U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES

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	PUBLIC HEALTH SERVICE

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	FOOD AND DRUG ADMINISTRATION

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	CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

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	VACCINES AND RELATED BIOLOGICAL

	PRODUCTS ADVISORY COMMITTEE MEETING

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	Friday, November 5, 1999

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The meeting took place in Versailles Rooms I and II, Holiday Inn, Bethesda, MD, at 9:00 a.m., Harry B. Greenberg, M.D., Chair, presiding.

PRESENT:

HARRY B. GREENBERG, M.D., Chair
NANCY CHERRY, Executive Secretary
ALICE S. HUANG, Ph.D., Member
MARY K. ESTES, Ph.D., Member
ROBERT S. DAUM, M.D., Member
KWANG SIK KIM, M.D., Member
DAVID S. STEPHENS, M.D., Member
DIXIE E. SNIDER, JR., M.D., M.P.H., Member
BARBARA LOE FISHER, Member
MARY GLODE, M.D., Invited Participant
ALISON O=BRIEN, Ph.D., Invited Participant
L. PATRICIA FERRIERI, M.D., Invited Participant
PAMELA HARTIGAN, Ph.D., Invited Participant
MARTIN MYERS, M.D., Invited Participant
KAREN GOLDENTHAL, M.D., FDA Representative

PRESENT: (CONT.)

DR. DOUGLAS PRATT, FDA Representative
DR. CARL FRASCH, FDA Representative
DR. LYDIA FALK, FDA Representative
GEORGE SIBER, M.D.C.M., Sponsor Representative
JILL HACKELL, M.D., Sponsor Representative
STEVE BLACK, M.D., Sponsor Representative
DR. TERHI KILPI, Speaker
JOHN BARTHELOW CLASSEN, M.D., Public Commenter
CARLA NEWBY, Public Commenter

