: Because otherwise we have to know how to interpret the fact that there were or were not an excess of septic workups in the combination group.

DR. KAUFHOLD: In general German pediatricians, the clinical practice that German pediatricians apply is very similar to what is applied in the U.S.

So -- and this includes a very high sensitivity of hospitalizations for sepsis workup. So we don't see a difference between the U.S. and Germany in this respect.

CHAIRMAN DAUM: Thank you. Dr. Gerber, then Dr. Kohl.

DR. GERBER: Could I just follow up on that? Was there an analysis done of just U.S. infants in terms of hospitalization rates, and septic workups between the combination group and the other group?

I believe all of the comments that have been made so far have been on the combined German-U.S. group.

DR. KAUFHOLD: Yes. A similar analysis has been done for the comparative study 015, and there were no differences between groups.

CHAIRMAN DAUM: Dr. Kohl?

DR. BALL: I think it should also be noted that, you know, the sample size is different between the two studies.

CHAIRMAN DAUM: Smaller. Thank you. Dr. Kohl, please.

DR. KOHL: I want to reinforce Ms. Fisher's point with what I see as a ten percent rate of fever greater than 101.5 in the combination group, versus a five percent rate in the separate immunization group.

And I honestly don't know enough about U.S. practices. But if you have a four or five week old with a 101.5, you are talking about a febrile neonate.

And that pretty much triggers the into the hospital sepsis work. Maybe Dr. Faggett can help us these days with what is going on in the real world out there.

DR. FAGGETT: I would be very concerned with the managed care impact you would have fewer hospitalizations in the U.S. than Germany. I would submit that that would be my inkling. I don't have the figures, but I think that we have to look at it in context of limited hospitalizations here, recently.

CHAIRMAN DAUM: Dr. Stephens?

DR. FAGGETT: Let me, while I have the mike, I think this speaks to the whole point that was brought up about small sample size as well. I think as a general comment I'm very concerned about small sample size, here, 200 U.S. children compared to 500, etcetera.

CHAIRMAN DAUM: Dr. Stephens, please.

DR. STEPHENS: My questions are on a different subject, and that is the interference with immunogenicity questions that arise, to some degree, with the pertussis.

My specific question has to do with the Hib data. And at least in some of the other studies, that I think you gave us as part of the handout, there was some evidence that the levels achieved against anti-PRP for one were less.

Do you recall those data?

DR. BALL: I'm sorry, for one what?

DR. STEPHENS: For one microgram.

DR. BALL: One microgram.

DR. STEPHENS: Yes, the one microgram levels for anti-PRP were somewhat less, as I recall, in some of the other studies. I think 17 was one of them. Do you remember that issue?

DR. BALL: Well, I can't speak to, on the specifics. But I think that the PRP, while looked at, was considered a secondary endpoint, and with regard to statistical significance, there wasn't as much emphasis to looking at a pre-specified limit of non-inferiority for the PRP response.

But I think that the GMTs across the study are reassuring.

DR. STEPHENS: Can you also comment, further, on the Prevnar? I realize that is not data related to this particular product, but it is troublesome in terms of the -- I think it is Pertactin, low levels with Pertactin with Prevnar.

DR. BALL: Right, and that information was presented in the briefing materials, and it is basically to highlight, I think that the underlying concept is that we don't have data with Prevnar, and so we don't really know what the effect of administration of this combination would be with concomitant Prevnar.

Although it should also be noted that the same thing is holding true with infants that are given Prevnar in the U.S., and some of the acellular pertussis vaccines that are -- for which we don't have specific data on, say, the Pertactin immune response.

And so then getting to your other point with regard to the interference that was observed, there were -- basically there were two vaccines that we have some information on, Acel-Imune, which was a part of the whole licensure package, and that information is in the package insert for Prevnar, where diminished immune response to the Pertactin component was observed.

In addition there, as part of a post-licensure commitment on the part of Wyeth Lederle, a study in Germany was performed using an Infanrix based combination, DTPa-IPV mixed with HIb, not the specific combination in question here today.

And, again, with this particular vaccine, a diminished immune response to the Pertactin component was observed.

I think I also would defer to any specific comments from my colleagues in the Pertussis labs, Theresa Finn, with regard to what the potential clinical relevance of the observed immune response difference is.

CHAIRMAN DAUM: Dr. Finn, do you care to make a response?

DR. FINN: With respect to the pertussis components I think that the data that the manufacturer has presented on study 027, which was the exact same lots in a larger study, and there was also in that study a separate administration arm.

I think that that study met all pre-specified endpoints with respect to percent responders to all pertussis antigens, and GMTs to the P-antigens. And also for lot-to-lot consistency, as well as comparison to the separate administration vaccines, which included Infanrix.

CHAIRMAN DAUM: Thank you. Dr. Ball, I have a question for you.

I was thinking, reflecting on some of the comments that were made about the German subjects, and the lack of ethnic diversity among them.

But I recall seeing something in the briefing materials we were sent for this meeting that in the U.S. subjects there wasn't that much ethnic diversity, either.

And I wonder if you would comment, from FDA's perspective, about what you asked for, and how you guide manufacturers in preparing for a meeting like this in terms of enrolling individuals of multi-ethnic groups, and are there any requirements being set there, and what are we doing to ensure that everybody participates in these trials?

DR. BALL: I think with regard to your first point, I just wanted to clarify that there was one study in the U.S. that did have, you know, a broader diversity of the study population.

And so it is possible, I think, particularly in the U.S., to gather those data. I think that I might defer to Dr. Midthun in terms of any specific requirements. I'm not aware that there is any regulations that indicated, with regard to racial makeup of the participants, what that should be for clinical trials.

DR. MIDTHUN: I think obviously that -- is this on?

CHAIRMAN DAUM: Come to the table up here.

DR. MIDTHUN: Obviously we always encourage diversity, and also there are guidelines that also speak to having, you know, gender presentation also, to make sure that one has a broad group, that one has encompassed.

But with regard to any specific types of numbers, I'm not aware that there are any. But, obviously, we always look for diversity and for gender representation.

CHAIRMAN DAUM: More comments? Dr. Griffin, please, Dr. Fleming next.

DR. GRIFFIN: Could I just clarify what is proposed here, from a broader perspective, with respect to hepatitis B?

It is my understanding that the current recommendations are for immunization at 0, 1, and 6 months in the U.S., and some of that is based on the thought that there is significant amount of transmission that may be occurring peri-natally, or in the early time of infancy.

So is the proposal here that you would continue to give that dose at birth, and then add 2, 4, and 5? I just don't understand how this would fit.

DR. BALL: I think we have Dr. Wharton that can clarify any remarks I made. There is not a recommendation for a preferred dose at birth. It is my understanding that it is basically, and if you look at the immunization schedule that I put up, there is a range, it is from zero to 2 months of age.

And so I think that we asked for data on this vaccine after a birth dose, recognizing that a large proportion of infants in the U.S. do receive a birth dose, and that there may be some public health reasons.

I also wanted to clarify that, you know, in terms of the FDA review, we evaluate the proposed indication, which is 2, 4, 6 months of age. Vaccine recommendations are made by Advisory Committees such as ACIP, or the AAP Red Book.

CHAIRMAN DAUM: Dr. Wharton, do you want to comment on this very issue, birth dose?

DR. WHARTON: Yes. Just to emphasize what Leslie said. The ACIP recommendations incorporate lots of flexibility, and do not at present indicate a preference for the birth dose.

And clearly it is a good thing to do in many settings, where there is mothers in whom screening has not been performed, and results are not available at the time of birth.

But I don't expect as the ACIP recommendations for hepatitis B vaccine are revised, that there will be a preference for the birth dose, although it is a good idea in many settings to deliver it.

CHAIRMAN DAUM: And I guess before I call on Dr. Fleming I can't resist one comment, and that is that the CDC investigators, as well as people from our group in Chicago, have shown that birth dose administration does, depending on how you slice and add, make it more likely that you will be caught up to date in your hepatitis B series, and in our study it looked like it was more likely that you would be caught up to date in all the series by the time you were two years old.

So there was, beyond the scope of this meeting, and not an issue for us to delve into, probably, further here, because it is a policy committee issue, but there is some benefit to the first dose, perhaps unexpectedly, perhaps by bonding with mothers at birth.

DR. WHARTON: And just to amplify, I think a related issue has to do with the complexity of the childhood immunization schedule, and the current necessity of delivering a large number of injections at the 2, 4, and 6 month visit, in the absence of much choice in the way of licensed combination vaccines.

And, clearly, administering the first, and even the second dose of hepatitis B vaccine prior to the two month immunization visit, is one way to avoid having to deliver so many injections in those early visits, at 2, and 4 months of age.

CHAIRMAN DAUM: Dr. Fleming. Thank you, Dr. Wharton. Dr. Fleming, Dr. Kohl, and Dr. Diaz.

DR. FLEMING: I think I will defer until after lunch most of the discussions of a lot of issues that are perplexing, from my perspective, on the immunogenicity analysis and the non-inferiority, specific non-inferiority analysis of that.

But there is one element with Dr. Ball here I would like to address. And that is, the real essence of the information on the immunogenicity is in 015, the most important data, group 1 and group 4.

And it is very noteworthy that that is based on 100 people in each group. And I would like to discuss, after lunch, how we have come up with these margins, and a lot of the controversies about those margins.

But putting that discussion aside, and saying we believe that they make sense, essentially if you have 2, or 3, or 4 people that fail to achieve the threshold target for any of these antigens, then essentially you are not going to hit the non-inferiority margin.

My understanding is we have 100 people per arm. And yet if we look, for colleagues that have the FDA briefing document, your briefing document, on page 16 you give us a very key table.

And there are some columns in there that we have largely ignored in all of the discussion today, and those are the ns. The ns here aren't 100 and 100. The ns here are around 90 in group 1, and in the 70s in group 4.

That is leaving a lot of people out of the analysis in settings in which 2 or 3 people failing to achieve targeted levels yields failure to achieve a non-inferiority.

Where are all those people?

DR. BALL: You mean the difference between the initial end enrolled, and the --

DR. FLEMING: The only number that I've heard referred to today, by your presentation, or the sponsor's, indicates we had 100 people per group in those four groups, in 015.

DR. BALL: That would be related to the total cohort, which would be defined, the manufacturer defined as infants that received one dose.

I didn't -- I think that some of this explanation is in the briefing material about how they defined the intent to treat cohort for immunogenicity, as well as according to protocol cohort for immunogenicity.

And so I think that perhaps the manufacturer can comment further about why there is a discrepancy between the numbers of infants that received the vaccine, versus the number that serology was drawn.

You will recall that serology was drawn after the third dose, so that there is some withdrawals, or other reasons that those information were not obtained from the infants.

I guess I'm trying to see your larger point. I think that it would be a big issue if we saw, maybe I'm misunderstanding where we are going with this, that it would be a big issue if the manufacturer failed to show a non-inferiority.

But for all of the antigens, with the exception of FHA, they did demonstrate non-inferiority. And I think that, you know, your larger point may be with regard to the small sample size.

And I think that, you know, that is acknowledged.

DR. FLEMING: There are two issues. One of them is with the small sample size there is considerable unreliability in these analysis. There is, in fact, a possibility of failing to achieve conclusive evidence of non-inferiority, even though in truth non-inferiority exists.

So, in essence, it may be that for FHA there is truly comparable levels of achieving the threshold targets, but in small numbers here it was entirely possible that you would see one, or two, or three cases that didn't, and that would be enough evidence to not carry you to the threshold.

Now, my argument there is that is the price the sponsor pays for having done a study that is really too small to be able to asses, conclusively, whether there is non-inferiority.

But the other question is very different, which was really the essence of what I was trying to get at here, is any one of these measures, any one of these ten antigens, if two or three, or four of those people in the 100, in group 1, that didn't get included in your analysis, in essence, didn't achieve a level of protection that was, in fact, related to their being randomized to this combination vaccine, it would have led to a conclusion of non-inferiority.

So because of the striking missingness here, all of this data are actually still consistent with non-inferiority, unless you can give me, in essence, a fairly ironclad argument that the people that aren't in these analysis are, in essence, just randomly eliminated, and not systematically different from the people that are in this analysis.

DR. BALL: Yes. I think the proper person to answer this is Dr. Howe.

DR. HOWE: So in general the main reason for elimination from the ATP analysis was lack of compliance to either the vaccination schedule, or the blood sampling schedule, which could definitely impact on the immunogenicity.

In addition, in looking at the table that you are referring to, I believe that in some cases the low n is just based on volume limitations, for instance, for the polio assays there is a large volume necessary to run those three assays.

And because the response rate is expected to be very high we set up a prioritization on what antigens should be run when. And they were in the lower priority. So it is really based on volume consideration, it is not that we had a result we threw away.

DR. FLEMING: But this is really confirming that this is an issue of concern. Actually it may be a bias against the product here, but I don't know for sure.

At least the reason I would be hopeful it is a bias against the product, hence we are actually confident that the result is more convincing than what we are seeing, is the fact that we are missing about ten percent of group one, and twenty to twenty-five percent of group four.

But what you said, a lot of these people are missing because of issues that relate to non-adherence. And, in fact, in the real world if I have a vaccine that twenty percent of the people can't adhere to, and as a result I don't achieve levels of seroprotection, that is a non-achievement of seroprotection levels.

That is just as important as when I don't achieve seroprotection in somebody that I do administer the vaccine to. And so those of us who believe in intention to treat believe in it not because it is the way to keep an analysis unbiased, but it reflects the real world.

I want to know, with this strategy, what percent of my infants will be protected. And if an infant is non-adherent, that is part of the failure to achieve protection.

At least here I'm a little bit reassured that there are more people who appear to be non-adherent to group 4 than group 1.

But if I were at the FDA I would nail this down and try to understand, exactly, what is going on here. Because it has a lot to do with interpreting the reliability of these conclusions as to whether you have non-inferiority.

CHAIRMAN DAUM: Thank you, Dr. Fleming. Dr. Kohl?

DR. KOHL: I wanted to get back to the seizure question in the briefing data. Again, we have seven seizures in the combined group, and we have zero seizures on a much smaller number, but zero seizures in the control, if you will.

And Dr. Fleming can probably help me here. When you have zero in the control, then you don't know if it is zero, or some much larger number. Please remind us somebody, and there are enough people in the audience who would know this, what the expected rate of seizures are at this age, or after these series of immunizations, just to put this in perspective.

But, again, it gets back to the question of not having enough numbers. We don't have enough numbers to tell whether there is a significantly increased incidence of seizures due to this vaccine.

DR. BALL: I think in terms of, you know, I think that we acknowledged that, and that was part of the point concerning the slide.

CHAIRMAN DAUM: Thank you. Dr. Diaz next, and Dr. Goldberg, and then we are going to take a break.

DR. DIAZ: I just had a comment that goes back to the schedule, the preferred schedule. And just make the comment that the children that we are dealing with in these studies, there is no real preferred, and 2, 4, 6 is adequate, but we have no data. And I think they were intentionally excluded, any child who was born to a HepB surface antigen positive mother. In that setting there is a preferred birth dose.

DR. BALL: Right.

CHAIRMAN DAUM: Thank you.

DR. BALL: Thank you for that clarification.

CHAIRMAN DAUM: Dr. Goldberg?

DR. GOLDBERG: Just to follow for a minute on what Dr. Fleming raised. Can someone, either the sponsor or you, just present for the group 1 and group 4 data in 015, the number of infants that had each dose in the schedule?

DR. BALL: I think that someone had this data.

DR. GOLDBERG: Someone should have that, and I think that would inform the discussion with regard to the meaning of that, the missingness.

DR. BALL: You mean the attrition rates between --

DR. GOLDBERG: How many, you know, what proportion of infants had dose 1, dose 2, dose 3 by group.

DR. KAHN: We can share this data, but we would ask if we could share it right after lunch.

DR. GOLDBERG: That is fine.

CHAIRMAN DAUM: Thank you. Okay, I think we've come to the point where we thank Dr. Ball for the presentation from the FDA.

It is 12:35, we will take a one hour lunch break, and reassemble at 1:45. Thank you very much.

(Whereupon, at 12:48 p.m. the above-entitled matter was recessed for lunch.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

(1:55 p.m.)

CHAIRMAN DAUM: Could we come to order please?

Good afternoon. The first agenda item for the afternoon is an open Public Hearing. There are several potential speakers, by my list here and while the are thinking about whether they want to speak we have in absentia, a letter to read from Dr. Peter Hotez as part of the open Public Hearing. Ms. Cherry will read it.

MS. CHERRY: Dr. Hotez had planned to speak today, but when he couldn't, he sent this and asked me to read it.

It's the statement of H.R. Shepherd, Chairman, Albert B. Sabine Vaccine Institute. The Albert B. Sabine Vaccine Institute eagerly anticipates U.S. approval for the new pentavalent vaccine that will protect children from five very serious diseases. Diphtheria, Tetanus, Pertussis, Hepatitis B and Polio.

By combining five vaccines into one, it will cut from nine to three the number of shots needed to get protection from five diseases. I am sure American children and their parents will join me in welcoming this development. Immunization is the cornerstone of disease prevention.

Thanks to mass vaccination, once commonplace deadly diseases such as polio, measles, meningitis, tetanus and pertussis are extraordinarily rare in the U.S. But disease prevention requires continuing immunization which combination vaccines make easier.

Combination vaccines make it easier for parents and children to comply with school vaccination requirements, by reducing the number of trips to the doctor's office and slashing the number of shots kids must get. They make it easier for health care providers to keep up with their young patient's vaccinations, by simplifying the immunization schedule. And that's it.

CHAIRMAN DAUM: Thank you, Ms. Cherry and Dr. Hotez wherever you are. Is there anyone else that would like to speak at this open Public Hearing? Dr. Peggy Reynolds.

DR. REYNOLDS: Margaret Reynolds, University of Maryland. I'm the Red Book representative to this meeting, but the comments I'm going to say are simply mine and not representing the Red Book.

I should mention that I do vaccine trials with Merck, GlaxoSmith Kline, although I have never had any involvement with this vaccine or any of its components, Aventis Pasteur and Wyeth-Lederle.

Because there, most the Committee members are not clinical pediatricians, I wanted to, to comment on the really very pressing need for combination vaccines in the country at this time, so that you can, you can, you can think about this vaccine in the context of the current public health situation in the U.S.

And that is, from my perspective, that, in a sense, we're drowning from our own success. There have been six new injectable vaccines introduced in the last ten years.

That in 1995 children by two years of age received five injections. They now receive twenty. And I think this is contributing greatly to the anxiety and fear about immunizations in this country.

Is it no wonder that twenty-five percent of parents think their children's immune systems are being overwhelmed and fourteen percent would opt out of some vaccinations.

I think if you went to an internist and they told you in the next two years I'm going to give you twenty immunizations, would think that was fairly strange.

Also having to give a fifth immunization was the last straw on the camel's back for many primary care physicians. Instead of doing that, instead they're putting off IPV, they're putting off hepatitis B. Some are bringing the children back every month and that's a recipe for diminished immunizations.

And one final point that I think probably many of you hadn't thought about but because of the number of injections, it has become exceedingly difficult to recruit children into pediatric vaccine trials.

Because very few parents are going to want to subject their children to yet more immunizations and blood draws and this is at a time that you want more safety information and not fewer.

And I'm, I fear that until we get combination vaccines, the only people who are going to be successfully able to recruit into trials are the contract research organizations where pediatricians are enrolling their own patients. And I fear that the academic investigators may be driven out of business in this current climate.

One last thing and that's that it really hasn't been brought out, the relative importance of FHA versus PT versus pertactin. And I think those who study the serologic immune response and serologic correlation to protection to pertussis would agree that FHA is probably the least important antibody in affording protection. That's it.

CHAIRMAN DAUM: Dr. Reynolds, we thank you for taking the time to address us.

Is there anyone else who would like to speak at the open Public Hearing?

(No response.)

CHAIRMAN DAUM: Okay. In that case we're going to move on to the following sequence. First, we will ask Dr. Taffs to remind us regarding, that sounded like the cell phone.

Could I ask again, please slap the wrists of my colleague Dr. Faggett and ask again that people please don't ring your cell phones in here. It's very distracting. So Dr. Taffs will reacquaint us with the questions as they were modified. And please pay attention to this version of them.

Then the sponsor has asked to show a couple of slides that will clarify some of the discussion items this morning. I believe there's three of them and we're going to allow that.

And then we're going to ask Dr. Fleming to begin the discussion, which at first can be general as far as I'm concerned.

And then after awhile I would ask that we focus it towards the questions themselves so that we can give the FDA the input that they need from us this afternoon. So, we'll go ahead now with Dr. Taffs and the four questions.

DR. TAFFS: Thank you. I would like to repeat my request, on behalf of the Center for Biologics Evaluation and Research, that the Committee assembled here today consider a series of questions and discussion points and provide their commentary and their recommendations regarding this vaccine.

On question number one, which is a voting question, are the available data adequate to support the efficacy of DTPa-HepB-IPV vaccine when given to infants in a primary series at 2, 4, and 6 months of age. If the data are not adequate to address efficacy, what additional information should be requested?

Discussion point two. Please discuss whether available clinical data are adequate to demonstrate the safety of the DTPa-HepB-IPV combination vaccine when given to infants in a primary series of 2, 4 and 6 months of age. Please comment on the increased rates of fever.

If the data are not adequate to demonstrate safety, what additional information should be requested?

Discussion point number three. Please discuss the data submitted in support of the concurrent administration of other routinely recommended childhood immunizations with the DTPa-HepB-IPV vaccine in infants. That is Haemophilus influenza Type B vaccine and 7-valent pneumococcal conjugate vaccine, Prevnar.

The final discussion point to consider, please identify any issues that should be addressed in post-licensure studies. Specifically, please include a discussion of the safety and immunogenicity of concurrent administration of other routinely-recommended vaccines. For example, Prevnar.

Safety and immunogenicity of fourth and fifth dose of Infanrix DTPa following a primary series of DTPa-HepB-IPV. Safety and immunogenicity of DTPa-HepB-IPV following a complete, or partial, primary series of Infanrix or other DTPa vaccine.

And finally, safety of a primary series of DTPa-HepB-IPV, following a birth dose of hepatitis B vaccine.

CHAIRMAN DAUM: Thank you, Dr. Taffs for reacquainting us with the issues at hand. We'll now call on Dr. Howe to show a maximum of three slides.

DR. HOWE: Actually, before you show the first slide, I just wanted to get back with the answer to the question about the attrition rate, I guess. Or the information about how many children received each dose of vaccine in Study 015, the U.S. Study.

And if we looked at the data for group one who received the combination Infanrix HepB-IPV, a hundred children received the first dose, ninety-six received the second dose and ninety-five received the third dose.

In group four, the separate administration, a hundred received the first dose, eighty-seven the second dose and eighty-four the third dose. So there was a higher attrition rate in the group that received separate injections.

The slides that I wanted to show you now are basically to help answer the question about the clinical relevance of FHA and the fact that the FHA was, for the vaccine response rate to FHA anyway in the 015 Study, was, was not found to be statistically non-inferior to separate injection DTPa.

So this is just a series of the three RCCs looking at each pertussis antigen, comparing the results from Infanrix HepB-IPV vaccinated children in Study 015 to data from our household contacts study conducted in Germany and with sera run in the same lab in order to make the comparison valid.

And the black line here is, the black curve is data from Infanrix HepB-IPV vaccinated individuals in Study 015. And the two lines here, as was alluded to earlier, multiple lots of vaccine were used in the household contacts study in Germany.

So we have data for the most immunogenic lot in red and the least immunogenic lot in yellow, for each antigen. And you can see that for anti-PT, obviously Infanrix HepB-IPV was at least as immunogenic, actually a little bit more, the curve is to the right.

Here are the results for anti-FHA. Again Infanrix HepB-IPV vaccinated and most and least immunogenic lots for the household contacts study. And here are the results for anti-pertactin. The curve for anti-pertactin fell largely in between the most and least immunogenic lots.

So based on these results, we don't feel that there is any, that the lack, ability to show non-inferiority for FHA has any clinical relevance.

The other question I'd hoped I might shed a little bit of light or maybe help put in perspective was the question about the rates of seizures in this age group.

And what we did is, we went back and looked at the package insert for Infanrix and from that package insert we have rates of febrile seizures and afebrile seizures. For Febrile seizures there were actually none. And this is data from the large household contacts study which was the largest self-contained study for afebrile seizures, 0.13, and that's per thousand doses.

If we then take the same type of approach and look at the largest self-contained study in the Infanrix HepB-IPV file. The rate of Febrile seizures within seven days was 0.07 per thousand doses and for afebrile seizures again 0.07 per thousand doses.

So the rate is comparable to that in the Infanrix package insert and lower than that for historical data following whole cell vaccine.

The last comment that I wanted to make was with respect to the overall safety database, because there was a question about the n of 7000 and the fact that that seemed small I guess to some people in the room.

I think the reason for that is because what we're talking about here is a combination vaccine that is made up of individual components that are already licensed in the U.S. in the case of DTPa and the hepatitis B and similar to U.S.-licensed product in the case of IPV and each of those individual components has its own well-established safety profile and in point of fact the safety trial that we did in Germany was powered for safety.

We specifically did that study to look at safety. And what we found was, and the only thing that we found was a higher rate of low-grade fever. Based on that, the question was what's the clinical relevance of the low-grade fever and carefully looking at all the data and looking at things such as sepsis work up, hospitalization with fever, antipyretic use, duration of fever, Febrile seizures, we believe that there are, that there is no clinically-relevant consequences of the high or low-grade fever that was seen in the study.

CHAIRMAN DAUM: Thank you, Dr. Howe.

What we'll do now is have, try and get a sense of how many general comments Committee members might wish to make. We'll start with Dr. Fleming. And then we'll see who else wants to talk, generally, and then, once we get a sense of where that's going, we'll start focusing on the individual questions themselves, beginning with our sole voting question, which is question one.

So Dr. Fleming, may I turn the floor over to you, please?

DR. FLEMING: All right. Thank you. I think what I will actually do is just focus my comments on those that relate to the immunogenicity or inefficacy issues and I'll wait for us later in the meeting to come to the safety issues.

The issues that I wanted to raise here, let me just preface what I'm saying to clarify that the issues that I'm raising don't lead me to the conclusion that the combination vaccine is inferior in its efficacy profile, but rather, that I'm, I'm left with a lot of uncertainty about whether there's adequate evidence here to establish non-inferiority as we have set this criteria.

The essence of the data, as I see it for this, is from in essence, the 015 trial, with some relevant information from 044 and 030.

Let me also preface my comments to say that I am well aware that doing a full-fledged efficacy trial, that would actually be able to document non-inferiority in actual cases of disease, would be a very high standard to expect.

At the same time, there are, there are levels of differences in complexity when we are trying to rely on a immunogenicity surrogate. If we were looking at lot-to-lot variability, it's the standard that we would use immunogenicity surrogates.

I just point out here, there are a number of specific challenges that I would argue should lead us to wanting to have a fairly rigorous establishment of immunogenicity and those issues are, on the one hand we're looking at a combination vaccine and trying to address whether or not the actual biological process associated with delivering these vaccines in combination, would alter their immunogenicity and, in turn, their ultimate efficacy.

We also have, one of the components here, is an unlicensed component. The IPV component is unlicensed, which I would think should lead us to an additional level of rigor as we make this efficacy assessment.

And thirdly, the HepB is being administered in a different schedule than what has been the tradition. Not to mention that there still remain these issues of lot series and lot-to-lot variability.

So when I think about all of this it strikes me that this is a setting where we should be particularly rigorous in our assessment of whether there's adequate evidence of immunogenicity to make it plausible that efficacy is maintained.

Having said that, the way that this has been approached by the sponsor for the non-pertussis components, is to essentially identify an assay cut off, or what I might call a potential threshold, and look at the percent of infants that achieve antibody titers above that threshold. And it's been stated that that threshold, for example, has been arrived at by noting its correlation with immune protection.

So these thresholds might be the 0.1 international units for the diphtheria and tetanus and for the HepB it's ten milli International Units.

I guess, to my way of thinking, it is always important to step back and remember that even if we see in large data sets correlations between achieving certain antibody titers and rates of infection, it is important to remember that levels of immune response are undoubtedly a continuum and levels of protection would presumably be enhanced as you achieve more complete immune responses on those particular components that are really causal.

And this is always an incredibly difficult issue to sort out. Undoubtedly a vaccine will generate a myriad of different immune responses and really, fully understanding the essence of which of them are really causal is probably a task that would never be fully achieved. And essentially what we have done is we have dichotomized this myriad of different potential immune responses into looking at whether we see a given assay cut off.

And I just would like to step back and say it's entirely possible that you could have a correlate, and yet that correlate may be a marker for a myriad of other types of immune responses that are carrying a lot of the causal aspect of protection. And so it always makes me very cautious in interpreting these results.

But if we use, for one example, the HepB example, where we're trying to achieve a level of ten, I would challenge the FDA to go back and really be sure that the data are adequate to state that once you achieve a level of ten, that really is a threshold. And that that level is truly adequate to say that we have maintained a high level of protection.

And it's not enough to look at those with less than ten versus those with more than ten. Those with more than ten may be largely people with levels of a thousand. And so we have to be sure that we have a lot of data of people between ten and thirty to be able to say ten is enough to achieve protection.

So having said that as a background, the essence of the data that we have presented to us that's the most reliable here is the direct randomization between the combination of the individual component administration in 015. And as we've already discussed, this is based on a hundred people per arm.

So essentially, the most significant immunogenicity data that we're going to be using to address this complex situation that could lead to administration to tens of hundreds of thousands to millions of infants is based on the comparison in immune responses in a hundred per arm and I've already mentioned one of the issues there is that there's ten to twenty-five percent missing information there as well.

But essentially the primary analysis that's being addressed here is did we achieve a comparable fraction of participants who had this cut off, this threshold?

And essentially what we're saying here is we're using a weaker standard, and appropriately so, than requiring superiority.

We're not saying that the combination has to have a significantly higher fraction that achieved its cut off, we're saying that it has to be high enough so that you can rule out that you're ten percent less.

Well the first statistical issue I'd like to say about that is if we were trying to show superiority, if we were talking about a combination that was adding an antigen to a standard and you had to show superiority, we would ask that the ninety-five percent confidence interval rule out equality.

We would basically say we want to have, and this is the standard for strength of evidence for superiority, a two and a half percent false positive error rate. The way this has been set up, is we are expecting a weaker standard.

We only have to rule out that we're not ten percent worse. And yet we're allowing a five percent false positive error rate by using ninety percent confidence intervals.

So the first issue I would urge the FDA to consider here is to move back into the world of standard statistics to say the standard for strength of evidence is a two and a half percent false positive error rate. Meaning that these confidence intervals should be ninety five percent confidence intervals.

Is that irrelevant? Well, it's not at all irrelevant. Because the levels of differences that are consistent with the data are much higher. If we go to the FHA data in 015, we have failed to establish non-inferiority, relative to the seropositivity rate. We also have failed to establish non-inferiority with the GMT if you're using a ninety-five percent confidence interval.

So that data there, in my view, don't prove inferiority, but because of inadequate sample size this year, if one was using a proper statistical approach, they do, though, fail to be strong enough to establish non-inferiority. And that essence is in essence in my view as confirmed by the 044 trial where we're looking at lot-to-lot.

It's quite striking the variability that we have in rates of achieving seropositivity and in the GMT rates for PRN and for FHA.

And, I guess the last issue I'd want to raise, is if the sponsor could put up again the slide. And it was one that Dr. Howe had shown when she was discussing the 030 data. And specifically it related to trying to address the relevance or importance of the fact that we see about a four-fold reduction in the GMT for HepB in the 030 trial.

In the sponsor's presentations, my big concern with the way we have set up the primary end point is that we have essentially defined the primary end point, achieving the threshold level or assay level for positivity.

And it may well be that that assay level for positivity is lower than what it truly has to be to represent a patient or a participant or an infant that truly has the global level of immune response that renders protection.

PARTICIPANT: Which slide do you want to see?

DR. FLEMING: It's the slide that showed the historical data. Because you put into context with previous studies what the level of GMT would have been for other vaccines.

And it in particular, it contrasted the thousand, this slide, thank you. In this particular study, if I'm following your logic here, you're pointing out that the, whereas the combination vaccine was one of those orange dots in this trial around a thousand and the other relevant dot is the dot of 3,500 up there under the 016?

DR. HOWE: This is the data from the HepB study itself that I showed you.

DR. FLEMING: Yes.

DR. HOWE: And this is data from any of the Infanrix HepB-IPV studies that were given on a 2, 4 and 6 month schedule. So, all of the orange dots come from Infanrix HepB-IPV studies. One of them would be 015, another would be, I think two of them actually are 044. And the green dot --

DR. FLEMING: So where would the 030, are the 030 dots up here on this? The thousand. And where would the dot be that corresponds to the 3,700 GMT for the comparator group in 030?