	A-G-E-N-D-A

	Page

Introduction, DR. CARL FRASCH, FDA	39

Sponsor=s Presentation, Wyeth-Lederle             42

Questions on the Sponsor=s Presentation          102

CBER Clinical Review of Safety and Efficacy,     114
DR. DOUGLAS PRATT, FDA

Questions/Comments on the CBER Presentation      148

Results of the Finnish Otitis Media Trial,       167
DR. TERHI KILPI

Questions/Comments on the presentation           175

Summary and Presentation of Questions,           178
DR. DOUGLAS PRATT, FDA

Open Public hearing                              179

Committee Discussion and Voting                  189

Open Public Hearing                              232

	P-R-O-C-E-E-D-I-N-G-S
	(9:00 a.m.)
CHAIR GREENBERG: If people could start getting into their seats.  People, please take your seats.  
Well, good morning, everybody.  I=d like to welcome you to the open session on Friday, November 5th, of the VRBPAC Committee Meeting, and to start off we have a few administrative announcements.
EXECUTIVE SECRETARY CHERRY: Good morning, everyone, and welcome.
Yesterday, I announced that some of our committee members could not be here.  I neglected to mention that Doctor Faggett could not join us at the committee table.  It also looks like Doctor Finkelstein won=t be able to, and also on your roster you may see that we had intended to bring in Doctor Butler, he=s unable to be with us today.
I have a short conflict of interest statement to read.  The Director of the Center for Biologics Evaluation and Research has appointed Doctors Butler, Ferrieri, Glode, Hartigan and O=Brien as temporary voting members.  The following announcement addresses conflict of interest issues associated with the session of the Vaccines and Related Biological Products Advisory Committee on November 5, 1999, for the committee discussions on safety and efficacy of pneumococcal 7-valent conjugate vaccine for prevention of invasive disease.
To determine if any conflicts of interest existed, the agency reviewed the submitted agenda and all financial interests reported by the meeting participants.  In accordance with 18 USC 208, Doctor Robert Daum has been granted a waiver which permits him to participate in committee discussions.  In accordance with the Food and Drug Administration Modernization Act of 1997, Section 505, Doctor Patricia Ferrieri has been granted a waiver which allows her to participate fully in the committee discussions.  Doctor Kathryn Edwards has recused herself from this discussion.  Doctor Estes disclosed a potential conflict of interest which was deemed by FDA as not requiring a waiver, but does suggest an appearance of a conflict of interest.  A written appearance determination under Section 2635.502 of the Standards of Ethical Conduct has been granted to permit her to participate in the committee discussions.
In the event that discussions involve specific products or firms not on the agenda, and for which FDA=s participants have a financial interest, the participants are reminded of the need to exclude themselves from the discussion.  Their recusals will be noted for the public record.
With respect to all other meeting participants, we ask in the interest of fairness that you state your name and affiliation, and address any current or previous involvement with any firm whose products you wish to comment on.
Copies of all waivers and appearance determinations addressed in this announcement are available by written request under the Freedom of Information Act.
CHAIR GREENBERG: Thank you, Nancy.
I=d just like to make a brief announcement.  It=s my intention when we get to lunch to hold a very, very brief lunch break of 15 minutes.  I apologize to people in the audience, most of you are  probably, unlike me, unable to eat in a minute or two, but we have a number of committee members who have planes to catch and I=m trying to keep everybody here for a very important meeting as long as possible.  So, whenever the morning session ends, there will be a brief 15-minute break, eat as fast as you can and get back here.
And, without further ado, I=ll start with, again, I want to admonish all speakers, you=ll get your time but no more, so be crisp and timely, and we=ll start with Doctor Carl Frasch.
DOCTOR FRASCH: Okay.  I would like to introduce the session.  As you all know, we are talking about the Wyeth-Lederle application for their pneumococcal 7-valent conjugate vaccine, diphtheria CRM protein.  This application was received as a rolling submission, and the official receipt date was June 1, 1999.  What we mean by rolling submission, we got the first parts for review, I think it was toward the end of February, and then the final submission was received C was dated May 31, and received June 1.
Now, CBER agreed with the company that the application would be given priority review for invasive disease.  I would like to point out that while we have over ten years of experience with another conjugate vaccine, the Hib conjugate, the pneumococcal conjugate represents a major increase in complexity for the manufacturing process, for clinical evaluation of seven different immune responses simultaneously.  This vaccine is a first multivalent conjugate vaccine, and it=s the first pneumococcal conjugate vaccine, and the indication being sought today is for invasive disease in infants and young children.
The pneumococcus causes a spectrum of clinical diseases, including pneumonia, with or without bacteremia, bacteremia, meningitis and acute otitis media.  Again, today we are going to focus upon the bacteremia and meningitis, which are the two primary invasive disease endpoints.
As you know, a high level of efficacy against invasive pneumococcal disease was found and has been reported at ICAAC and other meetings.  Thus, we will focus in the CBER presentation more upon the vaccine safety, the immunological consistency, efficacy lots versus manufacturing lots, manufacturing consistency, physical and chemical testing.  This part we=ve already heard a little bit about.  And, for the CBER, Doctor Douglas Pratt will represent a review of safety, efficacy and immunogenicity, and then he will conclude the formal presentations today with a brief summary and questions for the committee members to consider.
Thank you.
CHAIR GREENBERG: Thank you, Carl.
I neglected to ask my colleagues to introduce themselves, so before we start with the manufacturer I=d just like to go around the table and in my haste to move this along I neglected all of you.
Doctor Daum.
DOCTOR DAUM: I=m Robert Daum from the University of Chicago.
DOCTOR KIM: Kwang Sik Kim from Children=s Hospital Los Angeles.
DOCTOR SNIDER: Dixie Snider, Associate Director for Science, Centers for Disease Control and Prevention.
DOCTOR HUANG: Alice Huang from the California Institute of Technology.
DOCTOR STEPHENS: David Stephens, Emory University.
DOCTOR FISHER: Barbara Loe Fisher, National Vaccine Information Center.
DOCTOR ESTES: Mary Estes, Baylor College of Medicine, Houston, Texas.
DOCTOR HARTIGAN: Pamela Hartigan with the V.A. Cooperative Studies Program at Yale University.
CHAIR GREENBERG: Harry Greenberg, Standard University and the Palo Alto V.A. Medical Center.
DOCTOR FERRIERI: Patricia Ferrieri, University of Minnesota Medical School, Minneapolis.
DOCTOR GLODE: Mimi Glode, University of Colorado, Denver.
DOCTOR O=BRIEN: Alison O=Brien, Uniform Services, University of the Health Sciences, Bethesda.
DOCTOR MYERS: Martin Myers, National Vaccine Program Office.
DOCTOR GOLDENTHAL: Karen Goldenthal, FDA.
DOCTOR PRATT: Douglas Pratt, FDA.
DOCTOR FRASCH: Carl Frasch, FDA.
CHAIR GREENBERG: Thank you.
If the sponsors C my line of sight is blocked.
DOCTOR FALK: I=m Lydia Falk, FDA.
DOCTOR SIBER: Good morning.  My name is George Siber, I have no formal relationship with the agency with the homonymous name.
It=s my pleasure this morning to introduce the Wyeth-Lederle Vaccine=s presentation on the 7-valent pneumococcal conjugate vaccine, which is trade named Prevenar.
In the next hour and a quarter we will present four talks.  I will briefly discuss the rationale for pneumococcal conjugate vaccine and its design.  Jill Hackell will discuss immunogenicity and reactogenicity of the pneumococcal vaccine.  Phase III trial in northern California will be discussed by Steve Black, and he and Henry Shinefield are the co-investigators of this trial, and I will conclude briefly with the potential public health impact of Prevenar.
Later, after lunch, Doctor Terhi Kilpi of the KTL will discuss the thin-arm trial of otitis media in Finland briefly, the preliminary results.
To begin with then, the clinical manifestations of pneumococcal disease, the pneumococcus is the single most important bacterial pathogen of children.  This pie diagram shows you that it is a major cause of meningitis, bacteremia and sepsis, of pneumonia, and of otitis media and probably sinusitis as well.
Meningitis is a very severe, although somewhat rare, disease in all ages.  It=s estimated that each year there are 3,000 cases per year in the U.S., about half of which occur in children under five.  There are neurological sequelae, especially sensory motor and hearing loss, in up to 50 percent of the cases, and there is up to a ten percent mortality from meningitis.
This shows you the cerebrum of a patient who died from meningitis, and it=s not hard to imagine why there is substantial potential for neurologic damage when there is a purulent exudation over the cerebral convolutions like this.
Bacteremia is more common, 61,000 overall with about one quarter of these occurring in children under five years of age, typically occult, but the fear with bacteremia is that there will be seeding of  the bacteria to various sites in the body, systemic sites, as I mentioned meningitis, as well as other areas of the central nervous system, epidural empyema, that=s puss around the lining of the brain, and brain abscess.  There can also be rarely seeding of the heart, because purulent pericarditis, as well as the heart valves endocarditis, seeding of the peritoneum  with peritonitis.  In addition, the skin, soft tissue, the bone, and the joints can be seeded by the pneumococcus.
Pneumonia, more common, we have 5,000 estimated pneumonias in the U.S. in all ages, and about one sixth of these are children under five years of age.  As was already mentioned, typically, the pneumonias are not bacteremic and so they are difficult to diagnose.
Pneumococcal pneumonia can be extremely severe.  This shows a child with lobar pneumonia and  empyema, which means puss around the lining of the lung.  This can be complicated also by lung abscesses, requiring drainage and surgery.
Overall globally, pneumonia is actually one of the major killers, if not the major killer, of children.  WHO estimates that 4 million children each year die of acute lower respiratory disease, and that of these about a third, or 1.2 million children, die of pneumococcal pneumonia.
Finally, otitis media, an enormous burden of disease with otitis media, 7 million cases per year estimated by CDC, of which the majority, over 5 million, are children.  Complications include with recurrent otitis media, or especially severe otitis, chronic otitis, hearing loss, cognitive development problems, there may be a need to insert PE tubes, ear tubes.  This is the single, most common procedure of children that requires a surgical procedure that requires general anesthesia.
Another public health issue is that a lot of antibiotics are used because one is worried about pneumococcal disease, and that, as you all know, has led to emergence of antibiotic resistance in the pneumococcus and many other organisms as well.
This shows you an angry, red, bulging eardrum, typical of severe purulent  otitis media with the pneumococcus, and an occasional complication is mastoiditis, with a bulging area behind the ear.  In this case, a drainage tube has been placed to facilitate drainage of puss from the mastoid cavities.
Now moving on to epidemiology.  The age distribution is shown here, and really resembles very closely the age distribution that we had with haemophilus influenzae b, both in the shape of the curve and in its magnitude, with peak age of pneumococcal disease occurring between six months and 18 months of age.
Orin Levine, at CDC, and colleagues around the country, have performed recently a risk factor analysis for pneumococcal invasive disease, and a striking finding that is true for all age groups through six years is a two to three-fold increased relative risk if you are intending daycare, and that risk is especially high in the first year after entry into the daycare.  In the very young children, breast feeding appears to be quite protective, .27 relative risk.  And, in the older children having had a recent course of antibiotics is associated with a 2.4 fold increased risk and in 24 to 59 months old a two-fold relative risk for crowding conditions.
Different ethnic groups have different risks.  This again shows you age specific rates.  Whites are shown in black at the bottom.  What you can see is that African Americans have a five to ten-fold higher risk throughout all these age groups through six years of age invasive pneumococcal disease.  And, similarly, Alaska natives and American Indians could also be plotted here, five to ten-fold higher risk.  And, a very high-risk population are patients with sickle cell disease who have functional asplenia with a 50 to 100-fold higher risk again of having pneumococcal invasive disease, frequently very severe and fulminant.
Other conditions that predispose pneumococcal disease or a severe disease often are asplenia, various acquired genital immunodeficiencies, particularly, HIV, cancer, cancer chemotherapy, bone marrow transplantation, and, chronic diseases, kidney, liver, lung and heart.
Now, this shows the pneumococcus, and in particular what I want to emphasize is that this gram positive organism is coated by a capsule, a carbohydrate capsule, which serves a very important function for the organism.  It is not susceptible to antibody and complement lysis, it has to be opsonised for phagocytosis, and the capsule is an antiphagocytic structure, phagocytes don=t like to eat it unless it is covered by antibody and complement.  And so, the real focus of most vaccine development has been the capsule.
The problem has been that there are more than 90 serotypes of pneumococcus which fall within 45 serogroups.  There is no immunologic cross reactivity between these 45 serogroups.  There is some cross reactivity within some of the types within the serogroups, and recent evidence we have suggests also some cross protection.
Although these serotypes and serogroups vary by geography and over time, fortunately, a relatively small number of the 90 or 45 count for the majority of illness, both in the U.S. and elsewhere in the world.
In thinking initially about the U.S. formulation, we basically looked at serotype distribution of pneumococcus in the U.S., in young children, and this shows you an Austrio-Hausdorffogram which gives you types, 14 being the most common, down to 9b, so the top seven types, as you can see cumulatively, accounted for about 80 percent of all pneumococcal invasive disease in young children C if we see cross protection with the cross reactive type, that adds another eight percent or so to have almost 90 percent coverage of all pneumococci with the current 7-valent formulation.
This formulation would cover 88 percent of bacteremias, 82 percent of meningitis, and a somewhat lower percent, 71 percent, of otitis media.
Emergence of antibiotic resistance is one of the other reasons why a pneumococcal vaccine would be of substantial interest.  As I mentioned with the antibiotic use over time, there has been increased rates of pneumococcal resistance to penicillin intermediate or high-level resistance, and this has been a concern both for the medical community and for the public, because we fear that soon we may not have effective antibiotics against these serious infections.
This shows you actually the rise in resistance in the U.S., from five percent in 1988 to 32 percent in 1998, and of interest is that almost all the resistant strains fall into type six C or groups six, 14, 19, 23 and nine, and you should note that all of these types are in the 7-valent formulation.
Conjugate vaccine design and development, we have a pneumococcal vaccine already, it=s the 23-valent polysaccharide vaccine, which has had tremendous value because it works well immunogenic in older children and adults, and it=s very clearly effective against bacteremic disease, it is effective against pneumonia in young adults, as shown in south Africa.  There does remain controversy about how effective it is against pneumonia in the elderly.
But, a limitation of the polysaccharide vaccine is that it does activate T-cells, and nor does it prime for an anamnestic or memory response to subsequent exposure to polysaccharide.  In addition, infants do not respond to many of the polysaccharide serotypes, and for this reason this vaccine is not indicated in children under two years of age.  And, even older children often have somewhat lower and short-lived antibody responses compared to adults.
So, the solution to this problem was really that one couples the polysaccharide, shown here as graphically in white, to a protein molecule shown in green, a covalent coupling methodology, and when one does this the immune system sees this in a way that the T-cells that have polysaccharide antibody on their surface can enlist the help of T-cells by virtue of carrier epitopes, to get help to proliferate, differentiate and to produce larger amounts of anti-polysaccharide antibody and high quality, high affinity anti-polysaccharide antibody.
The best demonstration of the power of glyco conjugate vaccines is the Hib vaccine.  This shows U.S. data, what happened with the introduction of Hib vaccine in late >89, and this is Hib invasive disease declining to essentially C extremely low levels, let=s put it that way, currently.  Also of interest on this slide is that non type b disease shown here really did not increase to replace that niche.
The other expectation of glyco conjugate vaccine, in particular Prevenar, is that we expect this to be a safe vaccine, and the reason is that the two components of Prevenar have had extensive safety experience individually.  Hib TITER, which is Hib polysaccharide coupled to the CRM197 protein by reductive amination contains the same carrier protein, CRM, and the same linkage chemistry as we have with Prevenar.  129 million doses of Hib TITER are estimated have been distributed safely since its approval in 1989.
The pneumococcal polysaccharide vaccine is made by several manufacturers also have had extensive experience, albeit in children over two years of age, and about 55 million of doses of those polysaccharides have been distributed safely since 1983, and the seven types that are in the conjugate vaccine are also contained in the 23-valent formulation.
Now, in making the polysaccharide, I think it=s been said already that this is a very complex vaccine, and arguably the most complex vaccine that has ever been developed, and the reason for that is that there are seven distinct capsules that are purified, these are the organisms with the capsules around them.  These organisms are fermented and then the capsule is purified to high levels of purity, each individually shown here, and then each capsule is activated separately, conjugated separately to the CRM carrier protein to create seven separate conjugates, and then these seven conjugates are mixed together and formulated into the final vaccine.
In addition, there are quality control tests at multiple stages during the production process to ensure that we have total control over the production process and get consistent manufacture.
The final formulation contains two micrograms of each of six types, and four micrograms, as was previously mentioned, of type 6b to ensure the immunogenicity of the least immunogenic of types.
Notice that the total carrier dose of CRM is 20 micrograms, which is similar to the carrier dose in Hib TITER, and the adjuvant is aluminum phosphate, .5 milligrams, and there is no preservative in Prevenar.
Finally, the scope of the Wyeth clinical program, we have done a series of studies which will be described by Jill Hackell that look at polysaccharide size and linker initially to choose the optimal size and linker, also the dose response, and we also show the polysaccharide challenge results in an excellent immune response in primed individuals.
We looked at immunogenicity in infants and concomitant vaccines in a number of studies.  The Phase III efficacy trial was done in Kaiser, which we=ll hear about from Steve Black, lot consistency and bridging studies were performed and were successful.
Additionally, a series of studies have been done in various ages of catch-up cohorts, and again, you=ll hear more about that one.  So, all tolled, this submission to FDA covers 20,000 infants, 54,000 doses, as well as booster doses in more than 10,000 infants, in older children, 700 infants and 1,100 doses.
In addition, and I don=t have time to go into this, a large number of studies have been done with investigators externally listed here.  This reads like a Who=s Who of Bacterial Vaccine Investigators, and in particular I want to mention that NIH, NIAID, has supported this program for more than a decade, perhaps, 15 years, and in particular I want to mention the Program Officer, David Klein, Pam McInness, George  Corlin and John LaMontagne, who have been strong supporters throughout the development effort for pneumococcal conjugate vaccine.
These studies have covered a variety of high-risk populations that are shown here, and in addition there are three Phase III trials, one just completed in Finland, as well as a trial in Native Americans by Mathu Santosham, and one in South African infants by Keith Klugman that are underway.
All tolled at this time, 16,000 additional infants have been immunized under these programs, which are not part of the submission, for a total of about 46,000 C 36,000 in total.
We propose to you that the data we have collected supports a routine infant immunization schedule in two, four, six and 12 to 15 months, as well as we have regimens that we will propose for unvaccinated children over six months of age, which range from one to three doses depending on the age group.
So, with that, I=d like to introduce Jill Hackell, who will now cover the immunogenicity and reactogenicity of pneumococcal conjugate vaccine.
DOCTOR HACKELL: Thank you, George, and good morning everybody.  I have a lot of data to present in a very short time, so I=m going to get right into it.
I=m going to start with a series of studies on the immunogenicity of this vaccine.  And, I=m going to cover four broad topics.  First of all, you=ll see the kinetics of the antibody response in children who received the pneumococcal vaccine in the routine infant schedule.  Next, I will cover the consistency of manufacture of this vaccine.  After that, I=ll show you the data that supports the use of the pneumococcal vaccine with the routine childhood immunizations already in place, and finally, the immunogenicity that supports the catch-up schedule that we will be recommending.
The studies of the routine infant schedule will come from five studies at eight sites across the United States for about 1,500 subjects who data go into this immunogenicity subset.
The study design for all the studies that I=ll be presenting were similar.  Infants were randomized to study or control vaccines, which were administered at two, four, six and 12 to 15 months of age.  Serum for immunogenicity was collected at two months, seven months, 12 and 13 months, before and after the booster dose, and for a subset of subjects also after the second dose.
Serum was assayed by ELISA assay against the individual capsule of polysaccharides.  Also, a subset of individuals had opsonic assays performed.  I won=t show these here in the interest of time, but the ELISA assay correlated quite nicely with the opsonic assay, showing that functional antibody is produced.
These are reverse cumulative distribution curves of the immunogenicity after three doses of the pneumococcal vaccine in our Kaiser efficacy study.  You can see here along the X axis increasing antibody concentrations, along the Y axis the percent of subjects that achieved those antibody concentrations.  The different color lines here correspond to the seven different polysaccharide serotypes, and here is the control group, here is the immunized group.  You can see that the mean response of the immunized group is far higher than the control group, and if you pick any antibody concentration along the X axis you can see a much higher proportion of the immunized group respond as compared to the control group.
I=m going to show you a series of plots to illustrate the kinetics of the antibody response.  Again, here are geometric mean concentrations, and the time of dosing before the first dose, after the second dose, after the third dose, and before and after the fourth dose.  
This line here represents the control group, the blue lines represent the immunized cohort in several different studies.  Note that there=s a decline in the control group over the first six months, this represents a decline in maternal antibody, and after that there is virtually no increase in antibody level.  Contrast that with the immunized group, where there=s a good response over the primary series, a decrease, a decline over the next six to nine months, as we usually see with antibodies, and I=ll show in a few minutes evidence that these children are primed for polysaccharide challenge in this period of time, and then with the fourth dose a significant boost.