DR. HOWE: The comparator group in 030 isn't on here. This is published data from package inserts for the two U.S. licensed products as well as data in the literature for the two vaccines, including Recomavex, two different strengths, on a zero one six-month schedule administered to neonates.

DR. FLEMING: All right. So basically you're not, on this slide we really have no way of trying to put into context the relative difference we're seeing in the 030 trial. In the 030 trial, this is the data, if I'm working this correctly.

DR. HOWE: Right. If we had plotted the 030 and put it with Engerix 016, it would be closer to this dot, is what you're saying.

DR. FLEMING: Right. Well, and my concern is, if what we're seeing here is, in our comparison IN 030, an average level of response that's one quarter of what we're seeing with the comparator group, but all of this other experience is telling us that rates are much lower than the 3,700, it makes me wonder whether the thousand that we're seeing is an overestimate, i.e., is there something specific to the population that we had in this randomized trial 030.

If we're seeing in our comparator group, we had a level of 3,700, and if your argument is 3,700 is much higher than what you would have expected from prior experience, then my response to that isn't that more than one thousand is fine, but rather the one thousand might also be an overestimate of what you would achieve in a much broader context.

So it's, and probably it's not worth a lot more discussion there. I think the essence of the concern just to summarize as I think through this is that the data that we have that is the most informative to efficacy, is data on the immune response, specifically provided to us in the 015 trial, with basically on the order of a hundred patients.

And IF we were using statistical procedures with ninety-five confidence intervals, we're essentially seeing, not just for FHA, but for the polio virus types two and three, also some evidence of concern and this is confirmed in the 044 trial with FHA but also with the PRN showing considerable heterogeneity.

DR. HOWE: Can I just respond to the question about the DTPa-HepB and whether or not that would be an overestimate because in, I think the fact that we have multiple studies with Infanrix-HepB-IPV, giving consistent rates of 1,500, you know between 1,400 and 1,600 is one fact.

And actually in one of the studies, which was the 015 Study, we had a head-to-head comparison with the DTPA-HepB-IPV and DPTa-HepB and in point of fact we had a result of 1,600 here and 900 here, confirming the DPTa-HepB results for the GMT. And I think the other important point is that the sera protective cut off is down here.

DR. FLEMING: Well, that's what I'm trying, I'm trying to press the issue that where you define that seroprotective cut off is a very controversial issue.

And the other point that I'm trying to make here, let me just very quickly make it again, is the most relevant comparison comes from a randomized comparison. Not from what an array of different things would show in natural history. And what we have from a randomized comparison is a four-fold reduction.

CHAIRMAN DAUM: Okay, I'd like to, at this point, thank you, Dr. Fleming, Dr. Howe for commenting, see if the Committee has general comments they'd like to make before we put the first question up and start speaking directly to it. All right, Dr. Kohl.

DR. KOHL: I want to echo Dr. Reynolds comment and I kind of feel a little remiss. I'm a pediatrician. And we desperately need combination vaccines. There is no question about that in my mind.

And I just want to make sure that the Committee realizes that we need combination vaccines that are effective and safe. So keep those two in mind.

CHAIRMAN DAUM: Thank you, Dr. Kohl. I didn't see other hands up. And so I'm going to ask to have the first question put up on the board again and begin a discussion about this first question and that is to say that the, this is a voting question. It's the only voting question for the afternoon. And it concerns efficacy.

Are the available data adequate to support efficacy of this combination vaccine when given to infants in a 2, 4, 6 regimen.

So I'd like to have discussion about this question and then after we get a sense of people's opinions and where we're going, we'll have a vote about this question. Comments? Ms. Fisher.

MS. LOE FISHER: I'll just do my comments and my vote at the same time, if that's all right. I mean I only have to speak once then.

CHAIRMAN DAUM: It's --

MS. LOE FISHER: Save time.

CHAIRMAN DAUM: Economy is a good thing.

MS. LOE FISHER: My answer is no. That there needs to be a larger trial of this new combination vaccine in the U.S., in genetically diverse populations, with a 2, 4, and 6 month schedule.

And with a longer follow-up period than fourteen months to assure long-term immunogenicity with all antigens, particularly pertussis and hepatitis B. As well as an attempt to characterize the mechanisms for achieving immunity at the cellular level.

CHAIRMAN DAUM: Okay. We have a vote in and a comment. Other comments? Perhaps we've heard them. Dr. Broome, please.

DR. BROOME: Well, I mean, I appreciate your trying to surface some discussion before we move to voting, because I actually thing that's quite important. I mean I think Tom has raised, you know, perfectly valid points, but I do think they have to be put in the context of what is a reasonable body of data to expect for this kind of product and decision.

I also think it has to be put in the context of you may have one very well designed, randomized trial, but I think with immunogenicity data we've also been comfortable bridging between results from one study and others.

So to characterize this is decision based on one hundred or fewer subjects per arm I don't think is really representative of the data we've seen this morning.

I'm sort of scrambling to pull together what we do have. And it may be helpful to the Committee to sort of reprise, you know?

Specifically I myself and others have focused on the pertactin and FHA results from 044, but frankly I think we haven't paid enough attention to the fact that there's another consistency lot trial which has 300 subjects per arm in which the non-inferiority is very clear for those antigens, and I find quite convincing.

So I'm not particularly concerned about the possibility of nonequivalence with the FHA or pertactin results. So this is not a very conclusive comment, but just one to say that I think before we vote it's quite important to maybe, you know, reprise the data that bear on the immunogenicity question.

Also I'm really sorry we don't have Stan Lemon or somebody here who could speak more eloquently to the hepatitis surrogate. But my understanding is that's actually quite a good one.

CHAIRMAN DAUM: So, I take it you feel more, substantially more comfortable with these data than previous people that have --

DR. BROOME: Well, I'm flipping through a whole bunch of pieces of paper to try to put the whole thread together. But I, let's just say I don't feel maybe as pessimistic as the two preceding speakers have.

CHAIRMAN DAUM: I think the, we need to think about this question as what do we believe based on what we heard about the ability of this combination vaccine to protect against the diseases that the individual components protect against.

I mean that's sort of what efficacy's all about. And so, I think that in formulating that idea, do we know enough from the immunogenicity data that were presented this morning, about that to decide the question.

I think that's sort of what we're thinking about here. And I'd like to hear more discussion about whether you think we do know that or whether you think we don't know that and where the gaps are. Dr. Kohl.

DR. KOHL: I'm going to focus on the DTP or the P in particular. And the one piece of data that I was the most concerned about, initially, reading the pre-read and earlier this morning, was the FHA data.

And I think, again, the GMT level, which is all we have with FHA, unfortunately, shows nonequivalency. There's no question about that by the criterias which may even be weak as Dr. Fleming has mentioned.

On the other hand, we all sat through a very laborious session several months ago looking at a different preparation, and discussing what all this means.

And I think I would have to agree with Dr. Reynolds, which I enjoy doing actually, not would have to, that FHA is probably the least important of the antigens that we know about.

We know that Infanrix itself is quite a good protective vaccine against pertussis and I feel that to hold this up because of one out of three antigens that I don't know exactly what it means, would not be the appropriate thing to do on the basis of pertussis. So I feel, I think comfortable, passing on the pertussis protection from this vaccine.

CHAIRMAN DAUM: Well you want, before we let you put the microphone away, do you want to go a step further and talk about the polio part of the vaccine? Or --

DR. KOHL: Yes. I honestly don't have any problems with the other components of the vaccine. The hepatitis was lower. GMT, again, was lower than the comparator. But the levels are still quite good. And my understanding is those levels would be quite protective, although that is not my field and I'd love to hear from a hepatitis expert if possible.

CHAIRMAN DAUM: Okay. Other comments? Dr. Diaz, please?

DR. DIAZ: I just have a couple of comments in particular regarding the pertussis and the hepatitis, hepatitis B. I'm not that concerned in regards to pertussis about the FHA, the non-inferiority issues. But, I am still troubled by the lot-to-lot equivalency and immunogenicity results with pertactin.

And I'm not convinced that high maternal antibody accounts completely for those differences in those lot-to-lot variations. The, that coupled with sort of the lack of knowledge, I guess there's a lot of what ifs in my mind.

The data as it stands is reasonable in my mind and yet the what ifs, the issues regarding the lot-to-lot inconsistencies in pertactin, the lack of any knowledge about how this vaccine will behave when given in combination with prevnar, in particular, makes me a little bit uncomfortable and I wish we have more information in regards to that in terms of if there's any cumulative affect along those lines in decreasing antibody responses to pertactin.

That having been said, likewise I wish we had more information as to just how important pertactin is in the overall scheme of protection. Regarding the hepatitis B issues, I am not overwhelmingly troubled by the differences in the GMTs per se.

And yet, again, the lack of any longer-term data can of regarding the persistence of an antibody response in these subjects leads me to wonder about the overall protectiveness in the long run. Again those are sort of the what ifs that I have in my mind that are a little bit troubling.

CHAIRMAN DAUM: Okay. Again, I think this concept of dissecting in our minds the different components of this as Dr. Kohl and Dr. Diaz have done, it a helpful one. And it may allow you to consider why you do or do not think this is efficacious.

DR. WHARTON: Getting back to the lot-to-lot variation issue, again, if I remember the presentation correctly, although there was nonequivalence in the equivalence testing for the pertactin component, if you look at the reversed hemolytic distribution curves which are provided, they're actually strikingly similar.

Which raised the question in my mind, and I would appreciate someone who's wiser than I to enlighten me on what in fact does nonequivalence mean with such similar reverse cumulative distribution curves. Is the statistical standard that's being applied consistent with what we would consider clinically relevant?

With all the provisos that we don't know what to make of pertussis serology anyway. But they are strikingly similar curves and even the antiprotectant curve, though there's a little bit of daylight between the lines, it's not much, and were I to see these curves in a different context, I would be impressed with their similarity.

The second point is one again which I think has been made that the, that those same lots of vaccine were subsequently used during the second larger study and the confidence intervals were smaller, reflecting the larger sample size, and in fact nonequivalence was not found.

Now granted there was ad mixture with Hib vaccine so it was not exactly the same situation. But, this reassures me, and these consistency issues among the lots I don't find troubling based on these data.

CHAIRMAN DAUM: Thank you very much. Dr. McInnes.

DR. MCINNES: In study 015, comparing groups one and groups four.

CHAIRMAN DAUM: Pam, could I ask you to speak right into the microphone.

DR. MCINNES: Sure. Dr. Howe you gave us the numbers of children who had completed three doses of vaccine in those two groups.

In, there's a delta between those who completed three doses and those there weren't reported and I presumed that revolves they either didn't get a blood draw or they had window violations around the timing of the doses.

And so they're not accounted for in the, according to protocol analysis of the immunogenicity. What do you know about the immunogenicity of those delta children? The children who received three doses and had a blood draw, but had some window violation.

Is it possible to shed some light on them, because I think that addresses something Dr. Fleming raised earlier with if just two or three children had had a different response the impact would have been different on the non-inferiority analysis. So it goes more to the intent-to-treat concept than to, according to protocol analysis.

CHAIRMAN DAUM: We can ask the manufacturer to comment on that, if they would like to.

DR. HOWE: In terms of the numbers that I just quoted, they were actually just attrition from dose one to dose three, so that wasn't the numbers included in either the ATP or ITT analysis.

It's just the absolute number of children who came for dose one and then subsequently got dose three, whether or not they had blood drawn, sufficient volume were analyzed or what not. So that, the numbers I gave you earlier were simply the number who completed their vaccination.

DR. MCINNES: No. I understand that. For example group four. Eighty-four children received three doses you reported.

DR. HOWE: Yes, that's correct.

DR. MCINNES: The n reported under group four for immunogenicity is a maximum of seventy-eight.

I'm wanting to know if you have data on the six children?

DR. HOWE: So I can tell you their reason for elimination is what you want to know?

DR. MCINNES: Well I want to know if you have, did you get a blood draw on them, do you have immunogenicity data on those six children. I understand they might have had window violations, which would make them fall --

DR. HOWE: Right. Right.

DR. HOWE: -- outside of the ATP analysis but would be meaningful for understanding the spectrum of immune response, regardless of the window.

CHAIRMAN DAUM: Are there any sera on them?

DR. MCINNES: Yes. Do you have serology on them?

CHAIRMAN DAUM: Are there any antibody data?

DR. HOWE: Yes. I'm just looking at, I have in front of me the ITT analysis which means that if a child had sera available and the assay was run --

DR. MCINNES: Yes.

DR. HOWE: -- and so, do you want this by antigen or per specific, do you want for the pertussis antigens or --

DR. MCINNES: Do you have it for this spectrum of the an, do you have all of it?

DR. HOWE: I do. So again, if we look at a comparison of group one to group four for anti-diphtheria, it's ninety-eight point nine percent versus a hundred percent. And there would be ninety-two in group one, and seventy-nine in group four.

For anti-T it's a hundred percent and a hundred percent. For anti-PT here we have an n of ninety-three for each of the pertussis antigens and the ITT cohort for group one we have ninety-eight point nine percent, in group one and ninety-eight point seven in group four.

Ninety-five point seven in, for FHA and a hundred percent for group four for FHA. For anti-pertactin, ninety-five point seven versus ninety-one percent, that's group one versus group four.

I just looked quickly at polio. For anti-Hbs the n is ninety-one in group one and seventy-eight in group four, a hundred percent greater or equal to ten milli International Units per ml.

Again for polio one in group one we have an n of 88 with a hundred percent seroprotection. Group four an n of 74 with 98.6. For polio two, 98.9 versus 100 and for polio three 100 versus 100. The same n's as I previously quoted.

CHAIRMAN DAUM: How agile is the Committee with these numbers? We have the technical capability here of putting these on a transparency and showing them. Would you like to see them that way? Or is Dr. Howe's reading sufficient?

DR. MCINNES: I mean essentially, although I didn't write them all down, the percentage of seroprotection vaccine response is pretty much the same in the intent-to-treat as in the ATP. Is that a fair statement?

DR. HOWE: Yes.

DR. MCINNES: But you add some way between two and four sero values per depending?

CHAIRMAN DAUM: Would you like to have them written down to see them?

DR. MCINNES: No. I don't think so. Dr. Goldberg wanted --

CHAIRMAN DAUM: Dr. Howe would you be willing to take a few minutes and do that? We can banish you to the table to do that. Then we can put them up on the board and they might be easier to digest. Thank you Dr. McInnes. Other comments, queries? Dr. Goldberg?

DR. GOLDBERG: Just to follow this attrition --

CHAIRMAN DAUM: Microphone.

DR. GOLDBERG: Sorry.

CHAIRMAN DAUM: Thanks.

DR. GOLDBERG: Two things. One, to follow this attrition argument, I mean the reasons for the attrition between doses should need to be looked at. I mean are they related to safety events and the intolerability of being able to complete the course of the vaccine? I mean that's key into what the long-term protection from the vaccine would be in the population.

If you're only going to, if you're seriously only going to get the completed course in a differential group of patients. You know and the trick is really to make sure that it's operating the way it is, the way it appears to here which is that a higher percentage are getting the full course of the combination rather than the components.

And that the reasons for noncompliance are not related to outcome in group one like an untoward outcome in group one and annoyance with the vaccine in group, with the number of injections, but no real problems in group four. And I think that needs to be looked at in order to fully evaluate it.

The other point is that there was a discussion about the reverse curves. And I guess I'm not as sanguine that they're totally similar in the sense that what does the small difference in a small space between the two curves translate to in the large?

I mean we're really talking about vaccines that on a seroprotection basis, whether we like the cut off and we're happy with the definitions, really do a pretty good job in the abstract.

The question is, where they fail. Is that going to magnify in the hundreds of thousands and millions of kids that get this? And so I think we do need to go back to the data if you will and the data about what the levels actually are and I guess I'm concerned about that.

I mean, I'm torn between I think this is a good vaccine, but I'm not fully convinced and totally comfortable and it's these little niggling issues, I mean it's the, you know when you do an adjustment for the maternal levels at baseline. Well, you know, I mean I guess, I'd like, I need to look at that data so that I can see it.

But that's an issue. I mean the assumption's made that well if it's high it's going to stay high and there's nothing you can do. They can't respond.

But if you looked at subjects that achieved a certain level or maintained a certain level of titer, you could get at that issue. And you could get at it if you stratified by baseline levels. So that there are ways to begin to tease this apart and I think maybe we need to do a little bit of that.

CHAIRMAN DAUM: Thank you. Dr. Meade then Dr. Fleming, Dr. Griffin. Doctor?

DR. MEADE: Yes. Bruce Meade, from the Office of Vaccines at CBER and I'm not going to resolve the niggling issues because they are in fact difficult issues but I think it's important to acknowledge clearly that the cut offs, the values that we come up at cut offs for equivalents for the pertussis antigens are clearly arbitrary.

I mean I think we'd be kidding ourselves if we didn't acknowledge that the values we came up with were arbitrary, hopefully thoughtful, but clearly arbitrary.

And I think the, one of the important considerations as we did obviously what were realistic but I think one of the most important considerations is we were, when we chose what we thought were reasonably conservative criteria for equivalents, for non-inferiority and equivalents, so that when, in fact, differences were observed, we would have a signal, that would identify those that we need to look at and do exactly the kinds of things you're talking about, that if they are, if you see differences, are these, you can look at, choose which RCDs you want to look at in depth and look at.

And again, I think it's important to differentiate between shifts of an RCDs, you know a small shift, or in fact are you is there a population of individuals that are clearly non-responders. And again trying to put that into context of the value, the information that's available from Fixi trials.

Again, it's, I think we viewed it very much as a signal for which ones we need to look at more carefully. And do the kinds of analysis you're talking about.

And if I could make one more comment, again, in terms of lot consistency issues, I think it's important to recall important issues when we're talking about consistency in manufacturing.

It's a global issue. When we're evaluating consistency in manufacturing, you're looking at a large number of information on the manufacturing, the process, on the characterization and animal and human immunogenicity.

There's no question that the human immunogenicity is important and relevant but it's only one of the tools we use to look at for evaluating consistency in manufacturing. So it is, again, it's an important issue, but it's not the only issue that's relevant for consistency in manufacturing. Thanks.

CHAIRMAN DAUM: Thank you, Dr. Meade.

DR. GOLDBERG: Can I make another comment?

CHAIRMAN DAUM: If it's very brief, Dr. Goldberg.

DR. GOLDBERG: Very brief. I mean the lot-to-lot consistency vote, speaks to the same inconsistencies, speaks to the same issue.

What does the small difference, if you presume that the immunogenicity is really a surrogate for true efficacy, then a small difference there that goes against the lot that you're using has lower immunogenicity rate. And I may be reversing this.

Translating to potentially lower efficacy which in large here becomes a major issue in numbers. So it's really how close is close enough? And I think that some of that does need to be discussed and agreed upon.

CHAIRMAN DAUM: We're discussing it. Dr. Fleming?

DR. FLEMING: Just to kind of follow up on Judy's clarification and questions that had been raised about interpreting these data.

If we go to the 044 data and we look at the PRN and we look at the magnitude of the differences, essentially as has been reiterated, we don't have a clear sense of what measure of immunogenicity is a reliable way of addressing efficacy for pertussis.

A best attempt was made. And that best attempt said for this we're going to use the GMT and we want to be able to at least rule out that there could be a fifty percent higher GMT achieved on single administration as opposed to combination. That was what we set up.

Now we didn't observe something that was one-third lower, which corresponds to relative risk of one point five. We observed something that was about a relative risk of one point three, which is part of reason that the curves don't look so obviously separated. But part of the price you pay when you have a small study is that these data are statistically consistent with something more than one point five.

And so the bottom line to that typically is if you do a study and you see a positive trend and it's not significant, you say ah well, it's a positive trend and if the sample size had been big enough it would be significant, so approve. No you say, that's the price the sponsor has paid for not doing a study of adequate size to reliably understand immunogenicity.

That's in essence what's happening with the lot-to-lot assessment. There is, in fact, unfortunately an estimate that the GMT is lower and it's a variable estimate because it's a little trial and as a result we cannot state with confidence that you might not have a one and a half fold higher GMT in the individual administration.

And then back to Claire's point about the Hep surrogate. The comments that I have raised haven't challenged that the Hep surrogate might not be a good surrogate. That there is a correlation between these antibody levels and protection. The big question is are you capturing the essence of the importance of that surrogate by dichotomizing on whether you achieve a level of ten?

And that would mean you've got to have evidence on a lot of people that have ten to fifteen and show they're protected.

And I strongly suspect we don't have that and I've been probing to see if we do have it and I haven't yet been convinced that we do.

CHAIRMAN DAUM: I think we do. We're going to ask Dr. Feinstone from the FDA who's just come in to address that very question for us. We produce answers for this Committee. Dr. Feinstone thank you for coming. Feinstone. The recall.

DR. FEINSTONE: We've actually been struggling with this issue of hepatitis B titers for some time. Going back to the original plasma dry vaccine which gave actually much higher titers than the presently-sold vaccines that are recombinant yeast dry vaccines.

But the initial level of ten milliequivalent was set in some of the earliest trials on vaccine efficacy. In which it was found that people who did respond with relatively low titers, but over ten, were universally protected. Or protected at an extremely high rate.

And these were, as you might remember some of those trials, amongst very high risk individuals, primarily gay men in New York City, and these types of people who had a very high attack rate at that time. But what to do about the titers? Because this is an issue that I call a titer creep.

With all the changes in the vaccines, the changes in the schedules that we've seen, the changes in the doses, the changes in the formulation. We have seen a gradual decrease in the, in at least some of the titers.

But what I'm quite convinced of now is that the long-term studies that have been coming out over the past few years from Alaska and from Taiwan, have shown that people who, once they seroconvert, remain protected against disease.

Now they may be susceptible to actually being infected, but they universally have gotten subclinical infections. And no one has gotten chronic infections, once they've been vaccinated and seroconverted. So this is primarily what we've been operating on at this point.

With I would say one sort of caveat. And that is those long-term studies were done with vaccines that produced relatively high initial titers on the average. And so we don't really have long-term follow-up studies on newer schedules, newer doses that don't produce quite as high titers.

But it does appear that once people seroconvert, they are protected to the extent that the CDC still doesn't recommend booster doses for individuals who are even high risk individuals whose titers fall below the magic ten level.

CHAIRMAN DAUM: We thank you. You shed light. Someone had their hand up over here and then Mike Gerber is next. Can they refresh my memory. About four hands went up at once. Dr. Griffin, then Dr. Gerber.

DR. GRIFFIN: Well, I guess I'm not going to shed much light on this, I'm just going to ask another question, I think, probably of Tom and Judy, but, so what bothers me the most is that we have it just seems like the most minimal data on the antigenicity of this vaccine to compare and to use and to make a decision on.

I guess, from the top of my head I think okay you know if it were just three or four hundred people instead of one hundred or fewer, actually, that we actually have the data on, we'd just feel so much more confident that this is really correct and real and that we're making our decisions based on solid evidence. You know one way or the other.

But I guess what I would also, so that it addresses number B so that if you don't think they have enough data, how much data do you need?

I guess I don't have a good feeling if my guesstimate of three or four hundred people in these groups would be a whole lot better or if we're really talking about you need a thousand or two thousand or whatever to make these data much more confident that what we're deciding is correct. I'd just like some feedback on that.

CHAIRMAN DAUM: Thank you, Dr. Griffin. We have Dr. Gerber, Dr. Britt and soon we're going to start really coming to grips with this question head on.

DR. GERBER: Yes. In thinking about this question of efficacy, one population that I thought of that I haven't seen or heard mentioned are former premature infants.

And I just wonder if there are any data, if infants less than 36 weeks gestation were included in any of these trials and if we have immunogenicity or safety data on that population?

CHAIRMAN DAUM: Sponsor? Dr. Howe?

DR. HOWE: So prior to 1996, we did allow former pre-term infants to be enrolled into the clinical trials and that would include Study 011, which actually started in 1995, but there was a time point in 1996 where we began to exclude pre-term infants from, in terms of eligibility criteria, we mandated that the infants be of at least 36 weeks gestation.

In the 011 trial, despite the fact that we know we have, we allowed former pre-term infants, we did not collect information about gestational age, when they entered the trial.

So the answer to your question is yes there are former pre-term infants undoubtedly in study 011, but we don't know what percentage of individuals. So we don't have data per se.

Can I just make one comment about the number of subjects or the number of individuals in whom we have immunogenicity data for those three lots. And I just wanted to make sure it was clear that in the 027 --

CHAIRMAN DAUM: To clarify something factually.

DR. HOWE: Yes.

CHAIRMAN DAUM: Okay.

DR. HOWE: Yes. In the 027 Study, which was the study in which the Infanrix HepB-IPV was mixed with Hib, the n per group in that study was 360 and that was for immunogenicity, lot consistency and then a comparison head-to-head to commercial Infanrix.

DR. GRIFFIN: But in that same trial then each of the groups though that you were comparing is in the order of a hundred.

DR. HOWE: No, no, 360 per group.

DR. GRIFFIN: Is that the 2, 4, and 6 month schedule?

DR. HOWE: The 027 Study was a 2, 4, and 6 month schedule, 360 per group. It was a very large n.

CHAIRMAN DAUM: And where did you find that?

DR. HOWE: It's in Appendix, one of the Appendices to the sponsor's briefing document and it's a table in the FDA's briefing document. And I have it as a slide, but --

CHAIRMAN DAUM: Dr. Ball, can you help us?

DR. HOWE: And then, in terms of the comparison of Infanrix Hepb-IPV mixed with Hib, the data pooled and then compared to again on a head-to-head fashion with commercial Infanrix in that trial, the n would be about 1,000 versus 300. And in that trial non-inferiority to commercial Infanrix was demonstrated for each of the three pertussis antigens.

So it's a very large n and we showed lot consistency as well as non-inferiority to commercial Infanrix in that study.

Additionally Study 048 was also a relatively large study, I don't have the n's in front of me but it was of a similar magnitude and evaluated lot consistency of the same three lots. We're just having trouble finding that data.

CHAIRMAN DAUM: We should put these designs up if we're going, 027, for example, the specific regimens that are being compared.

DR. BALL: If you look at the briefing document from the FDA, the data from 027 on the various pertussis antigens is found on page twenty.

DR. FLEMING: On page twenty. But let's look at the regimens, the slide that shows the precise formulation of the regimens.

DR. HOWE: So this is the design of Study 027. Here's Infanrix HepB-IPV, the three consistency lots from Study 044 mixed with Hib. The n per group was about 360.

And then we had a control arm, which I didn't discuss during my presentation, but was alluded to by Dr. Ball, where Infanrix, again this is a commercial lot, Engerix B, Hib and Oral Polio. This is a U.S. Study given on a 2, 4, and 6 month schedule.

DR. FLEMING: And you didn't present that first arm because?

DR. HOWE: Well at the time I was only discussing consistency. And that's why during my presentation I didn't make any mention about the comparison to Infanrix. These are the results though for vaccine-response rates to PT, FHA and pertactin.

For groups two, three and four they received, again this is Infanrix, HepB-IPV, the three lots and 044 mixed with Hib. And then this is the results for commercial Infanrix given separately along with Engerix Oral Polio and Hib vaccine.

And what you can see is that comparable rates, vaccine-response rates, actually very high in all of the groups. And as I said when these three groups were pooled and compared to commercial Infanrix, using the same non-inferiority approach, same criteria, the results were such that the Infanrix HepB-IPV was not inferior to each of the three pertussis antigens with response to, with respect to the vaccine-response rates.

And then the next slide shows the geometric mean antibody titers in groups two, three and four, or Infanrix HepB-IPV mixed with Hib so anti- PT seventy eighty-two, for anti-FHA, approximately 300, anti-pertactin 120, that's in each of three groups, and then you see the comparison to commercial Infanrix right here.

And for each of the three pertussis antigens in the GMTs they were shown to be non-inferior to commercial Infanrix.

CHAIRMAN DAUM: Thank you, Dr. Howe. Dr. Britt and then Dr. Stephens.

DR. BRITT: I just got a brief question for Dr. Feinstone about, he mentioned seroconversion to hepatitis B in the long-term protection studies. What does that equate to with the titer?

DR. FEINSTONE: By seroconversion, we mean titers per milli International units.

DR. BRITT: Thank you.

CHAIRMAN DAUM: I'd like to know if there's burning points that haven't been raised yet. Because I'm, what I'd like to do is now ask each Committee member to speak to this question number one. Dr. Stephens you have such a burning point?

DR. STEPHENS: Well I just wanted to clarify the 027 data that we just heard about. That obviously is a different vaccine. It does contain Hib.

I presume the study was done to reinforce the fact of noninterference in some respects. And I just wanted you to clarify that point.

Because I think it is a valid point that you've added Hib in this particular instance as another antigen and presumably you didn't see interference in that 027 trial.

DR. HOWE: So the 027 Study was originally designed to assess the consistency of Infanrix HepB-IPV mixed with Hib. And lot consistency for all of the components contained in that product and then comparing it to the individual licensed products.

What I can tell you is that in head-to-head studies, the Infanrix HepB-IPV mixed with Hib as compared to separate injections of Infanrix HepB-IPV that is co-administered with Hib, the vaccine-response rates and GMTs to the pertussis antigens are completely comparable.

And again using sort of a non-inferiority equivalence approach, that those two products behave identically in terms of their response to pertussis.

CHAIRMAN DAUM: You can return to this question if you'd like when we get to question three. But for now I'd like to focus on question one, which is are the available data to support, are the data adequate to support the efficacy of this combination for these antigens?

DR. FLEMING: But this is certainly very relevant to the question one.

CHAIRMAN DAUM: Oh, its relevance.

DR. FLEMING: And ironically you've got three-fold as much data just coming back. You wish we had three-fold as much data, we do have three-fold as much data on a different combination vaccine than we've been asked to consider. And now we're trying to put into context what that different vaccine data in 027 contributes.

DR. GRIFFIN: Contributes, I understand.

DR. FLEMING: Contributes to the combination vaccine we've been asked to consider. It's ironic that the one we're being asked to consider in 015 has one-third the database from another combination that we're not being asked to consider.

CHAIRMAN DAUM: Thank you. Dr. Kohl you're up there. I think you're up there and you're the end member of the Committee today.

I'd like to hear your comments and your vote actually at this point on question one. And if you decide they are, your answer to part a is no, then I think you need to address part b. If that could be the format, I'd be grateful.

DR. KOHL: I've been dreading this moment ever since I realized I was in the Dixie Memorial Chair, Dixie Snider Memorial Chair, but I'll take a shot at it.

CHAIRMAN DAUM: You don't have any grandchildren.

DR. KOHL: Not yet. It's the same old deal with how comfortable do you feel compared to how much do we need this vaccine. And trying to do that balancing act I was and still am somewhat concerned with the initial data presented on the FHA levels and the HepB GMT levels with the new schedule.

I am somewhat pleased with the data that just came out this minute, tripling a little bit of the immune response, but I think the point that it's different vaccine is important. Most of our problems with different vaccines have caused titers to lower not rise. So if anything I guess if something's unexpected I would have expected it to go South not North.

And I'm going to walk the plank and say given what I think is a real pressing need in this country for combined vaccines I will vote yes on this question.

CHAIRMAN DAUM: Thank you very much Dr. Kohl. And then we won't press you to address question b, which is nice. You get off the hook. Dr. Stephens.

DR. STEPHENS: As one of the evil, non- pediatricians on this Committee, I too am a big advocate of combination vaccines. And, in essence, I'm going to join my colleague to my right and walk the plank with a yes on this issue with certain caveats.

I think we are being asked to make certain assumptions regarding the efficacy of this vaccine. I am encouraged more by the 027 data than I am the 015 data that's been discussed. I am somewhat concerned about the issue of the efficacy of this vaccine and all races and ethnic groups which we really haven't heard a lot of data about.

And I'm concerned with the later discussion that we'll have about both Hib and Hib vaccines and Prevnar. But in essence I do think the data, from what I can read, is probably adequate to support the efficacy of the vaccine.

CHAIRMAN DAUM: Thank you very much. Dr. Faggett, you're up.

DR. FAGGETT: Well, as a pediatrician, I too appreciate the need for this vaccine. But I think Dr. Reynolds made the point that we need more data in terms of pediatric clinical trials and studies in general.

I don't think that the data that we've been presented is adequate to support the efficacy at this time, unless somebody as we go around can convince me otherwise.

CHAIRMAN DAUM: Okay, then Dr. Faggett, I have to ask you to do us a favor and address question b and that is what exactly do you need to be adequate?