There are a couple of patterns that we can see.  Each of these serotypes really is an individual.  This is serotype four, and here we see an early response.  By the time you=ve had the second dose, the antibody response has peaked, and addition of the third dose does not increase the antibody response further.  Contrast that to serotype 6b on the next slide, where the early response is rather sluggish, and between the second and the third dose, when you receive the third dose you see quite a good response, although even though this response is slow compared to the previous type, you already see after the second dose a significant difference compared to the control group.
Serotype 9v represents the pattern seen with all of the other serotypes, and that=s a more gradual response throughout the primary series.
These data from a study done by Doctor Daum, et. al., with a previous version of this vaccine, our 5-valent vaccine, demonstrates that these infants are primed after a primary series.  What you see here are children who were randomized in the primary series to receive either the pneumococcal vaccine or a control.  After the third dose, the recipients of the pneumococcal vaccine developed good geometric mean titers, ranging from two to 3.9.  You see the expected decline in antibody levels before the toddler period, and all of these children were challenged with a polysaccharide vaccine in the toddler period.  This is to mimic the natural exposure to polysaccharide, and you can see that in the group that was primed with the pneumococcal vaccine there=s a very vigorous response to the polysaccharide vaccine with geometric mean titers ranging between six and 29.  In the control group, there is virtually no response to a polysaccharide challenge, as you would expect in these young children.
So, in summary, I=ve shown that all of the serotypes are immunogenic and primed for polysaccharide challenge, that kinetics vary somewhat by serotype.  Antibody levels declined prior to the fourth dose, but remain above pre-immunization levels and, again, these children are primed.  And finally, the fourth dose boosts the response above the level seen in the infant series.
I=m now going to present briefly some data that illustrates the consistency of performance of this vaccine over several different vaccine lots.
In our consistency lot study, 340 some odd subjects at five different study sites were randomized to receive one of three different pilot scale lots, or a control where there was no pneumococcal vaccine given, but only the routine concomitant vaccines.  No significant differences were seen among lots, as is illustrated in this next slide.  Again, this is a reverse cumulative distribution curve.  This is the control group, and here you see the three lots of pneumococcal conjugate vaccine, and you can see that these curves virtually super impose, there were no differences in response among these three lots.
We also did a bridging study, which compared the pilot lot to two manufacturing lots, and again, a control group, and this is the control group, and the pilot lot and the manufacturing lot again had an antibody response that was equivalent, as is illustrated by these superimposed lines in the reverse cumulative distribution curve.
Okay.  I=m going to present a series of slides illustrating the response to the usual routine childhood immunizations that will be administered along with this vaccine.  And, we looked at virtually all of the routine vaccines that are administered at the times that they are usually administered, as shown in this slide.
You=ll see data on both geometric mean concentration and also the percentage of subjects that achieved levels that have been associated with protection, and I=ve listed these here so that I don=t have to list them on the subsequent slides.  Note here that the pertussis antigens, we=re using an arbitrary  but convention of a four-fold rise because there are no levels that have been associated clearly with protection for pertussis.
Okay.  What we are looking at here are children who received concomitant DTaP in the primary series.  The antibody responses that you see are those achieved after three doses in children who received simultaneous pneumococcal vaccine, compared to a control group that do not receive any pneumococcal vaccine.  Geometric mean concentrations first focus on diphtheria and tetanus.  You can see a good response in both groups.  For diphtheria, there=s no statistical difference, for tetanus 3.5, 4.1 in the control group, this does reach statistical significance, but note 100 percent of children achieve a level of 0.1 international units per ML.
For the four pertussis antigens, PT, Fimbriae, 69K or protactin, in FHA there were no significant differences between recipients of the pneumococcal vaccine and the control group.  We did see a difference for Fim only in the percent achieving a four-fold rise, with a lower response in the pneumococcal group, but the other three antigens showed no significant differences.
Again, looking at DTaP, this time after the fourth dose, for diphtheria and tetanus we see a statistically significant difference for diphtheria with a slightly higher response in GMCs in the control group compared to the group that received the pneumococcal vaccine, but 100 percent of infants achieved titers of .1 micrograms per ML or greater.  For tetanus, there were no statistically significant differences.  Looking at the four pertussis antigens, we see differences in favor of the control group for pertussis toxin and for Fimbriae.  The percent responders is somewhat closer, except in the Fim group, but none of these achieved statistical significance as differences.
The Hib response after the third dose, and I should point out that the Hib vaccine that we used here is the Hib vaccine manufactured by Wyeth which contains the same carrier protein, the CRM, and some studies with other carrier proteins have shown some interference at this level, and, in fact, we=ve not shown that, and have shown some augmentation of response.  These are two different studies.  These are the GMCs which are higher in the recipients of the pneumococcal vaccine, as compared to the control group in both studies, and in the second study this achieved statistical significance.  We see good response rates at both .15 and 1.0 micrograms per ML.
Interestingly, looking at the Hib response at the fourth dose, there is a decreased response among pneumococcal conjugate recipients compared to the control group.  It is possible that this is beginning to represent some carrier limitation, but the responses are very high and a very high percent of children, 100 percent greater than .15 and almost 98 percent greater than 1 is seen, so this is unlikely to have any clinical significance.
We have one more study here, where the Hib response after dose four was looked at.  This study did not have a control group, but you can see that the geometric mean titer achieved is very similar to the one achieved in the previous study, 100 percent of children achieved a titer of .15 and 88.5 percent achieved a titer of greater than or equal to one.
This is IPV, again we have pneumococcal group and children who did not receive the pneumococcal vaccine, who received IPV at two and four months of age.  For polios type one, two and three, these are the percentages of children who achieved a titer of at least one to ten, which is the lowest dilution in this assay, and that=s been associated with protection.  There are no differences between the two groups.
Here we are looking at hepatitis response.  We looked at two different hepatitis vaccines, the SmithKline vaccine administered at zero, two and six months of age, and this should be down here actually, this is a study with a control group, and you can see that the percentage of children who achieved at least ten micro international units after immunization was very similar in these two groups, with overlap between confidence intervals.  We have a second study where we looked at the Merck vaccine administered at two, four and six months of age, and almost 93 percent of children responded at the protective level, again, confidence intervals are similar to what we saw before.
For measles, mumps, rubella, we do not have a control group, but I have two different studies that were done to look at response to concomitantly administered MMR and varicella in the toddler period.  For measles, we see a 94 to 96 percent seroconversion rate.  For mumps, 80 to 82 percent, and for rubella, 89 to 95 percent, for varicella, 95 percent response rate.
In summary, the pneumococcal conjugate vaccine may be given concomitantly with all of the routine childhood immunizations in this current series.
The last part of the immunogenicity part of my talk will address the catch-up schedule that is recommended for this vaccine.  Children who are unvaccinated and over six months of age, if they are seven to 11 months of age we are recommending that they receive three doses, two doses separated by at least 28 days, with the third dose after the one year birthday, at least two months after the second dose.  If children are 12 to 23 months of age at their first dose they should receive two doses two months apart, and children over 24 months of age should receive one dose.  You can see that these recommendations are a little bit different than the haemophilus recommendations, and I=ll show you why in subsequent slides.  First, a slide that gives you an idea of the number of subjects studied and the different schedules that were studied in six different studies.
Okay.  This slide will take a little bit of orientation.  First notice these two red bars. These represent the antibody concentrations achieved in the Kaiser efficacy study.  In children who received pneumococcal vaccine together with whole cell DTaP vaccine or pneumococcal vaccine together with acell DTaP vaccine.  Doctor Black will present you the details of the Kaiser efficacy study later, but this study was started late in >95, so the switch to acellular pertussis vaccine happened halfway through the trial and we do have two populations with concomitant vaccine.
I=m drawing here a line that will serve as a reference to titers that should be achieved by children received a catch-up schedule.  This is antibody concentration along the Y axis, and what you can see are different schedules that we looked at.  These are children seven to 11 months of age who received two doses and three doses, 12 to 17 months of age, one doses, two doses, 18 to 23 months of age, one dose, two doses, and over 24 months of age, one dose, 36 to 59 months of age, five to nine years of age, and what you can see is that for children who received only one dose, if they are between 12 and 23 months of age, they don=t achieve levels quite as high as the reference Kaiser study and, therefore, for those age groups we are recommending two doses.  This is serotype 6b, but it=s fairly representative of the other types.
Okay.  In summary, Prevenar, the pneumococcal conjugate vaccine, is immunogenic in infants and primes.  It shows consistent immunogenicity.  It can be administered with routine childhood vaccines, and the data support a catch-up schedule.
I=m going to switch gears now and present the reactogenicity of the vaccine, specifically, the information on the incidence of local injection site reactions and also the more common systemic reactions that are commonly seen after routine childhood vaccines.  After my presentation, as part of his presentation, Steve Black will talk about the remainder of the safety data on this vaccine.
From the Kaiser study, a subset of the children in the study were selected for telephone interviews for study of these common events.  Children were selected by the last digit of their medical record number.  Scripted interviews were held at 48 hours and 14 days after each dose, and a total of 17,000, almost 17,500 interviews at 48 hours were performed for children who got concomitant whole cell DTP vaccine and 3,500 interviews for children who got concomitant acell DTaP vaccine.
This graph illustrates erythema at the injection site in children who received C okay, we are looking at injection site reactions after the first dose, second dose, third dose and fourth dose.  Erythema, any erythema is represented by the height of the bar, erythema of greater or equal to an inch is represented by the yellow part of the bar.  We look here at the site of the pneumococcal vaccine compared to the site of whole cell vaccine, or in other children at the site of the pneumococcal vaccine compared to the site of the acellular vaccine.
In this slide, focus on the first two bars at each dose, which compare pneumococcal vaccine to whole cell vaccine.  You can see that there=s substantially less reaction at the site of the pneumococcal vaccine compared to whole cell vaccine and this is significant for all four doses.
I=m going to look now separately at the DTaP site compared to the 7-valent site, because this is the routine immunization schedule at this time.
Okay.  Notice first that the scale has changed here, that=s why the bars are bigger.  Each dose at the 7-valent pneumococcal site, compared to the acellular pertussis site, you can see that there=s a slightly higher incidence of erythema at the injection site at all four doses, but this only reaches statistical significance at the first dose.  At the fourth dose, there=s also a statistically significant difference.  Recall, though, that with DTaP, with succeeding doses, you usually get an increased reaction rate.  It=s lower here at the fourth dose because these children did not receive four doses of DTaP in their schedule, a lot of these kids had some whole cell vaccine as part of their primary series.
This is induration at the injection site, and a very similar pattern is seen to what I showed you for erythema, and this is tenderness, again a similar pattern, although here nothing reaches statistical significance.
I=m going to show you results from two studies in which 7-valent vaccine plus routine vaccines were compared to routine vaccines alone, and we=ll use these studies to illustrate the incidence of common systemic events within 72 hours of vaccine.
In one study, the routine vaccines administered were DTaP, OPV and Hib.  In a second study, the vaccines administered were DTaP, Hib, IPV at two and four months, and Hepatitis B at two and six months.
Okay.  You can see the reaction rates after dose one, dose two and dose three in the pneumococcal group as compared to the control group for a number of different events.  Notice that for fever at the first dose the fever is somewhat lower in the pneumococcal group, although for dose two and dose three it=s higher in the pneumococcal group.  None of these are statistically significant.  Drowsiness does reach statistical significance with a higher rate in the pneumococcal group after dose three, and we did note that there=s an increased use of antipyretics in children after the second dose, indicating that, perhaps, there is slightly more reactogenicity at this dose level.
This is a different study, again, though the same setup, pneumococcal vaccine compared to children who just got the routine immunizations without the pneumococcal vaccine.  Here you see a statistically significant difference in the rate of fever, greater than or equal to 38 degrees centigrade after dose one, and after dose two.  If you look at fevers greater than 39, there is at dose two a slight tendency to an increase in percentage, and none of these children had fevers greater than 40.5.  We see a statistically significant increase in irritability, again, with the second dose, drowsiness here, and decreased appetite here.
What I=ve done here is I=ve combined the reactogenicity data across all the studies that we=ve done in infants for this vaccine, for fever, drowsiness, fussiness and decreased appetite, this is  the primary series, systemic reactions were measured within two or three days, depending on the study, and I=ve combined all three doses of the primary series.  The pink bars represent children who received the pneumococcal vaccine as the same time as the whole cell DTP vaccine.  The blue bars represent children who receive it at the same time as the acellular vaccine, and the green bars are children who received routine immunizations including acellular pertussis vaccine alone, without the pneumococcal vaccine.
First, you can see that the highest responses, the highest reaction rates are with the whole cell vaccine.  It=s substantially lower with DTaP vaccine, but the addition of the 7-valent pneumococcal vaccine does seem to add a slight increase in reactogenicity rate.
These are similar graphs, only for the booster dose.  Again, this is pneumococcal vaccine with whole cell vaccine, with acell vaccine, and this is the pneumococcal vaccine alone without concurrent routine childhood vaccines.  The rate in the standard schedule of pneumococcal vaccine with DTaP vaccine is a little bit higher than the pneumococcal vaccine alone, similar for drowsiness, fussiness and decreased appetite, but much less than what you see with concomitant whole cell vaccine.
I want to focus in on the fever because it=s sometimes hard to see the fever breakdown in those bars, so this is dose one, dose two, dose three, dose four across all of our trials, fever rate of greater than or equal to 38 degrees with concomitant whole cell, with concomitant acell and with acell vaccine alone without the pneumococcal vaccine there is a slight increase in the rate of fever, particularly, after the second dose.
On the next slide you can see fevers of greater than 39, again notice with whole cell vaccine it ranges from 1.3 to 5.2 with an increase with subsequent doses.  For DTaP vaccine, plus pneumococcal vaccine, it ranges from .8 to 2.8 and, again, there seems to be a slight predominance at the second dose, and the rates for DTaP range between zero and .6 percent.
To conclude, we see mild transient local and systemic reactions similar to that seen with other childhood vaccines.  For local reactions, the rate is significantly lower at the pneumococcal vaccine sites compared to the whole cell vaccine site, but similar or, perhaps, slightly higher than at the acell site.  We don=t see an increase with increasing dose number.  For systemic reactions, there is a slightly higher rate of summary actions when administered with routine vaccines compared with when the routine vaccines are administered alone.
Okay. I want to now introduce Doctor Steve Black, who will present the data from the Kaiser efficacy trial and the remainder of the safety data for these sets of trials.
DOCTOR BLACK: Good morning, everybody.
What I=d like to do this morning is to describe to you the results of the Kaiser Permanente efficacy trial which was conducted in northern California in 37,868 children.
There are several characteristics of Kaiser Permanente which facilitate conducting this trial.  Kaiser Permanente is a comprehensive integrated HMO with 2.8 million members in northern California.  There is a birth cohort of about 30,000 children per year, and there are automated centralized bacteriology laboratories services with associated databases, as well as databases for clinical information services.  A unique medical record number is assigned to members at birth and allows us to track events across laboratory and utilization databases.
Kaiser Permanente is also self-insured, and what means is that members seek care, either emergency or referral care, outside the system, that is submitted back for reimbursement and allows us to identify those events as well.  In addition, there=s an extensive research infrastructure which facilitated this trial.
We did some preliminary studies prior to the trial, which looked at the incidence of disease in our population, and I=d like to show you those results now.  What you see here is the incidence of invasive pneumococcal disease within Kaiser Permanente in cases per hundred person years, in years prior to the trial, 1988 to 1991, compared to data from the U.S., from the active bacterial core surveillance system from CDC in 1998.  And I think what is striking here is that the incidence of disease is very similar between our site and the national data, with a slightly higher incidence in the youngest children in the CDC data.
We also in a separate study looked at the sera epidemiology of disease, and we determined that approximately 83 percent of invasive disease was accounted for by the seven serotypes in the heptavalent vaccine.
So, I=d now like to describe the study to you and the study results.  There are several study components, safety surveillance, Doctor Hackell described to you the results of the telephone interviews that were conducted.  We also had surveillance for rare events, using automated data sources for all emergency and hospital visits, as well as looked at clinic diagnoses.  We did serology on two subsets of children, which Doctor Hackell has reported on, and there are several efficacy outcomes which I=ll describe to you in a moment.
The study design was a randomized, double blind control trial with one-to-one randomization.  Children were either assigned to receive the 7-valent pneumococcal conjugate or a meningococcal c conjugate vaccine. This vaccine was chosen as the control for several reasons, one of them is that it=s visually identical to the pneumococcal conjugate vaccine.  We also felt that offering the potential of some benefit to these many children getting four doses of vaccine would facilitate enrollment into the trial.
Healthy infants were targeted for enrollment at two months of age, and the immunization schedule was two, four and six months, with a booster between 12 and 15 months of age.
Invasive disease was the primary endpoint in the trial, and specifically the primary endpoint was invasive disease due to vaccine serotype in children vaccinated per protocol.  Cases had to occur at least 14 days after the third dose of vaccine, and they had to occur in immunocompetent subjects.  Secondary endpoints included invasive disease analyzed in an attempt to treat format, in which follow-up began as of the randomization of the children at the time they signed consent. And, in addition, invasive disease due to any pneumococcal serotype was evaluated, both in per protocol and intent to treat format.
This was a group sequential design with one interim look analysis that was planned at 17 cases of invasive disease due to vaccine serotype.  The plan total sample size was 26 cases, and the stopping rule was that at the look at 17 cases we would stop the trial if there were two or fewer vaccine failures.
The study utilized a study advisory group, which was independent of the investigators of the sponsor.  They had several functions, one of which was to monitor the safety of the study as the trial progressed.  They had the option of unblinding if there were safety concerns, but that was not done, there was no unblinding that took place prior to the interim analysis, and the members of the study advisory group are shown here.
As of the time of the identification of the 17 cases of per protocol invasive disease due to vaccine serotype, the following procedure took place.  A list of all the cases of disease, in vaccinated and partially vaccinated children, was sent to the study advisory group members, and the blinding key was sent to the advisory group members under separate cover by the project statistician.
During a conference call, the study advisory group unblinded cases, and because the interim stopping rule was met we, as the investigators, were notified of the case split in the trial.
So, let me describe the study population to you.  Northern California is a very diverse area, racially and ethnically, and our population represents that or reflects that.  What you see here is the racial ethnic composition in the pneumococcal group, the meningococcal group, and the entire Kaiser Permanente birth cohort during that time period, and what you can see here are several things, is that the randomization was quite successful and that the distribution here between the two groups is very similar.  But then also, we recruited a population which was very representative of our population as a whole.
As of the time of the interim look, there was 37,868 children in the study, as I mentioned to you, and these are the number of children who had received at least one dose, two dose, three dose, or four doses during the trial. You can see again, these numbers are very similar between the two groups.
The age of vaccination is shown here, the mean age of vaccination, and this was virtually identical in the two groups as well.
There are several follow-up dates that I=ll be talking about in these results, and I want to show you these in advance, because they can be confusing.  The primary safety analyses was through April 30, 1998, and we looked at safety there, otitis media, tube placement and pneumonia. The interim analysis, as I described to you, was on August 20th of 1998, and there=s also results of a reporting on extended efficacy, safety analyses and spontaneously draining ears as an outcome through April 20th of 1999.
This slide shows the cumulative follow-up in the two different analyses, as of the first of each of these months, and what you can see here is that in the per protocol analysis the numbers are very similar between the two groups, and similarly, in the intent to treat analysis that=s true as the study progressed.
So, we were quite happy to hear from the study advisory group the following results, and I think many of you have heard these already so I=ll go through them rather quickly.  But, in the per protocol analysis, all 17 cases of invasive disease due to vaccine serotype were in the control group, for a point estimate for efficacy of 100 percent and the lower bounds 75.7 percent.  In the intent to treat analysis, which includes both fully and partially vaccinated children, all children in the study, again, all cases were in the control group, point estimate for efficacy is 100 percent and the lower bound is 81.7 percent.  For someone with my level of statistical sophistication, I was glad that it was this black and white.
These are the diagnoses that we observed as of the time of the interim look, and what you can see here is, of the 22 cases the majority of them were bacteremia, but there were two cases of meningitis, three of sepsis, one of cellulitis and one of pneumonia.
This looks at serotype specific effect.  Well, actually, this is just the number of cases, all in the control group, by serotype here, and you can see the case splits as they occurred.
This looks at effectiveness of the vaccine against the total disease burden, due to pneumococci, in other words, what we are doing here is looking at all of pneumococcal invasive disease cases regardless of vaccine serotype.  In the per protocol analysis, there are two cases in the pneumococcal group, 20 in the mening., for an impact of 90 percent of total disease burden.  In the intent to treat analysis, there is a 88.9 percent reduction in total disease burden.
I=d now like to report to you on the extended follow beyond the interim look, up through April 20th of this year.  Enrollment was terminated, as I described to you, in August of 1998, but blinded immunization continued per protocol until April 20th, at which time we received permission to offer the pneumococcal conjugate vaccine to the control group and the study was unblinded.  During that interval, blinded immunization per protocol continued, and the study nurses, physicians and parents remained blinded, as was the case ascertainment as well.
These are the results as of April 20th of 1999.  In the per protocol analysis, there were 39 cases, in the control group, and one case in the pneumococcal group, and a fully vaccinated child after four doses of disease, and that child was apparently healthy as far as we know.  In the intent to treat analysis there were three children in the pneumococcal group who developed invasive disease.  The one case I just described to you in the per protocol analysis,  one child had received only one dose of vaccine and then developed invasive disease almost a year later, and the third child, though, had acute myelogenous leukemia and was immunosuppressed due to chemotherapy.  The overall impact here is 93.9 percent in the intent to treat analysis.
These are the diagnoses as of the time of that look, and what we can see here is that there are two deaths in the population, one child died of meningitis in the control group, one child died of bacteremic pneumonia in the control group as well.
If we look at bacteremic pneumonia as a specific outcome, and these are children who had pneumonia, but also had invasive disease at the same time as evidenced by positive blood culture, in a per protocol analysis what we see here is seven children in the meningococcal group, one in the pneumococcal group, a point estimate for efficacy of 85.7 percent, which is not statistically significant.  However, in the intent to treat analysis, the case split is 8/1, the efficacy is 87.5, and that is statistically significant.  And, interestingly enough, if you look at all serotypes we see a 90 percent reduction of disease which is statistically significant as well.
This looks at serotype specific efficacy, and in an intent to treat format.  Again, where fully and partially vaccinated children are included, and we can see that we have sufficient power to demonstrate serotype specific efficacy in five of the seven serotypes, and not sufficient power to do so for 6b or 9v.  You=ll not that there are only six serotypes listed here, type four there were no cases during the entire study period in our population.
If we look at this by dose number, we can see interestingly that children who received one or two doses of vaccine, although it=s not statistically significant, there is a 7/1 case split suggesting efficacy of partial vaccination in a schedule of three primary doses and then a follow-up booster dose.
If we look at non-vaccine serotypes here, we also see a suggestion of an effect as well.  The serotypes shown in yellow are potentially cross reacting serotypes, of which you can see there are three out of six total cases in the meningococcal group, control group, are potentially cross reacting.  There are only three cases in the pneumococcal group, one of which is potentially cross reacting, and actually this child had a thyroglossal duct cyst abscess, this is not a bloodstream infection.  The drainage of that abscess is what yielded this organism.
If we look at all serotypes as of April 20th, we see a 92.9 percent reduction in total disease burden per protocol, and virtually almost 90 percent, 89 percent reduction in total disease burden in the intent to treat analysis.  So, we=ve interpreted this to mean that at least during the course of there=s trial there=s no evidence of replacement, and there might be some evidence of cross protection, given that initially we estimated 83 percent coverage by the seven serotypes.
I=d like to reshow you the incidence slide I showed you earlier.  This is the U.S. incidence from the active bacterial core surveillance from CDC.  This is the pre-study results which I showed you earlier as well, and this next column is the incidence of invasive disease in the control group, and there=s  a remarkable similarity between the incidence of disease in the control group in the study to the pre-study results that we identified earlier.
I=d now like to talk to you about otitis media.  Otitis media, there are several outcomes. Visits for otitis media were routinely captured from  electrically scanned or optically scanned forms.  An episode for the purposes of analysis was defined when a visit was not considered a follow-up visit, and I apologize for the double negatives here, but it=s actually easier to explain this way than the other way.  A visit was called a follow-up visit if it occurred within three weeks of another visit for otitis media, or if it occurred four to six weeks from a prior visit and a visit C appointment for that second visit was scheduled more than three days in advance, indicating this was not due to an acute illness.  So that, if we took all the visits and then subtracted the follow-up visits out, we came up with episodes.  We also looked at frequent otitis using several definitions, and I=ll show you what those are,
tube placement and serotype specific efficacy.
This is intended as a frame of reference, and we could spend the rest of the afternoon arguing as to what the real numbers are that go in these boxes, but I just want to let you know that the clinical episodes of otitis media we=re talking about are any visit where a physician made the diagnosis of otitis media.  These individuals were not cross trained, there were more than 500 observers, and this is more the reality of what gets called otitis media in the clinic.  Of those, we estimate from literature and talking with Doctor Jerome Klein, that 50 to 60 percent of these are likely to be bacterial, and between 20 and 40 percent, depending on whether you use U.S. or Finnish data, would be pneumococcal, and then 60 to 85 percent of those might be vaccine serotype.
The important point here is not these total numbers, but the fact that overall we have to anticipate we are not going to see 100 percent effect against otitis media, the total potential impact is likely to be between six and 20 percent.
These are the number of events that we had available to analyze.  There are a lot of them.  There were more than 47,000 visits in the per protocol analysis, 73,000 visits in the intent to treat analysis.
These are the results in the per protocol analysis, and what we see here is there was an 8.9 percent reduction in the number of otitis media visits in the pneumococcal group, a seven percent reduction in the number of episodes.  However, if we look at frequent otitis media, the more frequent we make the definition we see an escalating effect of vaccination, such that if we start with three visits, three episodes within six months, or four or more within a year, we see a 9.5 percent effect on up to five or more episodes within six months, six or more with a year, we see a 22.8 percent reduction in number of children with this problem.
Similarly, for ear tube placement, there was 20.3 percent fewer children had ear tubes placed in the pneumococcal group.
These are similar results by intent to treat analysis, and rather than walking you through them let me say that they are very similar in magnitude, but smaller in each group.
We also asked physicians to, if they saw children with spontaneously ruptured tympanic membranes, to send cultures on that drainage to the laboratory for identification of pneumococcus, and if that was identified we sent that off for typing.  And, we had a total of 23 such cultures submitted during the study. You can see here in the fully vaccinated children, the serotype specific efficacy estimate here for this outcome was 66.7 percent, not statistically significant, and in the intent to treat analysis we saw 64.7 percent, and that was statistically significant.
So, now let me talk about safety.  You=ve heard quite a bit about reactogenicity from Doctor Hackell this morning, and what I=d like to talk to you now is review of medical utilization to evaluate any rare events or rare adverse events that might be associated with this vaccine.
There were a lot of comparisons made here, and I think it=s important to emphasize that, because the statistics that I=ll be showing you have nominal p values that do not take into account the number of comparisons that we=ll be reporting on.  For hospitalizations, you can see there are several intervals here ranging from three to 60 days.  The 60-day interval is the analysis that was specified in the protocol, and the numbers that are shown in yellow here are the ones that were originally specified in the protocol, the ones in white are additional analyses that we=ve conducted.
For emergency room, we did three, 14 and 30 days, and for clinic visits we looked at specified outcomes, seizures within three days and 30 days, asthma and allergic reactions within three days.
There are also multiple comparison groups.  By series, we looked overall combining primary and booster dose, and we looked at those two separately, and we also broke this down by concomitant whole cell pertussis vaccine, either one, whole cell alone, acell alone or neither.
Now, you don=t need to read all this, but what this shows is a list of the 92 diagnoses that we identified, different diagnostic categories that we identified in children during this trial.  It=s important to emphasize that we did not a priori specify which diagnoses we were going to evaluate.  We had evaluated all the diagnoses that occurred in these children, of which there are 92 shown here.
In addition, in the emergency room as well, there are 80 different diagnostic categories in which children have these during the trial period, and comparisons were made for all of these.  And, we=ve calculated for the hospital comparisons alone, and not added them up for the emergency room yet, that for hospitalizations alone, because of the 92 categories and all the other possible comparisons, there were about 1,400, a little bit more than 1,400 different statistical comparisons that were made.
Let me first go through the emergency room results, and what we see here, these are diagnoses that have statistically elevated emergency room visit rates in the pneumococcal group, again using a nominal p value which did not take into account all of the comparisons that were made.  And, what this shows, let me orient you to this table, this is the diagnosis, ear poisoning and ingestion, under that it was only significantly elevated when we looked at all doses combined, not for either the primary series or the booster series alone, and this is the windows where we saw statistical significance, three days and 14 days, interestingly not the 30 day window which was originally specified in the protocol, and it was only statistically significant when we combined both DTB groups.
And, what we see here is an elevation for poisoning and ingestion in the children, given the lack of a physiologic basis for this, we feel this is just due to the number we would expect by chance alone, because of the large number of comparisons.  You see some diagnoses here.
We also saw, within the three day window only, an elevation for croup, trauma, breath holding and urinary tract infection.
This is a different type of slide, and I need to orient you to this as well.  What this shows is for the outcomes which we felt were physiologically feasible.  What we did is then plot the events over the time window to see whether there was any consistent time association with vaccination, because we felt that if this were a physiologic event we would see some consistent time association there.
And, what we see here is that for the five events, all in the pneumococcal group, they are spread out pretty evenly over the 30 day window.  Of these events, three of them were with whole cell vaccine, two of them were in children who had no concomitant DTB, and there were no visits with concomitant acellular pertussis.
This looks at croup, which was another diagnosis from the same table, and as you can see here the events are spread out quite uniformly over the 30 day window, there does not appear to be any consistent time association.
Now we=ll look at hospitalization rates, elevated hospitalization rates were seen in three categories, acute gastroenteritis for both all doses and the primary series alone.  In fact, we can see here that it=s the primary series that=s driving this, really, these are shown as two separate lines, but this group, the primary series, is a subset of the all doses group.  We also saw for febrile seizures, for all doses and in the primary series, just in the 30 and 60 day window, interestingly enough, not in the shorter time windows.  And, asthma, only over the 60 day window, and only for the DTaP group. 
I should emphasize that for the seizures this was only seen in the whole cell group.
This looks at hospitalizations for gastroenteritis.  I=m glad we didn=t have a longer time window, because it wouldn=t fit on the slide, but we see here is that the events for gastroenteritis are, again, spread out over the 60 day window, with no consistent time association.
That was with all vaccines, what this looks at is with whole cell vaccine alone.  Again, we see that this is spread out over the whole window, and the next slide, if we look for DTaP alone there really are very few events altogether.
We looked also at seizures, and one of the things that we looked at is seizures within three days, because we felt that that=s when fever is seen with vaccination, as you saw, and if there was going to be an increased risk this was where we would see that.  These are identified from any source, and I=ll explain to you what that means in the following slide in a moment, but you can see here that there were seven events with whole cell in the pneumococcal group, three in the meningococcal group, that=s not statistically significant, but I think even more important there=s only one event each in each group in the DTaP children. 
And, what this slide shows is that the subset of the children in the prior slide, who had seizures within three days, who had seizures with fever, and what we see here, of the children who had seizures with fever in the pneumococcal group, and this is hierarchical, so if they were seen in the hospital we didn=t list them again in the ER, and so on down the line, there were no children hospitalized within three days.  Three were seen in the emergency room in the whole cell group.  Two of them had urinary tract infections, as the source for their fever, and in the DTaP group the one child who had a febrile seizure had a viral syndrome that was most compatible with roseola.  So, again, another cause of the seizures within this short three day time window, and if you were willing to attribute that seizure to the viral illness there were no febrile seizures in either group in association with DTaP vaccine.
Because we were looking at fever, and because fever was seen as being increased following dose two, for example, in the data that was presented by Doctor Hackell, we also looked at emergency room visits for any febrile illness in the 30 day window, and what you can see again is that it=s relatively uniform over the 30 day window, but there does seem to be a suggestion, which is not statistically significant, and, perhaps, a little more visits to the emergency room early on in the window.
If we break this down by whole cell vaccine, we can see that this pattern persists, although you can see there are other bars further out during the window.  For DTaP you can see that that pattern disappears, that there really does not seem to be any suggestion of that.
Asthma was another event that showed up as increased on the hospitalization table, and, again, we see in blue for the pneumococcus there is no suggestion of any consistent time association with vaccination.  We see this with whole cell pertussis again, and acellular pertussis as well.
I=d also like to talk to you about the clinic events.  The clinic diagnoses that were evaluated were allergic reactions, neurologic reactions, asthma and wheezing, and there was no significant elevation for any of those in the pneumococcal group within the time windows that I showed you earlier.
Now, one of the things that we were asked to do by statisticians at the FDA was to look at selected hospital diagnosis any time during the study, and it=s important you understand this is a different analytic framework than what I showed you.  This is basically designed to look for chronic illnesses, because we are taking children once they are enrolled, and if they develop this diagnosis any time from the beginning of the study to the end of surveillance we included those hospitalizations in this table.
And, the diagnostic categories that we were asked to evaluate were aplastic anemia, autoimmune disease, autoimmune hemolytic anemia, diabetes, neutropenia and thrombocytopenia.  And, I=ll show you first the results of the automated data and then results of chart reviews which followed.  You can see here that the case split is four in the meningococcal group, six in the pneumococcal group, and there=s an extra column here.  And, what we did, our site is part of the vaccine safety data link project funded by the CDC, and we took the data set from 1995 from CDC, which was largely prior to this study, from our site and calculated in the age group of the study population how many cases we would expect to see in each group.  So, here we have four in the mening. group, six in the pneumococcal group, we would expect six in each group.  This is very consistent with that.
For autoimmune disease, there=s 17 in the meningococcal group, 11 in the pneumococcal group.  We=d expect 16 in both groups, et cetera.
For diabetes, there are five in the meningococcal group, one in pneumococcal group, we would actually expect 11 in each group.
So, let me go through each one of these when we reviewed the charts and tell you what we found.  For the children who has aplastic anemia coded as one of their diagnoses in a hospitalization, one of the children had chronic anemia secondary to pertussis infection, another child had anemia and salmonella gastroenteritis, another child anemia secondary to chronic renal infection.  So, three of them were due to C three of the categories were due to infection and associated anemia, and the largest category by far was anemia and neutropenia, secondary to cancer or cancer chemotherapy.
In terms of autoimmune disease, this is what we found.  The largest diagnostic category here was Kawasaki=s disease, and the other categories are shown.  There=s one child in the meningococcal group with ITP.
For autoimmune hemolytic anemia, we have one child here who will show up again in another diagnostic category for another hospitalization, who has a congenital defect in terms of bone marrow function which leads to anemia and neutropenia, who is in this category in the pneumococcal group.
For diabetes, as I showed you, the case split is 5/1.  There=s another child who expired due to diabetic keto acidosis, who was not included in these results because the child was not hospitalized, died in the emergency room, so this is our experience with diabetes in the study overall.
For neutropenia, what we see is the majority of these are secondary to cancer and cancer chemotherapy.  There was one child with neutropenia in the meningococcal group, and there=s another child reported by a nurse with chronic neutropenia who was not hospitalized within Kaiser Permanente that we are aware of.  That=s the total experience in our population.
For thrombocytopenia, these break down into children with cancer, and ITP per se you can see that there are three in the meningococcal group, three in the pneumococcal group, an even split.  There are other cases of thrombocytopenia in the study population, one hospitalization outside of our program due to ITP and two nurse reports, both of those are in the meningococcal group.
We also looked at deaths in the study population overall.  These are the categories, the diagnostic categories associated with mortality during the study.  You can see the ns here and the interval in days since most recent vaccine here in the pneumococcal group and in the meningococcal group.  The only diagnostic category with a substantial number of cases is SIDS, and I=ll show you a separate analysis for that in a second.
We looked at SIDS in two ways.  What we did is, using the 1995 to 1997 California Mortality Tape, which allowed us to calculate an age and season adjusted expected number of events in the study population during the study period, and that=s shown here, expected number within one week for the pneumococcal group is 1.06, we observed one, the expected within two weeks is, essentially, two, we observed two, and you can see up to a year of age in children overall we would expect eight cases in the pneumococcal group, we observed four, in the meningococcal group we expect eight, we observed eight.
Another way of looking at this, SIDS rates are also commonly presented as rates per thousand children during the first year of life, for the pneumococcal vaccine that rate was .2, .4 for the meningococcal group, and from 1996 and 1997 data from California, again, at age matched to our population, and eliminating cases less than two months of age, because that=s the age at which children are enrolled into the study, the expected rate from California would be .5, both of these rates are lower than that.
We also looked at HHE in the study population.  This was ascertained through the 48 hour telephone interviews, and if the parents stated that the child was weak, limp or floppy, the child was considered a potential case, and these were evaluated by further interview through the study nurse and then reviewed by one of the two principal investigators, myself or Henry Shinefield.  Through this surveillance, we identified one case of HHE, with a classic presentation two to three hours of duration out of 8,752 interviews in the pneumococcal group.  There were no cases in the DTaP group or in the mening. recipients.
Doctor Hackell asked me to summarize these events from other trials outside our own, and these are events that were considered at least possibly vaccine related in other trials.  The most common of these was fever, and what you can see here, there are only a couple HHE events that were associated with whole cell pertussis vaccine again, and only one SIDS case 47 days after receipt of vaccine.
So overall, we conclude that the pneumococcal conjugate vaccine was highly effective in preventing invasive disease, due to the seven vaccine strains used in the vaccine, when given in a two, four, six month schedule, with a booster dose in the second year of life.  There was a significant reduction of otitis media, and that was most prominent for children with frequent otitis media or tube placement, and that the pneumococcal conjugate vaccine was associated with mild and self-limited local and systemic reactions, and not associated with serious adverse events.
Thank you.
CHAIR GREENBERG: Thank you, Doctor Black, that was maybe the largest download of data in the shortest period of time that I=ve been associated with.
George, how much more C
DOCTOR SIBER: Mr. Chairman, I will be extremely crisp.  I=ll try to be.
In conclusion, just to summarize, the safety profile you=ve seen is comparable to other childhood vaccines for Prevenar.  There=s a high level of efficacy against serious disease.  We saw significant reductions in clinical otitis media.  We showed you that it was compatible with other childhood vaccines, and the epidemiologic data suggests that it will be directed against most of the antibiotic resistant pneumococci.