DR. FAGGETT: I think we need more numbers. I think maybe 300 should be a threshold. Again, I'm not just that knowledgeable statistically, in terms of statistics of it. But I think we do need more numbers to have more clinical data.

CHAIRMAN DAUM: Thank you. Dr. Griffin?

DR. GRIFFIN: Well, I'm on the fence. I'm not going to be comfortable with my decision either way because I don't think there is, for me there's not an obvious answer to this question.

I would be wildly more comfortable with much more data on this particular vaccine, using this schedule in U.S. children. And I think for right now that is going to carry the day for me and I will have to vote no and that I would like more data.

CHAIRMAN DAUM: Can I press you to be a little bit more specific about what more data you need? Because I think it would be helpful to FDA folks and sponsors and your colleagues about what it is that you're lacking here in terms of --

DR. GRIFFIN: I guess, and the reason I'm on the fence is that I think with more data it will show that everything is fine. Basically I think that this is probably an excellent vaccine, that it's immunogenicity is fine and that these vagaries of not being totally clear would be cleared up and everyone could be comfortable that we were making the right decision and wouldn't have some long-term consequence of lower immune responses or whatever in this group of children.

I'd like mainly, I guess mainly the 015 Study to bem have groups that were larger I guess my, I would be guessing around three or four hundred. I'm not a statistician so that's just what we might guess that would narrow those confidence intervals to having something I would feel more comfortable with.

CHAIRMAN DAUM: So you, I don't want to put words in your mouth, so let me play it back. You're asking for more U.S. immunogenicity data.

DR. GRIFFIN: U.S. immunogenicity data with this vaccine, head-to-head comparison with giving the components separately and diverse population would be great. I think that's actually in there, but more numbers.

CHAIRMAN DAUM: Thank you very much. Dr. Diaz.

DR. DIAZ: I too am very, very much on the fence regarding the adequacy of the data to convince me of its efficacy and immunogenicity in young children. And being a pediatrician I do recognize the need for combination vaccines desperately. And yet, again, they must be effective and safe.

I am somewhat reassured to some extent with some of the last minute data that was drawn to our attention regarding the 027 trial and yet I do recognize it was a, not the exact same combination vaccine that we're being asked to talk about today.

I would be more comfortable with more data from U.S. children and in particular more diverse populations, albeit there is some data in one of the studies.

So I feel I'm going to have to abstain, actually, in my response because I'm not convinced either way and I'm uncomfortable to vote either way.

CHAIRMAN DAUM: Okay. You made your reasons for abstaining clear. We thank you. Dr. Goldberg.

DR. GOLDBERG: I'm, in my gut I think this vaccine is probably fine. But the data is presented from the 015 trial, which I'm, really everything rests here, coupled with the lot-to-lot variation make me want more data as well.

And I guess what I would, I mean I'm troubled because it really, really is, I'm also on the fence, but I would have to vote no right now.

And what I would recommend is a head-to-head, two-arm comparison of the size to be determined to make sure, I wouldn't give you a number now. I think one needs to study the data a little bit to make sure that we can be convinced from the numbers that we get from the new trial.

And also I would try to do it in such a way that you can combine both trials so that you can cut the numbers there but in a sense increase your numbers and do sort of an analysis using, of combining the two studies to get at it.

I don't really think it should be that difficult to do it. But you know that's something I'm not going speak to right now. I think though that given the usage that this vaccine is going to have, we really need more data.

CHAIRMAN DAUM: Dr. Fleming? Dr. Fisher I've bypassed you because I presume you spoke. Dr. Fleming.

DR. FLEMING: I, my perspective's very similar to Judy's. I am hopeful that with adequate information that there is a very good likelihood that we could be reassured. I'm concerned. We're talking about a vaccine that will be administered to hundreds of thousands, millions of infants. And we have gone through extensive studies.

The Italian and the Swedish trials have been marvelous studies that have established efficacy for, for example the pertussis vaccines and I've been convinced in those studies that the multicomponent vaccines are, there is considerable evidence, are more effective.

I don't have a sense that I can tell you I know what FHA's component is. But I'm very concerned about stepping back in efficacy unless what we are achieving with that step back is of very significant importance.

I'm also, and we're going to get to it shortly, concerned that there might be a price in terms of safety with fever.

And so it seems to me that it's very rational to look to an expectation of having more than, and I consider 015 the core study. To having more than 100 per arm in that study. So I believe that these data do not establish lack of efficacy.

But they don't provide the level of evidence that I think would be appropriate for the FDA to expect in this setting, and hence would argue that the data don't adequately establish efficacy. How much would we need, which is the second part of the question?

I would specifically argue that that question should be answered with some considerable care as one looks more carefully, if you're going to do another study, at whether we can simplify immune responses into a simple threshold. And there are statistical methods that allow us to get at whether that's valid.

It might be that the proper way to assess immune response there is with the multivariant assessment of ways of assessing these immune responses. My general sense though is that we're probably talking about a study that would be three to four-fold larger if not larger and just as a rule of thumb, four-fold larger halves the confidence interval whipped.

It gives you a precision that's twice as great, which is as we can see from 027, compared to 015, certainly of real relevance here. And that sample size relative to the magnitude of use of this vaccine, to my way of thinking, is a very appropriate expectation by the FDA.

CHAIRMAN DAUM: Thank you Dr. Fleming. Dr. Wharton.

DR. WHARTON: Based on the findings in two of the three pivotal studies 015 and 044, both of which were done with the candidate product on a 2, 4, and 6 schedule in the United States, with 484 children receiving that product in study 044 as well as the supporting study 027, also done in the United States on the 2, 4, 6 schedule, with over a thousand children receiving the vaccine ad mixed with Hib, which I believe is unlikely to improve the immune response of the vaccine, I believe the data is sufficient to support efficacy.

CHAIRMAN DAUM: Thank you very much. Dr. Broome.

DR. BROOME: I agree with Melinda. I think she stated it very well. And I think she's included all of the relevant data which are appropriate to consider.

CHAIRMAN DAUM: Thank you, Dr. Broome. Dr. Britt.

DR. BRITT: I apologize to the other members of the Committee and the audience. I was not here this morning so I didn't hear lots of the lively discussion. I did read the material, I've listened to the discussion this afternoon and I am too a pediatrician and I don't enjoy giving children many injections.

However, the injections I give them now seem to work. And I would like to make sure that the succeeding, the next injections I give them also work. I'm having some trouble under, coming to grips with no-inferiority in some of the discussions that Dr. Fleming has given. And I don't believe that I can see the data yet that says that this is efficacious as what we're giving now.

And in terms of the answer to b, I think I would agree with my colleague across the table, Dr. Griffin, we need more patients and we need a more diverse group of patients. And I think that's something that should be really stressed because this is a pediatric vaccine.

CHAIRMAN DAUM: So I want to make sure I understood you. I'm sorry. You're voting no.

DR. BRITT: I'm voting no.

CHAIRMAN DAUM: Okay. I'm not snubbing the last three members at the table. But they are non-voting members for the purpose of this discussion. And so there remains my vote and I'm solidly in camp with Drs. Wharton and Broome. I think that with respect to the effectiveness issue, I would definitely like to see more numbers.

I kind of wish the large study hadn't been done in Germany with a different schedule. But I'm looking at the individual components of the vaccine and trying to decide whether I really believe we've seen something that concerns me about efficacy. And I really haven't.

The most important concern is perhaps some compromise in pertussis antibody but I'm not sure I know how to interpret the information that I saw about that. So, I would like to see more ethnic diversity and I would actually like to call on colleagues at the FDA to begin to insist on that.

We all seem to want it. I've heard the Committee members say it over and over again, that even studies performed in the United States, tend to maximize participation of individuals likely to come back and perform in the study protocols. And I'd like to see us begin to move beyond that.

I think the risk of sponsor who undertakes trials internationally is that you're going to have a scheduling problem. You're going to have an ethnicity problem and we're always going to be a little nervous about importing those things directly into this country. But that's not to say they're not valid, can't be done and can't be looked at. You learn a lot from several thousand children in Germany.

So I'm inclined to think that on the effectiveness issue that I vote yes. And report that the Committee votes five members yes, six members no and one absentia. And all of the people who voted no I must say I wanted more U.S. children entered into trials that focused on immunogenicity with an occasional call for more ethnic diversity.

So question one is done. I'd like to take a fifteen minute break. It's three fifteen, we'll reassemble at three thirty and begin with question two.

(Whereupon, the above-entitled matter went off the record at 3:20 p.m. and went back on the record at 3:38 p.m.)

CHAIRMAN DAUM: We are now ready to go back into session. If people would take their seats and finish their conversations.

I'd like to begin by announcing to the Committee members that anything left on the tables tonight, in the way of paper, will be shredded, gone by tomorrow morning. So please, if it's important to you, take it with you as is appropriate.

I'd like to move now to discussion point two. We are not going to have a Committee vote on discussion point two because there are outstanding manufacturing issues that need to be addressed before it's appropriate for this Committee to do that.

However, we are going to have the same kind and Committee members willing, the same quality discussion that we would have, were we to bring this matter to a vote at the end.

So I'd like to begin with some general comments on this question as the Committee wishes and then we'll begin focusing each member to make a comment. General comments and discussion point two which Nancy has given me body english we should maybe read it.

The following discussion points pertain to safety. Please discuss whether there are, whether available clinical data are adequate to demonstrate the safety of this combination vaccine we're asked to comment on today, when given to infants at a primary series of 2, 4, 6 months of age are adequate?

I paraphrased a little bit but I think I got it right. Please comment on the increased rates of fever in infants receiving this combination vaccine. And then, again, if you're feeling is that the data are not adequate, what additional information should be requested?

So I'll have general comments first and Steve, I see you're getting into the habit of jumping into the abyss here.

DR. KOHL: Take Dixie's spot. The biggest concern I have is fever. I think it's real. I think the FDA has helped me because I think it's real and it's not trivial. We see fever that is increased both at the lower range and also at the intermediate range to the point where fever of a 101, and 101.5, I believe it was, or greater, is increased by about five percent.

That may not sound trivial but if this is a vaccine that's going to be widely used which I would anticipate it would, we're talking about four million kids a year, roughly, that's about 200,000 extra kids a year who are going to have a significant fever.

If a large proportion of those children are in that first month of life, say at four weeks, some of those, and I think a fair number of those, are going to translate to sepsis work ups. Because that in this country I think is still a standard of care.

So I am, I'm quite concerned about that. I'm also concerned, as I mentioned, that the data for seizures are just not solid enough because of the zero in the control group. It was seven in the vaccine group and zero in the control group. And I would like to see more data on seizures to be assured that there's not an increased risk for seizure activity in children receiving this vaccine.

CHAIRMAN DAUM: Thank you very much. We're not necessarily going in order. So anybody that wants to jump in can do so. But we will hear from everybody before we're done. Ms. Fisher.

MS. LOE FISHER: Is it too late to ask the manufacturer a question?

CHAIRMAN DAUM: No, I don't think so. As it pertains to the statement on the screen.

MS. LOE FISHER: Yes.

CHAIRMAN DAUM: No, please, go ahead.

MS. LOE FISHER: During the trials, after which adverse events did you discontinue vaccinating with the combination vaccine and was the same criteria used in control arms?

And the second part of that question is, when a vaccine adverse event occurs with the combination vaccine, do you have any idea which component is responsible, which of course is relevant in terms of contraindications to continue vaccination after an adverse event occurs?

CHAIRMAN DAUM: Thank you, Dr. Howe?

DR. HOWE: Let me just make sure I understand your first question. You're asking in the context of the clinical trial for what type of adverse event would you intentionally discontinue vaccinating the child?

MS. LOE FISHER: Did you discontinue? Did you decide you were not going continue to vaccinate? They dropped out, then?

DR. HOWE: In the clinical trials, the typical type of precautions for further vaccination were specified in the protocol, which means hypersensitivity reactions, allergic reactions to any previous dose.

The precautions to DTP-whole cell, which apply to DTPa as well would also be precautions to further vaccination and those children could have been withdrawn. But other than that, there were no other mandates for withdrawing or discontinuing a child from continuing in the trial. The usual practice.

MS. LOE FISHER: Well, I want to be real specific about this. I think it's important in terms of the outcome of the trial. So, children in the trial who had high fevers, over 103, over 105?

DR. HOWE: It is 40.5, I believe.

MS. LOE FISHER: Children who had high pitched screaming or unusual crying?

DR. HOWE: Yes. Seizures.

MS. LOE FISHER: What about seizures? What about restlessness?

DR. HOWE: No.

MS. LOE FISHER: So it was basically three things. It would have been --

DR. HOWE: As well anaphylaxis, obviously to the previous dose.

MS. LOE FISHER: Anaphylaxis, but you didn't have that in there.

DR. HOWE: Right.

MS. LOE FISHER: And then, do you have, did you have any idea which component was involved and what would you consider a contraindication? Would it just be those three reactions?

DR. HOWE: I mean the contra, first of all we wouldn't know in a combination vaccine exactly which component would be causing an adverse event. However, if there was an adverse event explained or reasonably associated with a component of the vaccine based on historical data, such as for pertussis, one might presume that an AE such as that would be related to that component. But we don't really know when an AE occurs which component to attribute it to.

MS. LOE FISHER: So with the combo you'd basically want to, if an event occurred, you'd have to not vaccinate with any of the components.

DR. HOWE: Well if a contraindication to further pertussis vaccination occurred with the combo, you would stop vaccinating with this combo.

CHAIRMAN DAUM: Okay.

DR. HOWE: Whereas if an anaphylactic reaction, after the combination occurred, you would stop vaccinating with the combo.

CHAIRMAN DAUM: I think with respect to the discussion point, we've got the information we need on this question. Can we move on to other Committee comments about this discussion point. Dr. Stephens? Dr. Gerber next.

DR. STEPHENS: You were kind enough to provide us with data, I mean immunogenicity data on 027. Can you share any reactogenicity data on 027?

DR. HOWE: Yes, I have information on, do you have the slide for fever? So, again, this study involved nearly, well actually a thousand subjects who received the DTPA-HepB-IPV mixed with Hib, given at 2, 4, 6 in U.S. infants as compared to separate injections of Infanrix, Engerix, Hib and Oral Polio.

This shows the fever rates in the study. You can see for the lower cut off rates those who received the combined vaccine, forty-two percent had a fever greater than or equal to 104.4 degrees versus 38.4 in those who received separate injections. And once again for the higher cut off the rate was lower, 2.2 versus 1.4.

CHAIRMAN DAUM: Thank you. Dr. Gerber.

DR. GERBER: I wanted to echo Steve Kohl's concern about the increased incidence in fever, particularly in the youngest of the infants and also my concern about extrapolating from what is primarily a German experience with respect to the clinical implications of this increased incidence of fever.

Although we're told that German physicians' approach to fever in infants is essentially the same as physicians in this country, looking at the use of antipyretics, there was some data about the very substantial use of antipyretics, routine antipyretics in this country compared to Germany.

That would to me suggest that the approach to fever, that the feelings about fever, in this country might very well be quite different from Germany. And so I would very much like to see data in this country as to the actual clinical implications of this increased incidence in fever.

CHAIRMAN DAUM: Okay, thank you Dr. Gerber. Other comments. Dr. Diaz, please.

DR. DIAZ: I, likewise, am somewhat concerned about the increase in fever and yet I don't know enough about how that increase in fever translates into the end point of the, of disease prevention.

And I might step back by making a comment. I think in the manufacturer's package they comment for safety overall. I think there were about 6,900 plus children who had at least turned in one sheet regarding some safety measures and that about 5,300 of those were eligible for the analysis according to protocol.

So there were about 1,600 plus children that weren't overall in studies combined able to be analyzed in terms of safety and it's, they were excluded, I believe, at least the wording was due to a departure from the visit schedule according to pre-specified criteria. So what I was trying, I see people shaking their heads. Is that incorrect?

DR. HOWE: The vast majority of the children that were excluded from the ATP analysis for safety were in study 011 and the reason was because in study 011, if you recall, it was originally an uncontrolled study with respect to U.S. license separate injections and there were approximately 1,600 infants who were enrolled prior to the amendment which allowed for the introduction of the relevant control group, the U.S. license separate administration group.

So in terms of a controlled comparison, it was felt invalid to include those first 1,600 children in the ATP analysis. However, we did an ITT analysis which does include all of those children and those data, the ITT analysis, were actually in the FDA's briefing document. And the conclusions are the same.

Furthermore, with all of the more significant adverse events that we're talking about such as the SAEs, seizures, what not, we're certainly talking about the ITT cohorts. So we're taking all of the children into account.