The point I want to make really is that I think Prevenar, if introduced, has the potential to substantially reduce the disease burden of the single, most common invasive bacterial pathogen of children.  From a public health vantage, Prevenar has the potential to reduce the use of antibiotics and, thus, to reduce the pressure on bacteria to become resistant to antibiotics.
We have calculated approximately how many cases of pneumococcal disease would be prevented by the general introduction of Prevenar, and with a single birth cohort of one year, and we=ve used for this the CDC disease rates, age specific disease rates, the percent coverage, vaccine serotypes that you=ve heard about, and the efficacy estimates from the Kaiser study that you just heard.
So, in a single birth cohort, assuming efficacy up to 16 months of age, but not beyond, one would expect to prevent more than 13,000 cases of invasive disease, more than 1,000 cases of meningitis, 1.3 million otitis media visits, and more than 60,000 cases of PE tube surgical procedures.
Made more graphic, perhaps, is if all U.S. children were immunized with Prevenar we would prevent three cases of meningitis, 37 cases of invasive disease, 173 PE tube procedures and 3,800 otitis media visits every day.
I really want to thank, at this point, the many investigators.  Shown here are only the subset of investigators who worked on the studies contributing to this PLA, these have been terrific collaborators for us and are responsible, I think, for the quality of the data that you are seeing today.  I=d also like to thank colleagues at NIH, and I see Doctor Bill Jordan in the front row, under whose auspices I think the pneumococcal work was initiated and is coming, I think, to fruition.
I=d also like to thank our colleagues at FDA, who have done an enormous amount of work, especially in the last six to nine months, reviewing these data in a very timely manner.
Thank you.
CHAIR GREENBERG: Thank you, and I=d like to thank the manufacturer for really adhering to time lines.  We have C I hope all of you got all of that, and we=re ready to ask some questions.
Doctor Kim?
DOCTOR KIM: Let me begin by asking some specific questions related to immunogenicity.  I know you talked about ELISA and opsonic antibody, and then I presume that in the future pneumococcal conjugate vaccine of this nature will not, perhaps, go through the clinical trials as we heard today.  So, based on the data available, what would you say that a protective level of antibodies for each serotype or, you know, different serotypes, and/or would you say that level of antibody would be comfortably extrapolated to other vaccines of this nature?
DOCTOR SIBER: What a set up.
I could spend quite a long time talking about protective levels of antibody to pneumococcus.  In the interest of time, I think it=s fair to say that looking at the reverse hemolytic distribution curve, and if one picks a population based method for discriminating between the protective immunized population and the unimmunized at-risk population, you can see that levels in the order of .15 to .5 can be chosen as protection.
There=s been intense debate between FDA and ourselves about precisely where that might be, and I think we probably have not reached a firm conclusion, but I think it will be possible to define protective levels, which is really what you are asking about, which will facilitate, I think, in the future the development of combination vaccines or other pneumococcal conjugate vaccines and so forth.
DOCTOR KIM: And then second question related to that is, since this vaccine is introduced, then it will be given to very young infants.  Is there any information available regarding the effect of anybody under immunogenicity of these vaccines?
DOCTOR SIBER: That=s a good question, actually.  It=s one that I have raised a couple times. I=m not sure that we have done a formal analysis of that.  Jill, are you aware of a formal analysis C yes, Bob Kohberger is going to address that question.
DOCTOR KOHBERGER: In most of the analyses of the immunogenicity, if we put the pre-value and use it as an adjustment to what we get for the post, in general we don=t find that it=s correlated, so that the pre-level doesn=t seem to interfere or change the response.
CHAIR GREENBERG: Doctor Daum and then Doctor Snider.
DOCTOR KIM: Can I ask one more to Doctor Black?
CHAIR GREENBERG: Yes.
DOCTOR KIM: If I understand, I guess after April or May, 1999, that all individuals have been offered this conjugate vaccine.  Is there any data or information available that, indeed, invasive pneumococcal disease in your organization has decreased by 80 to 90 percent, let=s say, from April, May up to now, about six months of time, for any analysis you have done?
DOCTOR BLACK: That=s an interesting question, and I think you are trying to get at, perhaps, herd immunity or other things.  And, you know, if you look within short time windows, which six months for pneumococcal epidemiology is relatively short, there=s so much variation anyway, it=s difficult to say.
I can tell you that since April 20th we=ve only had two cases of invasive disease, but we=ve had similar time windows in the past where that=s occurred.  So, I think we need to wait longer.
CHAIR GREENBERG: Doctor Daum, then Doctor Snider.
DOCTOR DAUM: I also join in congratulating you all for a really amazing presentation this morning.  I found it very helpful.
I=m sort of excited about the idea of being able to remove some of the antibiotic pressure on these organisms, and thereby diminish rates of antibiotic resistant pneumococci, but a concern, potentially at least, is that we are going to put, as we phase in this program of immunizing every American child, every child in the world hopefully, a different kind of pressure on the organisms, as an antibody pressure.  And, this organism, unlike many others, is less offended by taking up for a DNA, or DNA from another organism, and thereby being able to change its capsular serotype without modifying a whole lot else in its genetic make-up.
And so, I guess I=m wondering, on a philosophical, thoughtful basis, what kind of program do you believe should be put into place, if any, to look at serotypes causing invasive disease, colonizing children, or causing otitis media for that matter, after we introduce this program on a mass scale.
DOCTOR SIBER: Well, it=s actually not mine to comment on, the program that should be put in place, but what I can comment on are what we as manufacturers are thinking about.  To begin with, with colonization studies that have been done in South Africa, as well as by Dagon Ron in Israel, it=s been clear that about 40 to 50 percent reduction occurs in carriage of vaccine type pneumococci.  There=s also a reduction in carriage of a cross reactive type 6a.
At the same time as that occurs, there is an increased rate of carriage of non-vaccine types, so that the net pneumococcal carriage is reduced only slightly, and not significantly.  The question is whether that will also result in an increased rate of otitis by non-vaccine types over time, or an increased rate in invasive disease by non-vaccine types over time, and that=s a question we share your concern about.  I think as you said, the pneumococcus is not offended if you take up foreign DNA and, in fact, some people have said that the pneumococcus is promiscuous in taking up foreign DAN from other pneumococci.  And so, you might anticipate capsular switching over time in response to antibody pressure.
The real question is, are the types that we have been seeing now and are including in the vaccine the bad actors, and the other types have chassis=, if you will, other than capsule, that are not as good as pathogenic.  Well, capsules are not pathogenic, as is true for haemophilus.  We don=t know the answer to that question right now, but certainly would like to be ready for the possibility of this, and I think the ways that one can be ready is to increase coverage to other common types around the world that are known to have invasive potential, and I think you are aware that there is a plan to add additional serotypes to this vaccine in second and third generation products.  And, the other, I think, possibility is to consider protein antigens of the organism in the tentative capsule.  There, I think, you are in a higher risk proposition because no one has really convincingly showed that these protein antigens would be effective as human vaccines, that needs to be demonstrated, but that would then take the pressure off the capsule from an immunologic selection point of view.
CHAIR GREENBERG: Doctor Snider, then Ms. Fisher, and then Doctor Stephens, and then that will be it.  And, please try, panel, to formulate your questions so that they are also crisp.
DOCTOR SNIDER: George, could you remind us how much follow-up we=ve been looking at in terms of the efficacy data thus far, and how much is planned?
DOCTOR SIBER: I=d like to turn that question over to Steve Black, in terms of duration of follow-up in the efficacy trial.
DOCTOR BLACK: These children are just now turning four years of age, and we anticipate following this population indefinitely, so we are still following the original cohort of Hib TITER children that we immunized as well.
Does that answer your question?
DOCTOR SNIDER: So, most of C we=ve had about a three year follow-up, I forget what the accrual period was, I think 1998?
DOCTOR BLACK: There are several end dates, it was October of 1995 for the primary safety analysis was through April of 1998.  The interim analysis was August of >98, and then the extended follow-up was through April of this year.
DOCTOR SNIDER: So, the mean follow-up, what would you guess?
DOCTOR BLACK: About two years.
DOCTOR SNIDER: I was just thinking about the incidence that George was showing us, what we might be able to accrue with the additional follow-up period.
Thanks.
CHAIR GREENBERG: Ms. Fisher.
MS. FISHER: This is a question for both Kaiser and Wyeth-Lederle.  It=s my understanding that this Kaiser trial took place between October, 1995 and August of 1998, that there were 17,457 interviews of children who got whole cell pertussis vaccine in this trial, and 3,541 interviews of those who received DTaP.  
In July, 1996, the FDA licensed the DTaP vaccine for the fourth C primary doses and the fourth dose, and I=d like to know why ethically Kaiser and Wyeth-Lederle used the whole cell pertussis vaccine in these trials, and it confounds the picture, particularly with regard when the children receive whole cell pertussis vaccine and the pneumococcal vaccine, and seizures occurred, and fever, and all these other things, we don=t really know whether the pneumococcal vaccine causes those reactions, because whole cell vaccine was used.  And, I=d like to know why it was.
DOCTOR SIBER:  I=d be delighted actually to pass that question to Mr. Black to address.
DOCTOR BLACK: Yes, at the beginning of the trial in October of >95, a cellular pertussis vaccine was not licensed for the primary infant series.  And, as the recommendation for its use came about, we encouraged physicians to switch from the whole cell vaccination to a cellular vaccination.  And, in fact, as of this point of time, there were a couple of transitions during the trial, one of them was for acellular pertussis, the other was from OPV to IPV as well.  And, you know, the recommendations, our physicians follow the recommendations for use of vaccines, as outlined by the ACIP, and that=s what was used during this trial, were vaccines that were licensed and recommended for use at that time.
MS. FISHER: It does confound the picture in terms of safety.
DOCTOR BLACK: But, that C the acellular pertussis vaccine was not available to us as part of the protocol at the inception of the trial, and that=s why we conducted a second set of telephone interviews and have stratified the data by vaccine, by acellular pertussis group, and all the safety tables that I presented to you.
MS. FISHER: But, the majority of the trial was conducted after the licensure of the DTaP vaccine, there were only eight months where the DTaP was not used in infants, so I don=t know, you know, Kaiser or somebody needs to get the word to the physicians that they need to use DTaP, because I think it=s shocking that this many whole cell vaccines were given, vaccinations were given.
DOCTOR BLACK: Yes, just one quick comment, in that I think nationally in pediatric offices coast to coast when new vaccine recommendations come about there is a transition from one to the other, and especially when that transition involves from a combination vaccine which was very well accepted by pediatricians to two separate injections, it takes a while to change.  That was true for IPV as well.
CHAIR GREENBERG: I=d like to move on now to Doctor Stephens, last question.
DOCTOR STEPHENS: I do want to commend you for an excellent presentation.  My question concerns persistence of antibody levels.  Your graph suggests that 60 months is, in terms of the last couple of slides you presented, impact.  Do you have data that suggests that there is persistence of antibody to 60 months?  That=s my first question.
The second question concerns the case or cases, there=s one case I know of a vaccine failure, and whether that case has been looked at immunologically.
DOCTOR SIBER: With regard to the first question, I don=t believe we have data to 60 months, am I wrong about that?  It=s two years.  But, I think I=d like to make a point on that, and that is you=ll notice, of course, that antibody levels declined to 15 months, often to fairly low levels in individual patients, and we seem to have a benefit out to 15 months without breakthrough in this limited efficacy trial.
And, in fact, we seem to see a benefit even after one or two doses, although not statistically significantly so at this time.  What this suggests is that priming in the case of pneumococcus may be quite important, and I think it=s very clear that the vaccine primes.
I think with pneumococcus, and I=m speculating, there=s probably a period of time when you get colonized when you have a chance to mount an antibody response if you=ve been primed, and so I think having been primed by conjugate, even if your level drops, may give you a substantial amount of protection.
We do not have, in any group yet, six year antibody data, if I=m correct on that, two years C is it four years C two years.  
With regard to your question about the single older breakthrough in immunologic status, Steve?
DOCTOR BLACK: Yes, the only thing I can tell you about that child is that the child had grown healthy, was growing well, did not have any other infectious problems, however, the parents refused to have blood drawn for immunologic analysis, so we don=t have that data.
CHAIR GREENBERG: I=d like to thank the panel and the committee.  We are going to take now a 12 minute break, and be back here at 11:05 to start again.
Thank you.
(Whereupon, at 10:51 a.m., a recess until 11:06 a.m.)
CHAIR GREENBERG: If people would take their seats.  If people could please take their seats.  Doctor Siber, take your seat.  
I apologize to all of you for pushing you on the time of breaks. I hope you all were at least able to take whatever necessary things you had to do in that time, but we have a very full day and I want to move things along.
We are now going to have a CBER presentation by Doctor Douglas Pratt, and after that we=ll have the ability of the committee to ask some more questions, and I know there were a few questions here that I had to cut short, and maybe we=ll be able to get those.  So, there may be a few questions for the manufacturer lingering from the last session as well.
Doctor Pratt?
DOCTOR PRATT: Good morning.  My name is Douglas Pratt.  I=m a Medical officer in the Division of Vaccine Applications, within the Office of Vaccine Research and Review at FDA.
FDA received a product license application from Wyeth-Lederle Vaccines in Pediatrics for Prevenar on June 1, 1999.  The application was granted priority review status based on the severity of the disease for which the vaccine would be indicated, that is, invasive pneumococcal disease, meningitis and bacteremia, and preliminary results indicating substantial evidence of efficacy.
Preliminary efficacy data were presented at this committee at the November, 1998 committee meeting.
Regulatory approval has been requested to market Prevenar for active immunization of infants and children, beginning as early as six weeks of age, to help protect against invasive diseases caused by Streptococcus pneumoniae due to capsular serotypes included in the vaccine.
Prevenar has also been studied for prevention of otitis media and pneumonia.  The Advisory Committee will not be consulted at this session regarding those other potential indications.
Study of the 7-valent pneumococcal conjugate vaccine as an investigational new drug began in November of 1994.  The pivotal efficacy trial was initiated about a year later in October of >95.  The safety database and databases for secondary endpoints of otitis media and pneumonia were locked on April 30, 1998, in anticipation of eminent accrual of sufficient cases of invasive disease for a planned interim analysis.  That analysis occurred on August 20, 1998, after which enrollment ceased as results indicated evidence of efficacy.  That analysis is considered a primary efficacy analysis.
The otitis media analysis planned for the efficacy study was finalized later that year, and a pneumonia analysis plan was finalized in March of this year.  On April 20, 1999, a follow-up of subjects for invasive disease ended and control subjects were offered the pneumococcal vaccine.  
The last component of the complete application was the manufacturing bridging study which was completed in May of this year.  The meeting today is taking place about five months after receipt of the application.
Data from 11 different clinical studies were included in the application, studies 18, three and seven were early studies conducted among infants to demonstrate satisfactory safety and immunogenicity in preparation for the large safety and efficacy trial, which is trial 118-8.  Clinical studies 118-12 and 16 served to demonstrate consistency of vaccine production and ability to scale up production as will be discussed.
Data from these additional studies were also included in the application.  92-5 was an early study of 5-valent conjugate vaccines, which direct saccharide dose and model selection.  Study 18-2 is the only study of the vaccine in adults.  Its objective was to demonstrate acceptable safety and immunogenicity in a small number of adults before proceeding to study the vaccine in infants.
Study 118-15 is an ongoing clinical efficacy trial conducted among Native American Navajo and Apache populations.  Only immunogenicity data intended to support catch-up schedules was provided to the PLA, and in studies 124-2 and 124-501 provide data for a 9-valent pneumococcal conjugate vaccine intended to support vaccine compatibility in catch-up schedules.
Not included in the application are data addressing use of the vaccine among some high-risk populations, including children with sickle cell disease, HIV infection, and Hodgkins disease.  Also not included in the application are data from a trial conducted in Finland, evaluating the effectiveness of the vaccine in preventing otitis media.
Clinical studies essential for regulatory approval were a large safety and efficacy study conducted at the northern California Kaiser Permanente system, a lot consistency study 118-12, and the manufacturing bridging study, 118-16.  These latter two studies are also important for the assessment of safety, as these are the only studies in the application conducted among infants which did not make use of the meningococcal c investigational vaccine in the control arm, thus allowing a more clear assessment of vaccine reactions.
Antigen content of the pneumococcal vaccine was presented earlier.  Shown here is a comparison to the antigen content of the meningococcal c vaccine used as a control in the efficacy trial.  Contents of the diphtheria toxoid carrier is similar.  Total saccharide content was also similar, although the meningococcal vaccine contains oligosaccharide while most of the saccharide in the pneumococcal vaccine is polysaccharide.
Prevenar is a liquid formulation which is preservative free, and it does not contain thimerosal.
All data in the application supporting a claim of efficacy against invasive disease come from the northern California Kaiser Permanente trial.  The original plan for the efficacy study had included interim looks at eight, 20 and 40 cases of invasive disease, with stopping rules for case splits at each look.  FDA did not recommend the early look after eight cases.
As the trial progressed, the sponsor requested a determination for a minimum number of cases, for which an interim analysis might be conducted with specific case splits leading to a termination of enrollment and a claim of efficacy.  Agreement was reached in November of 1997 to modify the sequential analysis plan by eliminating the look at eight cases, and instead to provide for one interim analysis when 17 cases of invasive disease due to vaccine serotypes accrued among children who were vaccinated per protocol.
The test criterion at the interim analysis was specified as follows.  If no more than two cases out of the 17 were observed in the vaccinated group,  in the pneumococcal vaccine group, the vaccine was to be considered efficacious and the trial would be stopped for evidence of efficacy.
Enrollment into the efficacy trial was terminated in August of >98.  At that time, nearly 38,000 infants had been randomized and received at least one dose of study vaccine.  Exact follow-up times for all subjects were not available at the primary analysis.  Follow-up times established in April were used to project the estimated follow-up time for the August analysis.  Variation of actual from projected follow-up time would not affect the vaccine efficacy estimate, but could alter the confidence intervals.
The sponsor and FDA have conducted supplementary analyses demonstrating that plausible ratios of follow-up times between the two vaccine groups at the August analysis would not vary substantially with additional data and, therefore, the confidence intervals would not change.
As you can see, about 7,500 randomized subjects were not included in the per protocol analysis, but were included in the intent to treat analysis.  Reasons for exclusions from the per protocol analysis and protocol violations were provided as supplemental to the PLA.  The most common reasons for exclusion were not receiving the third dose by the date of cutoff, and the third dose not given within the first year of life.
Children were also excluded for failure to receive study vaccines in the designated time frames, receipt of incorrect vaccines, failure to meet entry criteria, receipt of immunoglobulin, invasive disease and death.  Loss of health plan membership did not result in exclusion from the per protocol follow-up unless a dosing violation occurred.
The number of subjects appears to be well balanced between the study groups by reason of exclusion.  The number of subjects randomized, as shown in this slide, differs from the number evaluated at the efficacy analysis seen in the previous slide, because the data cutoff for determining follow-up was the April 30th date, while the primary analysis took place four months later.
Doctor Black already presented the race and ethnicity study population.  The vaccine groups appear to be well balanced with respect to race and ethnicity.
Results of primary analysis were previously shown.  Results were remarkable.  No cases of invasive disease due to vaccine serotype were observed.  The vaccine efficacy estimate was 100 percent, and the lower bound, the 95 percent confidence interval, was 75 percent for the per protocol analysis and 82 percent for the intent to treat analysis.
Five cases of invasive disease had accrued in the control group among children who received one or two doses.  Efficacy for one or two doses cannot be inferred, however, as the lower bound of the 95 percent confidence interval including zero. Between the third and fourth doses ten cases had accrued.  This number of cases provided an estimate of the vaccine efficacy for the interval between after the third dose until the fourth dose, with a lower bound of the 95 percent confidence interval about 50 percent.  Protection after three doses beyond 12 to 15 months cannot be inferred, because most subjects received a fourth dose of vaccine.
In FDA=s review of the efficacy data, we sought to be assured that no cases of invasive disease may have been missed.  A few missed cases in the pneumococcal vaccine group would have a large effect on the efficacy estimate and on the confidence intervals.  To this end, we requested that all bacterial culture results for the study population at the time of the primary analysis be tabulated and reported.  The final summary of all non-pneumococcal culture results revealed no imbalance across the two groups.  All positive bacterial cultures were identified by genus and most were speciated.  Thus, for subjects who remained in the Kaiser plan throughout the study, the likelihood that cases of invasive disease may have been missed is low.
Although not relevant to the regulatory approval of Prevenar, it may be of interest to the committee that six meningococcal isolates were also identified, three in each vaccine group and none of the isolates was meningococcal type c.
Of the 22 cases of invasive disease in the control vaccine group, five were among partially vaccinated infants.  All five were less than six months of age.  One of the 17 cases among the older fully vaccinated subjects was hospitalized.  Three of the infants less than six months were hospitalized.  All cases were bacteremic.  Bacteria were also isolated from the spinal fluid of two infants less than six months of age.
In addition to the two infants with meningitis, two children were diagnosed with sepsis.  According to the case narratives provided, however, neither of these children were hospitalized.  Thus, the diagnosis of clinical sepsis appears to be of little value in assessing severity of disease in this trial, and illustrates the desirability of having common diagnostic criteria.
None of the cases of invasive disease at the primary analysis occurred among immuno compromised individuals.  There were no deaths.  One infant with meningitis suffered residual hearing loss, all others were said to have fully recovered and were doing well.
Well, in August of 1998, the enrollment ceased.  Partially vaccinated subjects continued to complete the vaccine schedule, and follow-up of subjects was added to the continuing surveillance of efficacy outcomes and safety.  An analysis of all invasive disease accrued through April 20th was provided with the PLA.  Complete data sets including safety and calculations of follow-up time are not yet available for the extended surveillance period.
Vaccine efficacy data for cases through April of >99 are consistent with data in the primary analysis.  One case of invasive disease due to vaccine serotype occurred among the fully vaccinated subjects, and 39 cases were observed in the control group.  The one case of invasive disease due to vaccine serotype in the pneumococcal group presented no unusual characteristics.  This child was two years old, Caucasian male, who received four doses of vaccine.  Onset of illness was about one year after the fourth dose. He presented with low-grade fever and a right lower lobe pneumonia.  Blood culture grew a serotype 19f, which is penicillin sensitive, and he recovered fully.
Two additional cases of invasive disease occurred in the intent to treat population.  A 12-1/2 month old African American female received one dose of vaccine, her illness was 317 days after the vaccine.  Blood culture was positive for serotype 6b.  She was treated out patient and had a full recovery.  The other child was a 2-1/2 year old Caucasian male who was fully avccinated, but he was diagnosed with acute myelogenous leukemia, received a single round of chemotherapy and when he came in for the second round was discovered the bacteremic 570 days after the fourth dose.  That serotype was 19f, which is penicillin resistant.  He subsequently died, however, apparently not of pneumococcal disease, which was successfully treated.
In this table compiled from case narratives, characteristics of all 61 cases were broken down by whether the case was due to vaccine serotype or not.  One case of invasive disease due to non-vaccine serotype did not have a positive blood culture, as Doctor Black mentioned, this was from, the pneumococcus was isolated from a thyroglossal duct cyst.  Five cases of meningitis were due to vaccine serotype and one case to non-vaccine serotype, accounting for about ten percent of invasive diseases cases overall.  Two children with invasive disease were immunocompromised. the child with leukemia was discussed earlier.  One child also had severe combined immunodeficiency disease in the control group, and he developed invasive disease to the non-vaccine serotype.
Four deaths occurred among the study population.  Two of the deaths could be attributed to pneumococcal disease.  Both were in the control group, an eight month old Caucasian female was diagnosed with pneumonia and meningitis, died due to complications of meningitis.  The serotype 14 was isolated, it was relatively resistant to penicillin.  It was isolated from both blood and spinal fluid, and there was no evidence that the child was Immunocompromised, and then a 28 month old Filipino make with a history of asthma was diagnosed with multiple lobe pneumonia and respiratory disease, serotype 19f drew from blood, which is penicillin sensitive.  There=s no history of prior corticosteroids or that the child was immunocompromised.
Penicillin susceptibilities of pneumococcal isolates in the trial were reported.  Of vaccine serotype isolates, 15 percent were resistant and 21 percent had intermediate resistance to penicillin.  One non-vaccine serotype case was penicillin resistant, that was type 23a.
Well, nine cases of invasive disease due to non-vaccine serotypes had accrued at the follow-up, at the end of the extended follow-up period.  This is only one additional case since the primary analysis in August.  During the same period, 30 additional cases of vaccine serotype had accrued, thus replacement of vaccine serotype by non-vaccine serotype was not observed during the follow-up period of this trial.
Overall, of the 61 cases of invasive disease, 52, or 85 percent, were due to vaccine serotype.
Race and ethnicity were determined for all cases of invasive disease.  Here I=ve put together the race and ethnicity of the various cases compared to the race and ethnicity in the representative sample seen earlier.  While the confidence limits about these percentages are wide, it does appear that invasive disease cases were disproportionately distributed with fewer Asians and more African Americans affected.
I=ll now discuss safety.  The bulk of the safety data does come from the efficacy study as well.  Hospitalizations within 60 days, emergency visits within 30 days, out-patient clinic visits for seizures, allergic reactions and asthma were reported in the PLA, also events resulting in study termination contributed to the ascertainment of adverse events.  A randomly selected subset of infants were actively monitored for vaccine reactions through the use of diary cards and telephone interviews.  The subset included about 7,500 infants who received whole cell pertussis vaccine and 1,500 who received acellular pertussis vaccine, and the same cohort was monitored for each vaccine dose.
When the efficacy study began, all children received whole cell vaccine with the primary series.  This table shows that about 75 percent of subjects received whole cell vaccine with all three doses of the primary series, and 17 percent received acellular pertussis vaccine for all three doses.  Various combinations were also possible.
Well, much of the vaccine reaction data has already been presented, most of it in graphic form, I=ll present a few table showing data with statistical analysis and click through a number of slides.  Local reactions were assessed pair wise between left and right legs of the same child, in order to compare pneumococcal vaccine to DTB Hib.  Some children also received hepatitis B vaccine in the same leg as DTB Hib.
It was also possible to compare local reaction rates across study groups in order to compare pneumococcal and meningococcal reaction rates, and both sets of comparisons are shown on this slide.  This is dose three of the whole cell pertussis with the primary series, erythema, induration and tenderness were more common for the whole cell Hib than for the pneumococcal conjugate.  Rates of clinically significant reactions were also greater for DTB Hib than for the pneumococcal vaccine.  In columns on the far right it can be seen that rates of local reactions and clinically significant local reactions were more common in the pneumococcal vaccine group than the meningococcal group.
Results after one and two doses are available and copies are provided to the committee.  I=m just going to click through them right now.  For those subjects who received acellular vaccines concurrently, Hib vaccine was administered in the same leg as the pneumococcal vaccine, and the worst of the reactions was reported.  Hepatitis B vaccine, if administered, was inoculated into the same leg as DTaP  and the worst reaction was recorded.  Again, comparisons to both DTaP and the control vaccine are shown in this slide. After dose one, higher rates of erythema, induration and tenderness interfering with limb motion were observed for the leg inoculated with the pneumococcal vaccine than for the DTaP, compared to the meningococcal group on the far right erythema and induration were greater in pneumococcal vaccine.
Tables for doses two and three are available to the committee, and copies of the slides.  Local reaction rates of the pneumococcal injection sites were similar with each dose, but reaction rates for DTaP increased and comparisons were not statistically significant for the doses two and three.
At the fourth dose, erythema and induration were reported more frequently for pneumococcal vaccine than for DTaP.   Subjects may have received mixed pertussis vaccines with the primary series, however, compared to the meningococcal vaccine clinically significant erythema, induration and tenderness were also more common with pneumococcal vaccine.
Data from the lot consistency study, 18-12, are presented to show a comparison between pneumococcal conjugate vaccine and Hib conjugate vaccine for local reactions.  This comparison is possible because the control group in the study did not receive either pneumococcal or meningococcal vaccines.
Shown are local reaction rates after dose three, erythema, induration and tenderness were more common at the injection sites of pneumococcal vaccine.  However, clinically significant reactions were uncommon.  Similar differences in local reactions were observed with each dose in the primary series.  Data for these doses are available to the committee in the briefing materials.
Summarizing local reactions, pneumococcal conjugate vaccine caused less local reactogenicity than whole cell pertussis Hib, but it appeared to cause more local reactions than DTaP, Hib conjugate and the investigational meningococcal vaccine.  Except for erythema, no pattern of increasing local reactogenicity with sequential doses of pneumococcal vaccines was apparent in the primary series, and no data are available to compare pneumococcal vaccine to a fourth consecutive dose of DTaP.
In the efficacy study assessment of systemic reactions and adverse events attributable to pneumococcal conjugate vaccine is complicated by concurrent recommended immunizations and the use of the investigational meningococcal vaccine in the comparator group.  Again, most of the data about systemic reactions have been shown previously graphically. I will show a few tables with statistical analysis.
Shown here are data for dose one, using whole cell vaccine, whole cell pertussis, against a background of concurrently administered whole cell pertussis Hib.  Fever and irritability were reported more frequently in the pneumococcal vaccine groups than the meningococcal vaccine group after reach dose in the primary series.
Rates of fever greater than 39 degrees in increased with subsequent doses, and were significantly more frequent after doses two and three compared to the control group.
Other systemic reactions, such as prolonged crying, restless sleep, loss of appetite and vomiting, were also more common in the pneumococcal vaccine group for one or more doses in the primary series.  Data for doses two and three are available in the briefing materials, I will show them briefly. This is dose one, dose two, and dose three.
Systemic reaction rates among infants who received acellular pertussis vaccine with the primary series are more likely to represent current practice in the U.S.  Shown in this table are common systemic reactions after dose two, as this is the dose for which systemic reactions were common.  Fever was more common in the pneumococcal vaccine group after each dose in the primary series, but fever greater than 39 degrees shown here were more common after dose two.  A loss of appetite occurred more frequently in the pneumococcal vaccine group after each dose, and that difference was significant after dose three.
Tables of systemic reactions for other doses are available in the briefing documents.  I=ll show them briefly.  Dose one, and then dose three.
After dose four, when given concurrently with DTaP no significant differences between study groups were observed for fever or other systemic reactions.  The fourth dose of acellular pertussis followed a primary series, though, in which most children received whole cell pertussis.
Data from the manufacturing bridging study are presented here, in order to compare a no-injection control all subjects received the acellular pertussis vaccine.  One pilot lot and two manufacturing lots were pools for these comparisons.  Systemic reactions were most prominent after dose two, and that=s what is shown here.  Fever, irritability, decreased appetite were more frequent in the pneumococcal vaccine group.
Data for doses and two and three are available with the committee=s materials, does three, dose one.
I think Doctor Hackell had a similar slide, febrile reaction rates are summarized here for the essential clinical studies.  Rates of fever increased with sequential doses of whole cell pertussis, in combination with pneumococcal vaccine. When administered with DTaP and Hib rates of fever and systemic reactions did not appear to increase with sequential doses.
Fever was least frequent after dose one, regardless of concurrent pertussis vaccine.  With concurrent DTaP rates of fever greater than 38 degrees ranged from five to 22 percent after dose one, 19 to 34 percent after dose two, and 19 to 28 percent after dose three.
Summarizing systemic reactions in the efficacy study, increased rates of fever were detectable above background rates, due to DTB Hib, DTaP and other concurrent vaccines.  Rates of fever increased with sequential doses when pneumococcal conjugate vaccine was administered with whole cell pertussis Hib vaccine.  Irritability, decreased appetite and drowsiness were also associated with pneumococcal vaccine, but without a consistent pattern.
However, comparisons to systemic reaction rates for the meningococcal group may mask excess reaction rates attributable to the pneumococcal vaccine.  When administered with acellular pertussis vaccine, fever rates and antipyretic use was greater in groups receiving 7-valent vaccine than in no injection controls.  For the fourth dose of pneumococcal vaccine no safety data are available at this time to evaluate systemic reactions with the fourth consecutive dose of DTaP.
Doctor Black has provided some data on adverse events today that appear to be somewhat more updated than what we had at our disposal.  This slide shows the number of deaths due to all causes through December 31, 1998.  I think his slide showed 11 deaths in the pneumococcal arm and 22 in the mening. arm.  With respect to overall mortality, data for all causes appear to be imbalanced with more deaths in the control arm.  Causes of death in each case were provided, and none of the deaths were considered by investigators to be vaccine related.
Doctor Black also presented data on SIDS, and I think his data are actually adjusted for the first two months of life and seasonality, which is appropriate.  These SIDS data provide no reason to be concerned about use of the pneumococcal vaccine.
Again, Doctor Black presented this data earlier. All hospitalizations within 60 days of vaccine dose were entered into the safety database.  The sponsor has conducted analyses of multiple safety comparisons by doses, by type of concurrent vaccine, and for various time periods after the vaccine dose.  Hospitalization rates for selected diagnosis of potential interest were identified by screening against the statistical significance levels, not adjusted for multiple comparisons.
Shown here are only those diagnoses for which an imbalance in the number of cases in the pneumococcal vaccine group was apparent.  Febrile seizures within 30 days and 60 days of the vaccine dose were more common in the pneumococcal vaccine group.  Increased rate of hospitalization for asthma were observed.  Doctor Black discussed this earlier.
The ER diagnosis of events occurring within 30 days of the vaccine dose were analyzed by concurrent vaccine.  ER visits for croup within three days, breath holding within 30 days, and urinary tract infections within 30 days showed a slight imbalance of cases in the pneumococcal vaccine group.  This was presented earlier as well.
Well, adverse events occurring outside the 60 day window following vaccine doses for hospitalizations may not have been captured in the adverse event monitoring in this trial and, therefore, FDA requested that the sponsor search the hospital databases for selected adverse events related to autoimmune diseases, blood abnormalities and diabetes.  These data were recently received by FDA.  Events were captured using various ICD9 codes and may not be specific for a particular clinical entity as Doctor Black pointed out earlier.  Preliminary review indicates no imbalance in the number of such events which would cause concern for the group receiving the pneumococcal vaccine.
Adverse events leading to study discontinuation provided an additional source of safety data.  More subjects in the meningococcal vaccine control group discontinued for adverse events, 74 versus 53.  The most common reasons for leaving the trial were seizures, which accounted for 83 of 127 events, or 65 percent of the subjects discontinuing.  The number leaving due to seizures in both groups was similar, however.  Other less common adverse events leading to study termination are shown.
Six serious adverse events were considered by study investigators to be possibly or probably related to study vaccine, three in each group.  All three serious adverse events considered related to pneumococcal vaccine were seizure events.
FDA asked the sponsor to provide an integrated summary of all seizure events, in which acute events were distinguished from follow-up events, follow-up visits, or an ongoing seizure disorder by means of chart review.  The sponsor has also reviewed other potential sources of information, including spontaneous reports from clinic study nurses.  Using data from all sources, the number of subjects that experienced acute seizure events occurring with three, 14 and 30 days of study dose were assessed.  Acute seizure events within 30 and 14 days of vaccine dose were well balanced across the two groups. Events occurring within three days of the vaccine dose were more common in the pneumococcal vaccine group.
Of the eight recipients of pneumococcal conjugate vaccine who had acute seizure events within three days of inoculation, seven were febrile seizures and one was afebrile, and seven had received whole cell pertussis vaccine concurrently with the study vaccines.  One child had a seizure after dose one, two had seizures after dose two, three after dose three, and two after dose four.  Two subjects were also diagnosed with urinary tract infections.  Doctor Black pointed that out earlier, and one subject in the pneumococcal group had a seizure after the DTaP dose, which was thought to be due to a viral infection.
In the meningococcal control group, acute seizure events within three days, two had afebrile seizures.  One subject actually had a history of cerebral palsy and another had a history of seizures.
Although most seizure events did occur after concurrent whole cell pertussis vaccine, it should be remembered that most of the children in the study received whole cell vaccine with the primary series.
In supporting studies, not shown here, in supporting studies there were two additional seizure events.  They occurred in the lot consistency study.  One occurred four days after a dose, which was thought to be, considered to be possibly vaccine related by the investigator.  The other occurred one day after the dose of the study vaccine, that was not thought to be related by the investigator, but it was certainly C related.  In those two cases, the concurrent pertussis vaccine was an acellular pertussis vaccine.
Well, a safety update of hospitalization rates and ER visits was provided for the period until December 31, 1998 as line listings, adverse events in the safety update which were considered by investigators to be possibly or probably related to study vaccines are shown.  There were two seizure events reported in the pneumococcal vaccine group, one occurred eight days after a dose, and the other three days after a dose, after a fourth dose.
That concludes my discussion of the safety analysis. I=ll not discuss compatibility of pneumococcal vaccine with concurrent immunizations.  Responses to haemophilus influenza when administered concurrently in the primary series with pneumococcal conjugate vaccine was studied in the lot consistency study, 18-12, and in the manufacturing bridging study.  Responses to Hib-PRP were significantly enhanced with concurrent pneumococcal vaccine, as shown by increases in GMCs after the third dose.
Enhancement of Hib responses when administered concurrently with pneumococcal vaccine was also observed in other and supporting studies.  When administered with the fourth dose, differences in GMCs between groups were statistically significant for GMCs, however, it=s been pointed out, GMC is relatively high, 22.7, and responses at clinically significant levels were greater than 97 percent.
Responses to IPV following concurrent immunization with pneumococcal vaccine and IPV in the primary series was evaluated in a single study.  That was the manufacturing bridging study.  IPV was administered at two and four months of age.  Serum neutralizing titers were determined at seven months.  Data for the preferred manufacturing lot only is shown here.  Highlighted are responses to serotype one, for which the lower 90 percent confidence interval for the difference in percent zero responders at an antibody titer of one to ten was 13.3 percent, thus a ten percent difference could not be ruled out.
No interference was seen with polio type two and type three.  The clinical significance of this apparent interference with IPV one responses is not clear.  No other studies in the application address concurrent immunizations with IPV.
Compatibility with acellular pertussis responses in the primary series was evaluated in study 18-12.  The control group received concurrent vaccines only, and the table show data for the three private lots of pneumococcal vaccine were pooled for comparisons to control.  A four-fold rise in responses to Fimbriae was 45 percent versus 62.5 percent in the control group.  The 90 percent lower bound of the difference exceeded 30 percent.  Responses to pertactin were also lower in the concurrent pneumococcal vaccine group.  Pertussis toxoid and FHA antigens did not show decreased responses with concurrent pneumococcal vaccine, and no data are presented in the PLA addressing responses to pertussis antigens after four consecutive doses of DTaP. 
Concurrent use of pneumococcal vaccine and MMR were studied in a very small group of infants in an early supporting study, although no direct comparisons were made the percent seroconverters to mumps and rubella are low by historical standards.  The FDA does not view these data from this small study as definitive.
I=ll now talk a little bit about catch-up schedules. The sponsor has proposed a catch-up schedule for previously unvaccinated children, which is reproduced here from the vaccine label, from the proposed vaccine label.  The catch-up schedule is based on comparisons of immunogenicity data, using these regimens to antibody levels achieved after three doses by children in the efficacy study.
For the catch-up schedules proposed, available data are summarized in this table. Safety data are limited to 24 subjects who received three doses between seven and 11 months of age.  There=s no safety data for subjects, excuse me, for the age interval between 12 and 24 months of age, and for children greater than 24 months of age there=s only data available for use of the 9-valent formulation which was collected among Israeli infants.
An additional study intended to support catch-up schedules was recently received by FDA.  Data files supporting the study results have not yet been submitted to FDA for review.  Therefore, the committee will not be asked to comment specifically on the adequacy of the data to support the proposed catch-up schedule, however, general comments on catch-up are welcome.
This slide is intended to show that when pneumococcal vaccine is given concurrently with either whole cell or acellular pertussis vaccine GMC titers after the third dose are comparable.
The efficacy trial provided data to assess protection after three doses until the fourth dose was administered, and subsequently after the fourth dose, to make inferences about long-term C longer-term protection it may be important to assess antibody levels after dose four.  
In this table, GMC is attained using the various catch-up schedules, are compared to GMC schedule, GMCs attained in the efficacy study after doses three and four, so the efficacy study results are on the right and the proposed catch-up schedule data that is available from the proposed catch-up schedules is on the left, and it=s broken down by serotype.