DR. DIAZ: Right. Thanks for clarifying that. Because that was my concern was the intent to treat and the issue of how much of the fever may have played into children not finishing the series per se. But it sounds like that was not the issue.

DR. HOWE: Yes. And the seven thousand twenty-eight children, the overall database includes those 1,600.

DR. DIAZ: Okay. That having been said, I feel a little bit more reassured about that, that aspect. Back to the fever, overall, I think, I still don't feel that there's enough information in terms how much that additional fever translates into, for instance, physicians visits, perhaps sepsis work ups, hospitalizations, etcetera and whether that will really play into issues of further safety associated with the vaccine.

The fever, slight increase in fever, in and of itself, may not be an issue. It's just that I don't feel that I have enough information from the studies to date to say how that increase in fever translates into the overall care of the child during that episode. I'd like to see more information.

CHAIRMAN DAUM: Thank you. Other comments from the Committee. I'd really would like to hear from everyone about this. Dr. Fleming then Dr. Wharton. Dr. Wharton, then Dr. Fleming?

DR. WHARTON: Well, it was very interesting to see the information that was just put up on the board from the 027 trial. Where the, if I interpreted this correctly, the rate of fever in the standard U.S. licensed vaccine group was I believe thirty-eight percent compared to I believe forty-one percent in the other group.

Which is not a striking difference in, and it's much less striking than the data we have been provided from study 011 and 015 where we had rates in the twenties compared to rates of forty or forty-one. So that's interesting. I too am concerned about the prevalence of fever in these studies.

While my impression is that these fevers are at least in the trials to date have been largely benign and the incidence of high fevers has been much lower, it still is of concern and I share others concern about the, it precipitating sepsis work ups in very young children.

There isn't, given that when this vaccine is licensed it will be given as part of the recommended childhood immunization schedule, though, I am concerned about concomitant administration with Prevnar, which has also been associated with fever at least by my interpretation of the data provided in the package insert.

With fever reported from thirty-three, in thirty-three percent of recipients of dose one to up to forty-one percent for dose three and forty-two percent for dose four.

And I don't know if these are going to be additive or multiplicative or what interaction is going to be between those two vaccines and I'm quite concerned about that. And believe that additional data are needed addressing that issue.

CHAIRMAN DAUM: So yours is a safety issue to do with the simultaneous administration of Prevnar. Okay thank you. Dr. Fleming.

DR. FLEMING: I think my thoughts are quite consistent with what many others have already indicated. My sense is that the data we have on safety and the sponsor has really focused in particular on the studies 015 and 011, provide us important insights about what, as they refer to the common AEs. The AEs that would occur at least as frequently or more frequently than one per one hundred.

Or it may be the only limitation to that insight is the vast majority of that data comes from 011 which is not only in Germany but with a different schedule than what we would be looking at here. I am struck, though, at the level of consistency across the studies, not only the 015 and the 011 but the 003 and the 027.

They all show patterns of increases anywhere from the most modest which is 027, about a ten percent increase, to the 015 and 011 trials that show more on the order of a fifty percent or more increase in fever.

What's interesting is if you look at 39.5, then those four studies are all very consistent. They all show about one and a half frequency increase in those high fevers.

I'm inclined to in any study try to put safety in the context of efficacy benefit to risk. We always expect with interventions that there are some risks, some safety issues.

Essentially if you're comparing a vaccine against a placebo where the upside is preventing disease, you're going to expect that, or you're going to be willing to accept a higher level of safety concern.

In this setting we're comparing the combination vaccine against separate administrations so it's to my knowledge we're not claiming that it's being done specifically to improve efficacy, although possibly to improve overall coverage.

But it does make me a bit more concerned about the level of additional safety risks that you all, that you would be willing to accept in a setting where you're not comparing to a placebo but you're comparing to another regimen that is presumably in the same level of efficacy.

The last point is to state maybe the obvious and that is that these data are not addressing the more rare events. It has been noted and it's reassuring at some level to note that there isn't any evidence of anaphylaxis, HHE, SIDS.

But these are events that would to have adequate power take trials anywhere from the size of ten to twenty thousand for us to really be in a position to rule out.

We do see the seven cases of seizures. It's entirely possible that that doesn't reflect a true increase and yet it certainly is possible that these increases in fever would translate to a two or three-fold increase in the risk of something on the order of seizures from a rate of one per thousand to three per thousand and these data obviously aren't of the magnitude that we would be able to address that.

CHAIRMAN DAUM: Thank you very much. Other Committee members, please. Dr. Faggett.

DR. FAGGETT: Yes, I just want to make a point that fever is a pretty good response, physiologically. Let's not forget that. However, in the younger child, there are problems with it. Fevers to the point of hospitalization are a problem.

I still restate my concern about the numbers. Again, it's a vaccine that we are very familiar with the components of, so seven thousand might be adequate. But I think we really need more information and we need to see what happens in more diverse populations as well.

I agree with Dr. Kohl that the preponderance of experience in Germany might not translate or be applicable here. So I have real reservations at this point.

I think that the, I appreciate the full disclosure we've gotten. I think we have the power curve. But I think we really need to really see what this is about.

I wasn't clear on how many of the children had septic work-ups. We implied that. So fever to the point of hospitalization I guess is one of my real concerns.

CHAIRMAN DAUM: Thank you very much. Dr. McInnes?

DR. MCINNES: Do you want me to respond to the number of septic work-ups, or?

CHAIRMAN DAUM: Do you have information about it?

DR. MCINNES: Yes.

CHAIRMAN DAUM: Oh sure. Thank you.

DR. HOWE: So there were only two children in the context of 015 or 011 or 044 so the two pivotal U.S. trials and the 011 study, who underwent a sepsis work-up. And one of the two children, I believe, there was also the possibility that they had influenza. So there was potentially an alternate explanation for the fever.

The other point I wanted to make is that in the hospitalizations with fever and the rates that were quoted in the context of 011, the proportion who were hospitalized with a fever in those who received the Infanrix HepB-IPV was identical to that in the control group.

And I emphasize that this is hospitalization with fever not necessarily for fever. In many cases the children had other things going on which clearly, gastroenteritis, dehydration, an alternate diagnosis to explain the fever.

So it wasn't, from what we can see, looking very carefully at the data, it's not as if we had a number of cases of unexplained fever, where the children went into for a sepsis work-up, came up empty handed and they said it's related to the vaccine. Does that help clarify?

CHAIRMAN DAUM: It does. Do you want to speak right to this issue?

DR. FLEMING: Right to this point.

CHAIRMAN DAUM: Okay.

DR. FLEMING: Just the distinction that if overall hospitalization rates are much higher than the specific rate of hospitalization for fever.

DR. HOWE: Yes.

DR. FLEMING: Then you could be inducing a five-fold increase in hospitalization for fever and not see an increase in hospitalization with fever if other causes of hospitalization are far more frequent than hospitalization for fever.

DR. HOWE: And the figures that we gave were for hospitalization with fever. Maybe one other thing that might help put this into context is that we did look at the issue of not only how similar were the reporting rates for the common solicited reactions in the German population as compared to the U.S. population where I think many people have pointed out that for the objective symptoms they were remarkably similar, within decimal points of each other, going from 100 children up to 4,000 children.

In Germany the rate of low-grade fever was identical in those who had received the Infanrix HepB-IPV. But we also looked at things such as serious adverse event reporting and hospitalizations in two studies that we have conducted using Infanrix Hepb-IPV-Hib. One run in the U.S. on a 2, 4, 6 month schedule.

And the other run in parallel, in the same time frame, in Germany and what we found was hospitalization rates and SAE rates, in point of fact they're generally pretty close. I mean usually all of the SAEs are for hospitalization. Were higher in the German population.

So I think it was two point five percent versus one point five percent in the U.S. population. So German children were more likely to be hospitalized. And that's with a shorter follow-up period.

So it's three to five months of age versus two to six months of age. And we consider this to be indicative of the fact that Germany is a more sensitive, you'll be able to pick up hospitalizations.

DR. FLEMING: And you do not have managed care.

DR. HOWE: Yes.

DR. FLEMING: But the other point too. Do you have a break-out on the age range of the hospitalized comparison, two month, four month?

DR. HOWE: We do have hospitalization by dose which you would be able --

DR. FLEMING: By age.

DR. HOWE: Well by dose will tell you by age. Yes. So let me see if I can get hold of that.

CHAIRMAN DAUM: Okay. In the meantime we'll go to Dr. McInnes and then Dr. Britt.

DR. MCINNES: Dr. Daum, I had a question regarding the ages from the German trial and extrapolating to what the safety profile was found to be in the U.S. And I want to go back to a comment Dr. Howe made earlier today.

I mean I'm impressed with the body of safety data from 011, from Germany. And I'm trying to think about how it's the same and how it's different from the U.S.

I note that the age of presentation for first dose of vaccine in the Germany study ranged I think between eight and fourteen weeks of age.

I'm trying to think about how a 2, 3, 4 regimen actually when vaccine was really delivered in Germany and how that tied to the 2, 4, 6 regimen in the U.S. And I think you mentioned earlier this morning that, in fact, they looked not that dissimilar.

And I'm wondering if we can go back to the real ages at which the first, second and third doses were delivered in Germany compared with the real ages when the vaccines were delivered in the U.S. Trying to address the comment of how young really were the children at receiving the first dose and the concerns about the work-ups for fever and for sepsis.

CHAIRMAN DAUM: So Dr. Howe, hurry up and produce the first round of data we asked so we bother you for the second. How are you coming?

DR. BALL: Maybe I can make a comment while they're gathering the data. On page forty-seven of the FDA briefing document there are two, three graphs. Dose one, dose two and dose three. And there's a comparison between the groups for study 011 and 015 in the age of the administration.

And you can see that particularly for dose two there was considerable overlap. There was sort of a biphasic look in I think it was in study 011 in terms of when the administration dose was administered. But you can see that the peaks were different. But there was probably more overlap for dose three.

And then subsequent tables in the, the two subsequent tables, actually I think it's three, compare studies 011 and 015 for each dose and overall for the incidence for both a local reactions as well as general reactions. And I think that it's hard to make sense of these fairly dense tables.

But for fever it was very similar between the two, particularly for a fever of greater than 38 degrees centigrade. For, also for the kinds of symptoms that are more objective. Such as redness and swelling where something was measured.

Those were fairly similar across the two studies. For the events that were perhaps more subjective and maybe more open to interpretation, those were different between the two studies. Such as like loss of appetite and that kind of symptom. So I don't know if that helps answer your question.

CHAIRMAN DAUM: I think it does. And it also has given us an opportunity to let Dr. Howe get these data up that Dr. McInnes has asked for.

DR. HOWE: Right. So this is the figure from the briefing document, which shows the overlap. The dotted line is the age at vaccination for the first dose, that is from the actual clinical trial 015 in the U.S. and the solid curve would be that for the pentavalent recipients in study 011 in Germany.

And what you can see is that the greatest overlap is dose two. Also, a fair amount of overlap in dose one, dose three, excuse me, some overlap at dose one, but the age of enrollment at age one for study 011 was a bit wider. The eligibility criteria in terms of age at enrollment.

CHAIRMAN DAUM: Thank you very much. Dr. Britt.

DR. BRITT: I just had a quick question about the adverse affects in the fever. Don't know the presenters name, but besides hospitalization, do you have any documentation on antibiotic usage for these children with fever?

DR. HOWE: We do collect information about co-administered medications throughout the course of the trial but we don't have that data analyzed.

CHAIRMAN DAUM: Okay. I'd like to hear from people who haven't addressed this question yet on the Committee, before I call on them. And then, also other issues that haven't been raised. It's clear that we're collectively, at least everyone who's spoken so far, concerned about the differential rates of fever.

It's also clear, at least from what I'm hearing that people want more information about what the consequences are of those increased rates of fever. And are hearing that we'd like more information about that. So other ideas. Dr. Goldberg, then Ms. Fisher.

DR. GOLDBERG: I just wanted to echo some of the other comments that have been already made. I'm very concerned about the fever as well. Particularly in face of my uncertainty about the efficacy.

I mean I think that to have an increase in a side affect such as fever, we need to be sure that the efficacy really is the same. At least the same.

And I think also that given the size of even the large trial, it is, we really, given that these vaccines are really not that dangerous, it's not surprising that we really don't have very many of them to deal with.

And I think it's unlikely with even the new trials that we'd be asking, the new trial that we might be asking for with regard to efficacy that we would gather much more organized trial safety data.

And so all I would urge is that at some point we'd be very careful about those surveillance that we put on products such as these to ensure that we are capturing the data, the outcomes and the handling of those severe outcomes so that they can be monitored actively.

CHAIRMAN DAUM: So do you think the data are adequate to address the fever issue and you just don't like the fact that it's there?

DR. GOLDBERG: I don't like the fact that it's there. I don't know who much more could be done in this context.

CHAIRMAN DAUM: Okay. Thank you. Ms. Fisher. Then Dr. Griffin.

MS. LOE FISHER: I'm concerned about limiting the active surveillance for adverse events to four days post vaccination and total adverse event surveillance to only thirty days. And the fact that only 700 U.S. children have been evaluated the 2, 4, 6 month schedule.

And I'm concerned about the seven seizures which occurred in seven thousand children with five of these being first-time afebrile seizures which are the kind most likely to result in long-term permanent neurological damage.

And I am concerned that without an understanding of the biological mechanism of adverse events, including fever, that when an adverse event occurs, there will be few clues about which component of the vaccine is at fault, or whether it is indeed the combination, thereby leading to confusion about whether to continue vaccinating with the combination vaccine versus eliminating one of the vaccines or giving the vaccines separately.

So I would like to see a larger trial in the U.S. in 2, 4, 6 month-old children, with at least a one-year follow-up to measure for all morbidity or mortality outcomes, including the development of autoimmune and neurological disorders.

This is the first five-in-one vaccine and will have an enormous impact on vaccine policy. And we have to be sure that it's the right one at the right time. Because if it turns out to be far more reactive in a real life setting because we failed to get enough information pre-licensure, then it will ultimately negatively affect the whole vaccination system.

And I think you have to have at least three thousand more U.S. children in your total database so you have ten thousand children that you have studied on this vaccine. So that the public has confidence that you have proven safety and efficacy.

CHAIRMAN DAUM: Thank you. I'm going to try and fill in the cracks here and get comments from people who haven't spoken to this issue so that we can move on. Before I do that though I'm going to call on Dr. Kohl.

DR. KOHL: I've spoken to the issue but I'm wrestling with a question that's sort of a basic question. If, let's assume this vaccine is as effective as the components are. Let's just assume that. And let's assume that the only side affect is increased fever.

And let's take the increased fever that sticks in my mind as a ten percent greater than 101.5 versus a five percent greater than 101.5 in the components.

Would you license this vaccine? Is it worth the extra fever for the convenience and one of the things that I could foresee is physicians finding it so much easier to have this vaccine because they wouldn't have to stock as many different kinds of vaccines and they'll only give one shot, etcetera.

That not only won't it be licensed but it might be the only one carried by the physician. And one of the questions asked earlier was well would you be able to go to the doctor and still get the other vaccine components if you didn't want this combo vaccine? I could see where lots of parents and their children would not be able to get component vaccine.

CHAIRMAN DAUM: Okay I think we've heard from Dr. Kohl. Dr. Faggett.

DR. FAGGETT: I just want to follow-up with Dr. Kohl's comment. I think a lot of my colleagues in practice in pediatrics would be a little concerned with a couple of four-week, two-month olds with fever, 101, might be enough to discourage them.

I would be concerned of the down side. That we'd lose the confidence of the practicing primary care provider, family practice pediatrician, who indeed is the most effective one in talking to those parents. So I think there is that aspect to it. The fever there would be a real concern.

That they were just getting over the hepatitis B issue and we're now convincing parent that you need to give HepB at birth. So I think that we need to consider that as well. That the pediatrician has to be convinced that this is a safe vaccine. I don't think that we have the data to do that right now.

CHAIRMAN DAUM: Thank you. Dr. Stephens. We haven't heard a peep out of you on this important issue. Could we ask for a comment?

DR. STEPHENS: Sure. There does appear to be more fever. The data we have suggest that there is more fever. There probably is more local reactogenicity if you look at the data as well with this particular vaccine.

I was kind of surprised by the 027 data because I thought that would be even more impressive. But it wasn't so that's interesting. I don't know quite how to interpret it. In any event, I think that we do see more fever, we do see more local reactions, there may be more seizures. We don't know that.