Post-dose four GMCs exceeded two micrograms per ML for all serotypes.  Response to the fourth dose was least robust for serotype 19f.  Serotype 19f, which is the serotype of the only case of invasive disease among the fully vaccinated infants C for serotype 19f, which is the serotype that the only case of invasive disease among fully vaccinated infants in the pneumococcal vaccine group, GMCs obtained for the three dose catch-up schedule between seven and 11 months of age, which is 1.6 micrograms per ML, exceeds the levels achieved post-dose three, but does not achieve levels post-dose four.
That=s all I have to say about the catch-up schedules, and finally, an essential component of the license application is to demonstrate ability to scale up production from private lots used in the clinical studies to manufacturing scale lots.  Vaccine produced in manufacturing scale as compared to private lots, in terms of safety and immunogenicity, the sponsor prepared two full-scale lots for comparison in the manufacturing bridging study, the design is shown here, about 175 subjects were enrolled for each, for the pilot scale lot and for the two manufacturing lots.  Acceptable criteria for demonstration of bridging were less than a two-fold difference in GMCs, and less than a ten percent difference in sero responders.
Well, the most appropriate antibody level on which to base sero responsiveness engendered much discussion.  The antibody level associated with protection for invasive disease is unknown.  Moreover, it=s not clear that a single level is appropriate for each of the seven serotypes.
The antibody levels chosen to define sero responsiveness are illustrated in this slide.  The antibody levels chosen were based on the maximal difference between immunized and unimmunized infants at seven months of age, and so the black curve, or the one that looks like a parabola, that is the difference curve, and the top of the difference curve then served to define the sero responder level.
Threshold values were determined for each of the seven serotypes which are shown here.  This is a busy slide, but it does show that acceptance criteria for sero responsiveness were met for each of the seven serotypes.  You can look at the far column on the right, that is, 90 percent lower limit of the difference between sero response rates for the pilot and the manufacturing lots did not exceed ten percent.
GMCs was the co-primary endpoint in the bridging study. GMC criteria were also met for all seven serotypes, that is, the 90 percent lower limit of the ratio of GMCs fell between .5 and two, thus, FDA accepts that clinical evidence of bridging has been demonstrated.
The last couple of slides have to do with the lot consistency study.  This is the study designed for the lot consistency study.  The three lots, three private lots of vaccine were compared, 75 subjects were enrolled for the group, and infants received concurrent immunizations.  The criteria, acceptance criteria were that GMCs would not differ by more than two-fold.  The multiple comparisons were, by nature, seven serotypes and comparisons between three lots, there were multiple comparisons, actually three comparisons marginally exceeded the criteria.  However, because they only marginally exceeded, and because of the multiple comparisons FDA does accept the clinical evidence of lot consistency as demonstrated.
Well, that concludes the presentation.  I=ll now present the questions to the committee, and then this afternoon we=ll represent the questions.
Do the data provide sufficient evidence of efficacy against invasive disease for Prevenar as it was studied in the efficacy trial, that is, after administration at two, four, six and 12 to 15 months of age?  If not, what additional information should be requested?
The second question, do the data provide sufficient evidence of safety for Prevenar?  If not, what additional information should be requested?
The next two are not questions, but number three reads, please discuss the data regarding concurrent use of Prevenar with other vaccines administered according to the recommended schedule of infant and childhood immunizations.
And, lastly, please provide C please identify any issues that should be addressed by post-marketing studies.
CHAIR GREENBERG: Thank you, Doctor Pratt.
We now have a little more time for the panel, for the committee to ask some questions, and I would remind you that you can address Doctor Pratt, or if you have some lingering questions from the manufacturer, for the manufacturer, perhaps, you could bring them up now.
I know Doctor O=Brien had a question.
DOCTOR O=BRIEN: I did, but I think Doctor Pratt answered it, but I=m going to make sure he did, so this is actually addressed to Doctor Pratt.
I was concerned by the fact that there were eight percent African Americans represented in the Kaiser study, and whether or not they=d be able to show in the efficacy data that in that group which appears to have an increased susceptibility to pneumococcal invasive disease, that they could show some efficacy in that group. But, because Doctor Pratt said that there was a higher representation of African Americans in the invasive disease group, which pretty much was the control arm of the study, I feel more comfortable that they were able to show that even in this more susceptible group there appeared to be efficacy.  That=s my summation from what Doctor Pratt said.
CHAIR GREENBERG: Does anybody want to comment on that summation, or was it just simply C you can simply say it=s correct if you want.
No comments?  Okay.
Doctor Snider?
DOCTOR SNIDER: Doctor Black made comments about multiple comparisons, when he was talking about health outcomes.  Doctor Pratt just talked about multiple comparisons and he talked about lot consistencies, but nobody talked about multiple comparisons when they were talking about the interference or potential interference between vaccines, but I wondered if someone had looked at that and whether there are patterns there that should be of concern to the committee.
It=s hard for me to dig out from what was presented to us whether there is a pattern of the 7-valent pneumococcal conjugate vaccine seeming to diminish responses to certain things, increase responses to others, or whether there is a pattern toward diminished responses, which I think would be quite different.
So, if someone could clarify those comparisons for me a little bit better, I would appreciate it.
CHAIR GREENBERG: In order to C I=ll ask first Doctor Pratt if he wants to, for the FDA, to clarify, and then ask the manufacturers whether they have anything additional to add.
DOCTOR PRATT: Yes, I think multiple comparisons are an issue.  I think that C
DOCTOR GOLDENTHAL: Well, I think that there were some differences that, perhaps, the committee should look at and focus on.  I think for the IPV it was polio type one, and for pertussis there was some differences known for pertactin and fimbriae.
These, you know, in talking C but there were no differences noted for pertussis toxin C in talking with regard to pertussis, in talking with staff of the pertussis labs who deal with this on a very regular basis, they thought it was difficult to make an exact clinical determination C you know, a clinical correlation, if you will, to these differences.
With regard to IPV, it was pretty close.  It was, I think, 89 percent with simultaneously administered 7-valent pneumococcal vaccine.  So, these may be, you know, again, they are multiple comparisons with the C even within looking at pertussis there were multiple comparisons, so I think that=s something that can be considered.
This also might C you know, these also might be things that are addressed with post-marketing studies.
CHAIR GREENBERG: I=m going to just push you a little bit, Doctor Goldenthal.  That was a perfect C that was a politically correct answer, but I=m not sure that was all C it wasn=t, for somebody like me, a dummy, that wasn=t that helpful an answer.  So, the critical question here, is it clinically relevant, do you think that this vaccine is going to affect other vaccines, and let=s just take polio, that was the simplest one.  Is there the feeling, when you talk to your colleagues about the effect of the 7-valent pneumococcal vaccine, that there=s a worry that it affects immunity to polio type one after delivery?
DOCTOR GOLDENTHAL: I believe that we would accept those data.  However, we still may ask for an additional follow-up study.
CHAIR GREENBERG: I think the key here is with all vaccines we want additional follow-up study, but the most important thing for the committee to know is whether you think that C what=s your likelihood that there=s going to be a real biologic effect.  So, you are saying you think there probably would C your bet is no.
First, Doctor Myers, then Ms. Fisher.
DOCTOR GOLDENTHAL: By the way, let me just add one thing about polio, that antibody was assessed seven C at the seven month time point, and the doses of polio vaccine were given at two and four months.
DOCTOR MYERS: A related question, I was wondering, has concomitant use of other HIV conjugate vaccines been examined for interference?  The HIV conjugate data presented was with the same CRM197 carrier protein, but what about outer membranes, protein conjugates and so on?
CHAIR GREENBERG: Can either the FDA or the manufacturer answer that question?
Doctor Siber?
DOCTOR SIBER: Let me comment on the first question from Doctor Snider, and then address Doctor Myers= question.
I think you can divide the apparent differences and responses with and without pneumococcal vaccines into two types.  The ones that have already been addressed of unrelated antigens, where I think mechanisms are pretty unclear, where many, many comparisons were done where some differences were found.
And then the second group is ones which are with antigens that are related in the sense that they have the same carrier, and so we did see significant and convincing evidence of interactions between the Hib vaccine using the same carrier as the pneumococcal vaccine.
We were fortunate that in the primary series, when we were most concerned about producing antibody levels quickly, that was a positive interaction, and the way at least one immunologic theory for that is that it limits how quickly you make antibody to the polysaccharides is how much T-cell help you have induced to the carrier molecule CRM, and during the primary series that seems to be better when you have more CRM in the form of conjugate.
We also showed that there was a significant reduction at the time of boosting in the response to Hib, and that=s a kind of interference, and although significant, because the levels were very high it didn=t seem to be of clinical importance.
The question Doctor Myers asked is, what would one see with an unrelated carrier, such as a tetanus-based pneumococcal conjugate or a tetanus-based Hib conjugate would be more relevant, we don=t have data addressing that, but the theory I=ve just mentioned would suggest there wouldn=t be a problem by adding a CRM-based pneumo conjugate to a regimen where Hib T was being used, or Hib O and P was being used, but we don=t data directly addressing the question.
CHAIR GREENBERG: Thank you, Doctor Siber.
Ms. Fisher?
MS. FISHER: Yes, I have two questions, one to Doctor Platt and the other to the vaccine manufacturer.  But, Doctor Platt, I want to congratulate you on this analysis that you provided to the committee, I thought it was excellent.
I guess I=m confused.  We are being asked to look at invasive disease efficacy.  What is the efficacy rate with this vaccine with all the data that you have, with regard to invasive disease?
DOCTOR PRATT: At the primary analysis, it was 100 percent.  At the follow-up analysis, my understanding is it=s 97 percent, or in that range.
MS. FISHER: With invasive disease, okay.
The manufacturer, local reactions, fever, irritability, drowsiness, decreased appetite, seizures, are more frequent in the pneumococcal vaccine group when compared to controls.  Has the manufacturer tried to determine the biological mechanism for these increased local systemic and neurologic reactions, and whether there are genetic or other differences in the children who are suffering these reactions versus those that are not?
DOCTOR SIBER: I think we need to discriminate between the reactogenicity of the vaccines, such as tenderness, and pain, and redness, and swelling, fever, which I think is seen with all vaccines essentially, to a greater or lesser extent, which are mild transient, self-limited.  Those were, I think, with this vaccine in a similar range that we have seen with childhood vaccines generally, and we were not alarmed by them, and I must say the mechanism presumably is that there are lymphokines released and cytokines released in the course of a normal immune response, and it=s part and parcel of inducing immunity in people, you can=t avoid that.
With regard to rare severe events, I think you saw quite an extensive and elegant database that our colleagues at Kaiser have assembled of baseline rates of rare severe events, chronic events, compared to the two groups that we have studied, and a very large number of children, and all we can do to further hone that down is to also look at intervals close to vaccine administration for any suggestion of a temporal relationship.
And, our interpretation of those data were that we really couldn=t see anything that suggested a relationship to a severe event.
CHAIR GREENBERG: Any C Doctor Stephens?
DOCTOR STEPHENS: I have a couple of questions regarding the surveillance part of the Kaiser study, and that had to do with whether there  were C was antigen positivity looked for in culture negative cases in meningitis, for example, and was that a part of the study?
DOCTOR BLACK: We did not look for that, because the primary outcome here was serotype specific efficacy, and there really is not a technology that I=m aware of to look at that.
And, antigen tests are done at the physician=s discretion, but we did not do them, institute them, as part of the study design.
DOCTOR STEPHENS: The second question as a part of the surveillance has to do with how many children were, in fact, lost from your surveillance pool, and, obviously, there were a number of children who received one dose and then were subsequently lost.  Do you have that exact C that number?
DOCTOR BLACK: Overall, about 15 percent of the total follow-up time was lost due to drop out over the study period of about four years.  Does that answer your question?
DOCTOR STEPHENS: And, that drop out was both children who may have moved or left the area, and children who decided not to complete the course of the study.
DOCTOR BLACK: Well, children who did not complete the course, the children who were still members of the health plan were contacted by the study nurses routinely to try and get them in, but, obviously, we could not coerce parents to come in, it=s a voluntary participation.
The total number that actually went on to get dose four, for example, by the end of the 15th month, was C most of the children in the study did continue participation throughout.  In terms of cases, I guess what you are asking, could a case occur outside that we would not be aware of.  You know, there were cases of disease and adverse events were identified outside the system, we tried to the best of our ability to identify all cases.  We are not aware of any cases that occurred outside the system, either in people who were members of the health plan or people who had left.  And, people within the area where we were at were aware of the study, had been contacted, and had been asked to report any events back to us.
DOCTOR STEPHENS: Did you say there were two additional cases since the April analysis was submitted?
DOCTOR BLACK: There have been two additional cases.
DOCTOR STEPHENS: In vaccinated individuals?
DOCTOR BLACK: In vaccinated individuals. They are both in the control group.
CHAIR GREENBERG: Doctor Estes, and then Doctor Globe.
DOCTOR ESTES: In the C when you had children dropping out and not finishing the fourth dose, did your study nurses ask the parents why they didn=t want to continue, or was that not possible?
DOCTOR BLACK: The most common C you know, we had children, there were about three percent of children who were still members who did not go on to get their C did not go on to get their fourth dose within that time period.  A substantial percentage of those did receive the dose, but after that time window.  It has to do with this many people, 97 percent we actually thought was pretty good.
CHAIR GREENBERG: Doctor Globe.
DOCTOR GLODE: I had sort of a two-part antipyretic question for Doctor Black.  Don=t leave.
If I recall, someone this morning, and I don=t recall if it was you, that were talking about excess visits for ingestion/poisoning, and I=m wondering, were any of those, you know, accidental Tylenol overdoses from treating fevers, or febrile seizures, or whatever?  That=s part one.
DOCTOR BLACK: Okay.  We looked at those over in terms of time period in a similar graph to what I showed you this morning, and they are spread out also over the surveillance period.  We=ve not looked to see which ones are due to Tylenol and which ones are not.  We=d have to go back and do that, but there was no clustering of those events close to receipt of vaccination.
DOCTOR GLODE: I see, and the second part of that was, in the actual design of the study, were the patients that were enrolled specifically not given any antipyretics at the time of administration of the vaccine, but then what type of instructions were given to people about using antipyretics?
DOCTOR BLACK: Yes, the use of antipyretics was at the discretion of the physician, and actually it=s one of the questions we asked during the telephone interview, and I can tell you that with children who received the whole cell vaccine that antipyretics were used routinely in about 90 percent of those children, and that number is about 80 percent in the DTaP recipients.
DOCTOR GLODE: But, used not at the time the vaccines were administered in the physicians= office, but used later by the family?
DOCTOR BLACK: No.
DOCTOR GLODE: Oh, used at the time.
DOCTOR BLACK: Used at the time.  That=s distinct at our site from the Colorado data where it was not used routinely.
CHAIR GREENBERG: I=m going to let this go a little further, because this is important.
Doctor Ferrieri and then Pamela Getson, who is in the audience, who is an FDA statistician over there, and then Doctor Daum.
DOCTOR FERRIERI: I had a different type of question for the sponsors.  Do we have an understanding of the genes that regulate the synthesis assembly of pneumococcal polysaccharides as we have some notion of in Group B Strep., and if you know this then do you see some future for application of PCR to address the question about looking for other serotypes that were not vaccine, or that might have been the vaccine serotypes on body fluids such as CSF.  Where are we in our state of knowledge on applying that type of basic science to the diagnostics?
DOCTOR SIBER: There is quite a bit of understanding, which I=m not an expert in, there=s an advocate locus where capsules are made. They are typically clustered genes, and it=s a particular locus in the pneumococcus, which is one of the reasons that the capsule machinery can be exchanged by transfection.
My understanding of the PCR assays that have been developed to date for the pneumococcuses, they have not focused on the capsule machinery for the probes, but for some common DNA sequences, common to all pneumococci.
Theoretically, it may be possible to get type-specific probes, but to my knowledge, unless somebody else in the audience can comment, that hasn=t been done yet.
DOCTOR STEPHENS: Such assays are being developed for meningococci, for example, and are working actually quite well.  I don=t see why they couldn=t be developed for pneumococcus.
DOCTOR FERRIERI: I know that.
CHAIR GREENBERG: Doctor Getson?
DOCTOR GETSON: I=d like to make sure that we are all clear about both what we in CBER FDA presented, as well as our response and the committee member=s question regarding race and ethnicity.  We are going to try to put up our slide, and Doctor Pratt can speak to it if necessary, but I want to be clear about something that I think I heard different in terms of the question from the committee member, Doctor O=Brien.
Here on the top two lines you see the relative representations of the different ethnic groupings that were in the efficacy study.  Below the middle line you begin to see the relative proportions represented among case invasive disease, and you see the 17, the 40 and the 61 represent the various time points for which these analyses were produced.
Now, when I use the word over representation, I think sample, and I believe our committee member had a question that would most closely parallel over representation in a sample.  That is not what this slide can give you information on, and, perhaps, you want to revisit, in fact, the question you were asking.  The over representation would be among the invasive disease cases, and clinically Doctor Pratt can comment more, or, perhaps, you want to go back to the committee with questions.
DOCTOR O=BRIEN: That=s exactly what I meant, though.  If they are over represented in the invasive diseases, and since the vaccinated group overall with the pneumococcal vaccine were not getting the invasive disease, I felt better that we would be able to see a difference in that small subset of more susceptible individuals.
DOCTOR GETSON: Good.  Several of us weren=t sure whether you had intuitive that there was an over representation per the sampling.  So, we wanted to get that slide up so it was clarified.
DOCTOR O=BRIEN: No.
DOCTOR GETSON: Good.
CHAIR GREENBERG: And, I think Doctor O=Brien had it right, and C 
Doctor Daum?
DOCTOR DAUM: I have a comment and then a question for FDA colleagues. The comment is that in addition to capsular typing there are a number of DNA based technologies in place and being developed for differentiating, or fingerprinting, if you will, different pneumococcal isolates.  And, I think that in terms of following serotypes and changes in epidemiology following introduction of immunization, these will be helpful and I have no doubt that more people will get involved with looking for genes that are sufficiently genetically diverse that allow fingerprinting by molecular-based techniques.
The question that I have is, we=ve heard some data from Doctor Pratt about inferences regarding the protective concentration of antibody based on the trial that we saw this morning, and I guess I=m anticipating that things are going to go smoothly in terms of approval of this vaccine, and I=m looking down the road to think that there will be other vaccines introduced for consideration, and wondering whether the FDA has given any thought yet to bridging, or how to bridge between what we saw this morning and different candidate vaccines, and whether the numbers that Doctor Pratt showed us, as best guess estimates of protective antibody concentrations, will, in fact, be those bridges.
CHAIR GREENBERG: I=m just going to C that is a question that even somebody out of the field like myself realizes could take two to six days to answer.  So, give us, you know, a global point of view, since we don=t have to have a definitive answer at this point.
DOCTOR GOLDENTHAL: That will be the subject of a future Advisory Committee meeting, but actually I can make a couple of quick comments.  You know, it=s a difficult area.  I mean, because the vaccine was so highly effective there were C and relatively few failures, and in addition to that there wasn=t correlation between post-vaccine immune response in even those few failures in the study that really I don=t believe that it=s possible to say exactly, you know, what level is protective. 
In the event that an immune C that some type of an immune response would be acceptable, I think the most logical approach would probably be one of looking at the immune response of a different vaccine, if you will, with using a non-inferiority approach, with a pretty tight confidence limit.
CHAIR GREENBERG: I am going to call a halt now.  It is now, by my watch, 12:20, and I=m going to resume right on time with the schedule, so we have 20 minutes for C we can have one question now from our statistician, and then you are all back at 12:40 to continue.
DOCTOR HARTIGAN: I have a question for the FDA.  How concerned is the FDA in considering safety that the control group in the major study was not an active control, and was not an approved product?
DOCTOR GOLDENTHAL: Well, we would agree that that does pose certain limitations, and the data have to be viewed in that context, including the reactogenicity data.  I mean, you know, I think Doug covered it quite well in his presentation.  I think that there is, you know, additional local and systemic reactogenicity added by having the 7-valent pneumococcal vaccine.
In terms of comparing some of the unusual events, I think that the comparison to the pneumococcal C to the meningococcal vaccine can still lend itself to some valid analyses.  Obviously, we are also interested in some of the historical background rates of some of these events, but I would agree that having the meningococcal vaccine as the control does add a complexity to the interpretation of the data.
CHAIR GREENBERG: Okay.  I=m going to close it down.  I=ll see you all in about 12 minutes, about 17 minutes.
(Whereupon, the meeting was recessed at 12:23 p.m., to reconvene at 12:43 p.m., this same day.)