It's not statistically evident. By certain seven and zero is of concern. So I think there are clearly issues regarding the reactogenicity of this particular product in comparison.

Now from an adult infectious disease perspective, this is, this would be a different issue I think than it is from a pediatric perspective. And I appreciate the comments the pediatricians.

CHAIRMAN DAUM: Thank you. Dr. Faggett, you've spoken. Do you want to embellish your comments.

DR. FAGGETT: Too much.

CHAIRMAN DAUM: Dr. Griffin?

DR. GRIFFIN: Well I think that, I think the big consideration is I think we're all convinced there's more fever and more reactogenicity. And I think the big consideration is what the trade off is there.

And so, you might be willing to have some percentage more children have fever for being able to use only one shot rather than multiple shots.

And even parents might say rather than poking my kid three times, you know, I'd be willing to have some more, deal with fever for twenty-four hours or something like that afterwards. So then I think the real issue becomes what the consequences are of that. And I think that is what we don't really know.

How, you wouldn't be willing to have your child be hospitalized and worked up for a fever because of that, I think, as an additional question. So I think that it really does depend on and in part and that could be seizures or other kinds of adverse events. You know how much it really translates into significant medical problems to have that increased reactogenicity.

CHAIRMAN DAUM: Thank you very much. Do you think the data are adequate?

DR. GRIFFIN: Adequate for what? I think they adequately say that we have a problem with more reactogenicity. But they aren't adequate to say, I don't think is that in our medical system what the consequence is as far as extra hospitalizations and that sort of thing for these kits.

CHAIRMAN DAUM: Thank you very much. Dr. Diaz. Do you want to comment further? We have heard from you. Okay. Dr. Goldberg, your pleasure.

DR. GOLDBERG: I mean I'm listening, I'm listening to the pediatricians and again it's being on the fence of when is enough, enough. And how serious is the fever problem. And I think that remains unanswered really.

CHAIRMAN DAUM: Mr. Fisher we've heard from you. Do you want to say anything else directly to this question. No. Thank you. Dr. Fleming?

DR. FLEMING: So is it accurate to say we should also be specifically answering the second part as well? If we need additional data.

CHAIRMAN DAUM: Yes. Absolutely.

DR. FLEMING: Okay. I just might begin by just adding to what Dr. Stephens has pointed out that one of your last comments related to the fact that there are the seven seizures versus zero. My understanding of the data I think though is it's pretty tenuous.

If it were seven versus one we would have equal rates. So it's very limited amount of information. I have raised the issue as well stating that it creates the suggestion that this is something to be addressed more reliably as opposed to providing any kind of direct reliable information that there is in fact an increase.

So having said that my sense of the two types of additional information that I would like to see would be tied into what might happen for efficacy. If in fact there is going to be further study to more conclusively address efficacy and immunogenicity related to the earlier discussion today, then I would certainly hope that this would be a great opportunity in the context of that larger comparative trial in the U.S. to more carefully follow, not just what is the relative increase in fever, but the sequelae, very carefully looking at what the consequences appear to be in those instances where particularly higher fever is occurring.

And in fact I would think that if it involved Prevnar, in the context of Prevnar it would be extremely important to see what that relative rate of fever would be in that context.

The other thing that I would hope for is if that study then is favorable, I think it's not realistic for us to expect as in other settings that we're going to be able to get at the rare event rates.

And so I would, if that study is favorable, and if marketing occurs, then certainly careful follow-up in post-marketing surveillance to get a better clue, particularly about issues such as seizures and sepsis but in general these rare events and is there in fact evidence to suggest that the occurrence of fever is translating into important but rare events that I think probably would have to be reliably addressed in large scale, post-marketing surveillance. So those are the two sources of information that I would hope to get.

CHAIRMAN DAUM: Dr. Broome would you like to go ahead? And then we'll come back to Dr. Wharton in a moment. You had your hand up.

DR. BROOME: Well I particularly wanted to clarify David Steven's comment because I think it's somewhat important rather than saying seven versus zero, to say seven out of about five thousand versus zero out of 876.

And as Tom clarified, you would expect one at the rate of seven per five thousand. And you'd expect one in the control group. So the fact that you observed zero, I don't think really you know. What it means is what the sponsors and Leslie have told us. The study is not powered to detect rates that occur at the frequency of one per thousand.

DR. STEPHENS: I think the concern is that we see this with the clear increase in fever with the clear increase in reactogenicity. That's my point.

DR. BROOME: I think we all are interested in good probably post-licensure in terms of the frequency of the one per thousand. But I think the issue in terms of voting as I certainly agree with everybody that there is an increase in low level fever and I think this is concerning.

And it's certainly, it would be nice to have additional clarifications on the Febrile episodes and the clinical implications of those Febrile episodes.

I guess I'm a little skeptical that you're likely to get real good quality information on that. I think the information around hospitalizations and septic work-ups is probably about as good as you're going to get.

So, you know, I'm particularly interested in you know should licensure occur, you know, continued follow-up to focus on both the local Febrile and any other possibly rare adverse events.

CHAIRMAN DAUM: Thank you. Dr. Ball wants to make a clarifying comment.

DR. BALL: Right. This is a clarifying comment. I think Dr. Stephens brought up the issue of the seizure, the difference in seizure between the combination recipients and the control, in the context of the increased fever.

And I think, as was shown in my slides, within the time period in which the fever was observed, the four-day time period, we're not talking seven to zero, we're talking two to zero, in terms of the absolute number of seizures.

CHAIRMAN DAUM: Thank you Dr. Ball. Dr. Wharton? Can we ask you to comment on this issue, question that's on the screen?

DR. WHARTON: Well, I am concerned about the fevers as well. Again I find some reassurance in that they tend to be, they appear to be relatively low-grade fever with the higher fevers being substantially less frequent.

I think it will be important should the vaccine be licensed to evaluate this in the context of the current recommended childhood immunization schedule.

CHAIRMAN DAUM: Thank you. Dr. Britt?

DR. BRITT: Yes, I'm coming back to just one point. I think, unfortunately, because I do, not unfortunately, that I do interface with community physicians, but I do interface with community physicians in treatment of infants with fevers is not only with antipyretics, it's often with antibiotics, in combination.

So I don't believe that we should ignore this either for a vaccine that may be used for a large number of children which does induce a high percent increase in fever. There may be a concomitant increase in the inappropriate use of antibiotics, which I don't think anyone, I don't think this is hiding needs right now.

CHAIRMAN DAUM: We have three non-voting members at the end of the table but since we're not voting we're about to hear their comments on this question. Would you be willing to give us a terse view on this question? Dr. Gerber, we'll start with you.

DR. GERBER: Yes. Well, I think as I already said, I am concerned about the increase in fever. As Steve Kohl said, it's a trade off. And no vaccine is a hundred percent safe. And what we need to decide is how much fever are we willing to accept given the potential benefits of this vaccine.

But it's not just how much fever, but what the implications of that fever are going to be. So, it's one thing if it's a temperature of 101 that get's treated with an antipyretic at home, it's another thing if it's going to result in getting antibiotics or hospitalization or physician visit. And I think that's the information that we need.

CHAIRMAN DAUM: Thank you very much. Ms. Libera?

MS. LIBERA: Well I understand that convenience of this vaccine may give you more compliance. I would hope that the convenience or the need, perceptive need, for this convenience wouldn't be the driving force.

CHAIRMAN DAUM: Thank you very much. Dr. McInnes. Not least.

DR. MCINNES: I think I'm sitting where Michael is in terms of really wrestling and looking at the data that Dr. Ball had prepared on the safety profile following each of the doses from 011 and trying to look at the four pooled groups compared to the group five that received the non-combination Infanrix vaccine and trying to get a sense of how fever, low-grade as well as high-grade fever, sat, per dose, and moving forward.

And I think the picture is, you're left with a sense of this overall increased fever, but I really can't get my hands around what it really means. The categories are broad and I don't really understand the antipyretic use pattern.

It makes me go back and remember ten years ago in wholesale DTP studies where clinical investigators used to send subjects out the door with antipyretic on board already to try to deal with the predictable Febrile response.

And so, I don't really have a handle on, I see the patent, I see the increase in frequency with dose, but I don't really know what it means and whether. I'm not overtly concerned about it but I'd like to be able to look at it more and know more about it.

CHAIRMAN DAUM: So that's your additional information requested category? Okay. I guess I'll complete this round of comment by saying that I think that data are adequate to make a number of comments about safety. I think that it's clear as many have said that this combination vaccine causes a little bit of excess low-grade and some intermediate-grade fevers.

My sense is that overall the pattern of the vaccine is a safe one. And whether people tolerate the excess of fevers or not, I think is a question to wait for the marketplace to decide. And I would like to see an effort made to gather more data about its implications, but, as a pediatrician, I can guess what some of its implications are.

If we start doing this to millions of children, there probably will be an occasional Febrile seizure. There probably will be an occasional septic work-up. And I think people will have to decide whether they think that's sufficient to not license this vaccine.

I think the safety profile overall that we've seen today is adequate and suggest that this vaccine is safe, but I too am troubled by the rate of fever. And what I would do in my own practice, counseling about saving an injection versus the higher risk of fever, I think is a, I think is a separate question.

I'm intrigued by one of, comments that only was said once by Dr. Wharton, and that is that the interaction with Prevnar from a point of view of safety. And I hadn't thought of it that way. And it would be pretty easy, I would think, to get enough data to reassure me and a small clinical trial, that looked at them together, to see about whether there's a synergy with fever.

Because that's something I don't think I would be comfortable with. As Dr. Fleming raised a point, I think with the rare events, we have choices here that are almost murderously difficult. One is to do pre-licensure trials so big that we have a confidence down to some minute level of comfort about rate side effects.

And the other is to get trials adequately big so that we as a vaccine community believe that something sufficiently safe to go to post-licensure surveillance and documentation as a way of getting at the very rare events that we hadn't seen any of in the pre-licensure trials.

I'm not wise enough to know the definitive answer to that, but, in general I would come down on the side of the post-licensure approach being a more efficient one to do that.

So that's a very complicated answer to what might at first seemed like a simple question, but I think we've seen a lot of data about safety and I think that, I hope FDA folks and sponsor folks have heard the concerns and heard the good points as well.

I'd like to move on to the next question now. Could we flash it up on the screen, there. God. Thank you. Discussion Point Three. We've heard a number of comments about this and we might be able to go through this part of the discussion fairly quickly.

And that's, we'd like, the FDA would like to hear us discuss the data submitted in support of the concurrent administration of other routinely recommended childhood immunizations. With this combination, this DTPa-HepB-IPV vaccine. Specifically, they've asked for Hib and Prevnar comment.

So we will again put out the net for general comments or clarifying things we need, but then I'd like to hear some specific comment directed at this discussion. We may have done this one. We may be able to go right to the specific comments. Shall we try? Dr. Fleming would you like to start?

DR. FLEMING: Well the aspect of this that strikes me as being particularly important is the interaction with Prevnar both in terms of effects in immunogenicity and effects on safety. We have been presented some data in our packages that certainly suggest that there could well be an affect on immunogenicity and others on this panel will be much more capable than I to address the fact that there is also the risk of interactions and safety and specifically with fever.

So, certainly I would urge that there be studies, in whichever strategy the sponsor and the FDA wish to pursue for future investigation, very important elements of that should be getting information that will allow us to adequately address overall effects on immunogenicity and on safety, in particular fever, when there's concurrent administration with Prevnar.

CHAIRMAN DAUM: Thank you very much. Dr. Wharton?

DR. WHARTON: On the issue of concomitant administration with Hib, it's nice to see in the material provided in the briefing package, testing of the combination vaccine with multiple different Hib products from different manufacturers. And those data I find very reassuring in terms of concomitant administration with Hib vaccine.

I am troubled though about the Prevnar issue based on the data provided in the briefing package as well as the more general issue of Prevnar interactions with other DTPa vaccines, as suggested in the Prevnar package insert. And I do think that's an area that requires additional information.

CHAIRMAN DAUM: I point out for no particular reason, except to try and be helpful, is that the company had no opportunity to study Prevnar, because of a variety of things that have occurred since this package was being put together and the approach to the agency and to this Committee was being made.

And so, I think it's perfectly legitimate for the Committee to decide that we need to have this information to reach conclusions, but on the other hand I think we should be careful to not believe anybody should be criticized for the fact that those data aren't here. So I'd like to just off-hand make that comment. And keep going around the circle. Dr. Broome?

DR. BROOME: Well, I mean I would hope that it would be fairly self evident since that's one of the routine childhood immunizations, we do need to have some data about concomitant administration with Prevnar, particularly in light of the potential for impact on immunogenicity of the pertussis components as well as the question of safety issues.

I think it has been clear that it wasn't possible to include it at the time the initial trials were done. So, I think it's appropriately discussed as the third issue.

CHAIRMAN DAUM: Can I press you about one thing? If it were, if it came down to this, I don't know if it does, but I know input is desired, should, is that information necessary before licensure, or could it be obtained after?

DR. BROOME: Well, it, you know, I would think you would ideally have some before since it is something you're proposing for mass concomitant administration. It's an unfortunate result of timing of availability that that couldn't be done with the initial studies.

But I think the ultimate bottom line is if you've got a product licensed for use in U.S. infants, you'd like to know how it interacts with the currently administered products.

CHAIRMAN DAUM: Thank you. Dr. Britt?

DR. BRITT: I have nothing to add. Those are my sentiments.

CHAIRMAN DAUM: Thank you. Your point of view has already been expressed I presume.

DR. BRITT: Yes.

CHAIRMAN DAUM: Okay. Dr. Gerber.

DR. GERBER: I agree with Linda, I feel very comfortable with the data that were presented on the concomitant use of this vaccine with Hib, both in terms of safety and immunogenicity. As far as Prevnar goes, I think we tell parents that all new vaccines are tested in combination with the current vaccines that they're going to be used.

I think that if we're going to be using this vaccine with Prevnar, which we would, I think that safety and immunogenicity of that combination needs to be established before licensure.

CHAIRMAN DAUM: Thank you. Ms. Libera.

MS. LIBERA: Nothing.

CHAIRMAN DAUM: Okay, Dr. McInnes?

DR. MCINNES: I love the Hib data. I'm very excited to see immunogenicity profile from that. I'm troubled by the concept that this has to work together with Prevnar as a condition of licensure, am inherently troubled by that.

I think in terms of understanding recommendations of how the entire pediatric immunization regimen is going to have to work, we need to see the data. But I'm not comfortable with it being a condition of licensure for this product.

CHAIRMAN DAUM: Post-licensure's okay with you? Thank you. I'm just, I'm not putting words in your mouth, I'm trying to understand what you said. Who's over there. Dr. Kohl. It's you.

DR. KOHL: I'm still over here. I agree with everything my colleagues have said. There's one problem that I foresee. Looking at the Prevnar prescription information it looks like there is already, at least preliminary data, that this Prevnar interferes with some antibody responses of currently-licensed vaccines.

So, I guess what I'm trying to focus, and some of my statistically-oriented colleagues might be able to help me better, is what are we going, how do we set the bar? Does it have to not interfere at all? Or does it not interfere as much as Prevnar interferes with Acel-Imune? How's that bar going to be set? It's an interesting problem.

CHAIRMAN DAUM: And if I could toss in, what about interpreting interference with respect to pertussis antigens?

DR. KOHL: Right. And is it even fair to. Fair is not the right word, but obviously Prevnar's licensed and all these other preparations are licensed and there may be major interferences there and that's not going to pull those products from the shelves.

But if this one doesn't meet whatever we're going to set it will preclude it from being licensed. So, there's some really sticky issues in the Prevnar and other vaccines.

DR. FLEMING: Should we comment on his, on Steve's statistical question?

CHAIRMAN DAUM: If you could make a brief helpful comment.

DR. FLEMING: Just a very brief comment. It's certainly a very relevant issue as to say, if in fact Prevnar interferes as the evidence that we've seen suggests it does with let's say components of a pertussis vaccine, how do we assess, in a clinical trial, what, in essence, what the impact is now on this combination.

My fundamental principle I guess of clinical trials is that I want to design a study to compare in a real-world setting, benefit-to-risk of an experimental approach versus standard of care. And so, if standard of care now involves wide-spread use of Prevnar with separately-administered components, then that's my control.

And I want to compare that to the administration with a combination vaccine, presumably in the context of Prevnar there as well. And I want to understand the relative difference. It's possible that if people are accepting the use of Prevnar with single components that diminishes some of the FHA responses, etcetera, that what we will see in that randomized trial is no relative further increase in reduction and that is, in fact, a relevant answer to my perspective.

We would then see that the combination, with Prevnar use, against how the current components are being administered with Prevnar use, doesn't provide any further diminishment of immunogenicity.

CHAIRMAN DAUM: Thank you. Dr. Stephens?

DR. STEPHENS: A couple of comments. One is and we've heard a lot of positive comments about the association with the Hib vaccines. I am troubled though, and maybe Dr. Ball can clarify, on page fifty-four of your hand-out, it is, we've talked, or you've indicated, looks, the equivalencies look very good for this vaccine in combination with most of the Hib products.

My only concern was on the level, and I mentioned this earlier this morning, on the level of Anti-PRP at one microgram for at least two of the doses, two of the dose schedules. Could you comment on those lower levels with?

DR. BALL: Are you talking about the 2, 3, 4 month schedule, 017?

DR. STEPHENS: Correct. Correct. It's a different schedule, I appreciate that.

DR. BALL: It's a different schedule. I really think that

DR. STEPHENS: It's just a schedule issue.

DR. BALL: I think it may be a schedule issue. Because if you look at

DR. HOWE: It's a phenomena for compressed schedules with Hib. So it's a one, six, ten, fourteen weeks. And the other is 2, 3, 4 months and that explains the results that you see there.

DR. BALL: If you look at the 2, 4, 6, which is at the top for the Anti-PRP response at the one microgram per mL level, it's between eighty-nine and ninety-four percent.

DR. STEPHENS: My concern has to do with the effectiveness of the Hib vaccines as we, if this were an effect, in terms of lowering levels that might interfere with transmission, and that would be an effect we would not want to see with this vaccine. And so that was the concern I had. And I think you're point is reassuring.

I must say I share the concerns about the Prevnar issues that have been raised by Dr. Wharton and Dr. Broome, in particular, and I think prefer to see this as a pre-licensure issue rather than a post-licensure issue.

CHAIRMAN DAUM: Thank you very much. Dr. Faggett, please.

DR. FAGGETT: Yes. I concur with my colleagues that the Hib data is impressive. And that we need more information about Prevnar. I think really pre-licensure investigation and clarification will enhance exceptions of both, of Prevnar and the combination vaccine.

CHAIRMAN DAUM: Thank you very much. Dr. Griffin.

DR. GRIFFIN: I agree and don't have much else to add.

CHAIRMAN DAUM: Dr. Diaz.

DR. DIAZ: Well, I agree in terms of needing more data, especially on the Prevnar issue. And I saved one of my safety comments for this round because it's pertinent at this point too.

From a pediatric, pediatrician's standpoint and a parent, I think I would be more than willing to tolerate a little extra fever for having a combination vaccine.

And yet, at the same time, again I think we've raised a lot of issues as to what that extra fever would lead to and sort of where does one draw the bar and I'm sure people have differing opinions of where they might draw the bar but, myself, I wouldn't certainly tolerate a combination along with Prevnar, leading to a higher incidence of fever such that there are many more febrile seizures.

Because when you get off into that realm then you're not only talking about the potential for hospital encounter and perhaps sepsis work-up, but the likelihood that a child will receive a spinal tap. And again, along with that sepsis work-up, is almost a hundred percent at that point in time.

Where somebody might not include the spinal tap if the child was there with just increased fever. Make a clinical judgment and delay that.

So that's where I would draw the bar and I think I would want to know prior to licensure, what the combination does with Prevnar along those lines in terms of just how much fever and what are the consequences again, as we pointed out, to that fever.

CHAIRMAN DAUM: Pre-licensure? Thank you.

DR. DIAZ: I mean, I hate to say that because I recognize the timing of this and it's unfortunate but better pre-licensure than after, I believe.

CHAIRMAN DAUM: Dr. Goldberg. Not least.

DR. GOLDBERG: I guess I'm concerned about two things. One is I think that the Prevnar issue has to be investigated and ideally pre-licensure. We've also, some of us believe that there ought to be some more combination efficacy trials done pre-licensure.

I have a question, though, to my colleagues. One is the Prevnar issue is kind of unfortunate and almost unfair here. And second of all, is it even possible to study the combination vaccine versus its components without putting it in the context of Prevnar, if Prevnar is being widely used now?

Therefore, I think it has to be incorporated into one new paradigm if you will, for study, unless there's some place in this country you can use, because I'm assuming it's being used and the kids would be in the trials, but then they would have Prevnar being given outside of the trial.

Which would be far worse that having it incorporated into the trial design and being able to evaluate the total combination and the way it's administered. So I defer to, I mean I'd like an answer actually, from my colleagues about Prevnar use to help me finish my thinking.

CHAIRMAN DAUM: What, you have to form the question a little more precisely, maybe we can get the whole --

DR. GOLDBERG: It's can you today do a trial of this combination vaccine, against its components, without some kind of co-administration or somewhere in the schedule during this period and administration of Prevnar, given, I mean am I understanding this, it's being widely used in these, in children of these ages. I mean?

CHAIRMAN DAUM: Well, it's recommended for, with universal immunization.

DR. GOLDBERG: Pardon?

CHAIRMAN DAUM: It's recommended.

DR. GOLDBERG: Okay. So, therefore, we're in a very sticky situation in requesting a trial of the combination against its components. Without having be a trial of the combination plus Prevnar against the components plus Prevnar.

So that would be my recommendation in that context and then with one trial we would accomplish pre-licensure what we need.

CHAIRMAN DAUM: Thank you very much. I just end this part of the discussion by saying, with the exception of Prevnar, I think we've been reasonably satisfied that there is unlikely to be vaccine-antigen interference.

The Prevnar issue, with respect to antigen interference, for me, could be done post-licensure. If it interfered with pertussis antibodies, I wouldn't know much about what to do with those data anyway and those are basically my comments.

I do want to say though that I keep coming back to this increased fever issue. And I guess I'm talking a little out of both sides of my mouth, but I would like to see some safety data in a small trial to reassure myself that there's not synergistic fever between Prevnar and this combination.

On that side, I guess I'm siding with the people concerned about safety, Dr. Diaz and others who made that point. So I'd like to move on now to Discussion Point Four. And I think that we've had enough discussion that we can do this pretty quickly and meet our five o'clock finish.

Please identify any issues that should be addressed in post-licensure studies. Please specifically include a discussion of the safety immunogenicity of concurrent administration of other routinely-administered vaccines, Prevnar. I think we've done that.

Safety and immunogenicity of a fourth and fifth dose of Infanrix DTPa, which we haven't talked about and we need to. Following a primary series of DTPa-HepB-IPV, this combination. And the safety of a primary series of this combination following a birth dose.

So I think the birth dose is one issue we need some discussion on, as is the fourth and fifth dose. And unless somebody objects on the Committee, I think we've addressed the Prevnar issue and the need for studies on that.

Some have spoken to pre-licensure preference and some to post-licensure preference, but discussed, nevertheless, it has been. So, let's deal with the birth dose issue and the fourth and fifth dose issue and any other post-licensure study issues that people want to talk about. Are there general comments that more information is needed or can we go right to -- yes, Dr. Finn?

DR. FINN: Dr. Daum.

CHAIRMAN DAUM: Yes.

DR. FINN: Just a point of clarification.

CHAIRMAN DAUM: Please.

DR. FINN: I'm not sure if you're reading the question from what's up on the screen versus what's on, in front of you, perhaps.

CHAIRMAN DAUM: Ah. Could be.

DR. FINN: And I would just like to point out that there's an extra clause in there.

CHAIRMAN DAUM: Thank you. You snuck it in.

DR. FINN: Yes. We snuck it in. Apologies. Safety and immunogenicity of the combination following a complete or partial primary series of Infanrix or other DTPa vaccine.

CHAIRMAN DAUM: Oh. Okay. The extra clause is the or other vaccine.

DR. FINN: Right.

CHAIRMAN DAUM: So, it speaks to the booster issue, nevertheless. So --

DR. FINN: To complete the primary, sorry, it's to complete the primary series with the kid who may have initiated with dose one or two.

CHAIRMAN DAUM: Yes. Thank you. Thank you. Thank you. So we have general discussion on this point and then we will sort of invite point and comment. Or we can go right to point and comment then. Dr. Kohl, start us off here.

DR. KOHL: Let me do what I think is the easier one first. I was satisfied with the birth dose hepatitis B, so I'm not going to ask for anything more of that. I think the, completing the primary series is not something that I would hold for a pre-licensure, but I would like to see that as a post-licensure.

It gets complex because, as we talk about multi-component vaccines, and multi, multi-component vaccines and multiple manufacturer's vaccines, the combinations, permutations get to be a little mind boggling. But I guess we do need that. And, where else are we?

The question of boosters. I think that's not being requested at this point in licensure for a booster. And I think the booster licensure dose should await a further discussion at a different time.

CHAIRMAN DAUM: All right. Dr. Stephens.

DR. STEPHENS: I basically agree with those comments. I think the hepatitis B data, was at least in my view, convincing enough that I'm not sure that we need in post-licensure kind of study. The other issues I think require further data and post-licensure types of studies.

CHAIRMAN DAUM: Dr. Faggett.

DR. FAGGETT: Yes. I agree with my colleagues' comments. I think we're going to find some variability in terms of the birth dose of hepatitis B, because there's still some concern for some parents, we're getting them back online, but I think its, you're going to find that those parents who don't want that birth dose are probably going to be resistive to the combination vaccine.

So that's going to be a real challenge for us in practice. But I think the post-licensure study of this issue will assist us in better accounts. In the booster issue, I agree it needs to be looked at.

CHAIRMAN DAUM: Thank you very much, Dr. Faggett. Dr. Griffin, please.

DR. GRIFFIN: I agree that hepatitis B I don't think is an issue from the point of view of immunogenicity. I think the only issue is the one I raised before which I just, would be how confusing it starts to get whether a child has actually had the birth dose or not and what kinds of series they needed and combinations. But I don't this that's an issue for this Committee.

The, and I think all of the other issues can really be post-licensure issues as far as the incredible, increasing complexity of what these different immunization schedules might be as these combination vaccines come on board. And children have had different varieties in different health care situations.

CHAIRMAN DAUM: Thank you. Dr. Diaz.

DR. DIAZ: I don't have anything to add that others haven't already stated, particularly Dr. Kohl, very well stated what I would comment on with the caveat of the birth dose of HepB vaccine. Just to reiterate that this, I feel comfortable with the HepB vaccine, birth dose data that was presented.

Again, only obviously for those children who are born to mothers who are HepB surface antigen-negative. And that would follow along with using the HepB vaccine in a 2, 4, 6 schedule. Again only with those particular children.

CHAIRMAN DAUM: Thank you. Dr. Goldberg?

DR. GOLDBERG: I have nothing to add really. I think the HepB data are adequate and the other issues should be post-licensure.

CHAIRMAN DAUM: Dr. Wharton?

DR. WHARTON: At least from my understanding from what's in the package, the safety data, the data on the safety of the 2, 4, 6 administration of this product to 2, 4, 6 following a birth dose are limited. That said, this has been an accepted practice in the United States for a number of years and I expect it will continue to be so.

So I think I can probably live with it, but clearly the data that I think have been presented are limited in quantity. Regarding the safety of this. The issue of the indication for use of this vaccine for completing the series, I have no doubt that the vaccine will be used in that way once it is licensed. I think doing those studies is bound to be difficult.

And clearly if information is needed on that it should be obtained post-licensure as that will be how the vaccine will be used to complete the series in those children who have already started the series with the individual vaccines. And I don't have concerns with that practice. I believe it is likely to be safe and effective but monitoring that in the post-licensure setting would seem to me to be appropriate.

CHAIRMAN DAUM: Thank you. Dr. Broome.

DR. BROOME: I think the thing we haven't commented on much is data that I assume will be forthcoming which is the impact of the booster doses. But I think it will be real important to take a careful look at those.

CHAIRMAN DAUM: Yes. I agree with you totally. I think that that's a separate whole concern for this Committee for the agency or sponsor, whatever the right -- of consideration ought to be but I don't think that's an add-on consideration or a given that it's either safe or effective. And I think we should really study that very carefully. Dr. Britt?

DR. BRITT: I have nothing to add.

CHAIRMAN DAUM: Dr. Gerber?

DR. GERBER: I have nothing to add.

CHAIRMAN DAUM: Well. I have nothing to add except for what I just said embellishing or agreeing with Dr. Broome's comments. And I think that brings the Committee's business to a close for the day, barring Dr. Midthun's appearance at the table.

DR. MIDTHUN: This will be short. I wanted to come back and I'm looking at Dr. Fleming because he had addressed this and I'd like a little bit more discussion on this. The question had been raised with regard to Prevnar.

And the potential for interference with some of the pertussis antigens and I think that you had indicated that what you would envision as a control arm for such a study would sort of be what is being done right now. I just want to make sure I understood that correctly.

In other words you would take the routinely-recommended vaccines, they're being administered right now. Let's say for example, Infanrix, Hepatitis B, Hib, and Prevnar and I'm missing one, IPV. And so that would be the control because that's what's currently in practice.

And then the study arm would be the combination vaccine plus Prevnar, plus Hib? Do I understand that correctly.

DR. FLEMING: Precisely. What I would assume is that standard of care, as it's currently being delivered, has factored in the benefits that are understood from each of these vaccines. And the theoretical or real risks that might be incurred, based on the effects that a given vaccine, like Prevnar may have on other vaccines, such as pertussis vaccines.

And in that setting I could readily believe that the benefit-to-risk is favorable because you're targeting a specific disease and influencing the occurrence of that disease and that is a benefit that offsets the theoretical, possibly negligible, possibly meaningful, risk to another disease, in this case for example, pertussis.

So, I will assume that standard of care has evolved in a way that judgment has led to a weighing of the known benefits against the known risks or perceived risks. What I want to know then is, if I change standard of care, in this specific case, by altering the administration of several of these vaccines in a combination form, what influence will that have overall on the safety profile and on efficacy, or if I can't get efficacy directly, on appropriate measures of immunogenicity?

So I would think that the very trial that would be the most natural one to do, would give me very important, real world answers. It may well be that, this is something that requires more than a quick response, that that study design might have some kind of stratification in it so that you ensure a proper balance, because there is a heterogeneity in what that standard of care administration would be.

CHAIRMAN DAUM: Thank you. Now that we've reopened the conversation. Dr. Kohl.

DR. KOHL: What if Prevnar really decreases the efficacy of pertussis vaccines?

CHAIRMAN DAUM: Do you mean efficacy?

DR. KOHL: I mean efficacy. Clinical efficacy or pertussis. It looks like it may decrease the antibody response, in a preliminary look at the Prevnar package insert. What if it really decreases efficacy?

And I can't envision a place where we can do an efficacy study. What I'd be interested to know is if my statistical colleagues can design a thought experiment where they can run kind of sensitivity data to show that if it reduces the efficacy to such and such a point, then the increased lives saved by the Prevnar is actually, is more than offset by the increased deaths or morbidity or whatever from pertussis.

DR. FLEMING: Should I respond?

CHAIRMAN DAUM: Sure. We're in outer space now.

DR. FLEMING: This is a good point, Steve. And it's one that I would say is particularly relevant to Prevnar and discussion about it's use, more so, than specifically the discussion today about the combination vaccine question. What you've said is a very important issue. And it needs post-marketing study as it relates to the continued use of Prevnar.

CHAIRMAN DAUM: And I would have a plea that the post-marketing study be designed if it's going to look at immunogenicity, alterations in pertussis antibodies to something that we know is biologically and clinically relevant to decreased efficacy.

Because I think we spend a lot of time worrying about a ten percent or five percent decrease in one or another pertussis antibodies. Without having any idea of what the consequences are for effectiveness. Dr. Broome?

DR. BROOME: Well, on the day we reach a hundred percent coverage of Prevnar, we're going to be in trouble. But in the meantime, that's why we do surveillance for vaccine-preventable diseases and do follow-up studies to assess whether there's any, like a case control approach suggestion of increased effectiveness.

CHAIRMAN DAUM: Thank you for reminding us of that. Last comments. We're ready for an on-time arrival here. It's five o'clock, or four minutes to five.

Nancy has asked me to give special thanks to those who braved the weather, those who are under the weather, and those who weathered red-eyes to get here. And thank everybody who presented and had a stimulating conversation here today. Tomorrow morning at eight a.m

(Whereupon, the above-entitled matter was concluded at 4:58 p.m.)