	A-F-T-E-R-N-O-O-N   S-E-S-S-I-O-N
	(12:43 p.m.)
CHAIR GREENBERG: If people could take their seats, please.  I think we need to hand out complimentary Tums along with C
Does the manufacturer make an H2 blocker or a proton pump inhibitor?
So, again, I=d like to thank all of you for being so expeditious, and I=m sorry to push you so hard, but I really want as many panel members as possible here to go over the questions.
So now, we are going to have, and again, please, everybody stick to your time limits or be quicker, so now we are going to have Doctor Kilpi from Finland give us a brief talk about otitis.
DOCTOR KILPI: Thank you, and good afternoon, everybody.  It=s an interesting experience for me to be here.
I=m going to tell you about results of the Finnish otitis media vaccine trial, which evaluated the efficacy of C conjugate vaccine against acute otitis media.
This was a large trial and, therefore, we had a very big study group, too, and these are the names of persons responsible for certain key areas in the trial.
The clinical phase of the study was started in December, >95, and ended in March, >99.  The study was conducted in Finald in Tampere, which is in the Finnish scale a middle-sized city with a population of 200,000, and in two smaller municipalities, Nokia and Kangasala, which are located close to Tampere.
During this time, we enrolled 1,662 children in the trial, and they were all randomized to receive either Pnc CRM or the control vaccine which was hepatitis B vaccine in our trial.
The children were followed from two to 24 months of age at study clinics which were especially established for the follow-up.  The follow-up consisted of scheduled visits and sick visits, and the aim was to evaluate and treat all respiratory infections requiring medical attention at the study clinics.
And, these were the vaccines used in the study, so all these children received either Pnc CRM vaccine or recombinant hepatitis B vaccine in a randomized fashion, blinded fashion, at two, four, six and 12 months of age.  In addition, they received whole cell DTB Hib combination, IPV and MMR.
This was the definition for acute otitis media we used.  First of all, we required that there has to be symptoms of acute infection, which could be almost anything, fever, earache, irritability, diarrhea, vomiting, otorrhea or any symptoms of respiratory infection, and then there had to be some signs of acute otitis media that is a visually abnormal tympanic membrane suggesting middle ear effusion.
In this trial, we really wanted to know what is the microbial course behind the case, what causes the acute otitis media, and that=s why whenever acute otitis media was diagnosed myringolomy was performed and a middle ear fluid sample aspirated for bacterial culture and chemical serotyping when needed.
We also need a definition for acute otitis media episodes for our analysis because as you very well may know acute otitis media is something that tends to repeat in the same individuals over and over again.  And, we defined that acute otitis media episode starts at diagnosis and lasts for 30 days, so after 30 days a new episode could start.
We also focused on safety.  The parents were asked to record local and systemic reactions on diary cards on the first, second and third day after each vaccination.  Information on all serious adverse events was collected and reported, and also in this category the unexpected adverse events considered possibly, probably or definitely related to the study vaccine were reported.
Randomization went very well.  We have 831 children in the Pnc CRM group and the same number of children in the control group.  Our discontinuation rate was very low, 82 subjects had to be excluded from the per protocol analysis at some point, and only 65 dropped out from the follow-up, so that=s four percent of all.
Here are some baseline characteristics of the study population, just to show that there is no over representation of either sex, prematurity, low birth rate in either of the treatment groups.  Maternal education score was also very similar in the treatment groups, and so was the number of children living in the same household.
Daycare attendance is a known risk factor for acute otitis media, and in our study the proportions of children attending either daycare center or family daycare were similar in both treatment groups throughout the follow-up.
Breast feeding was also equally common in both treatment groups, 54 percent of the children were breast fed for longer than six months, and very few families admitted smoking.
Okay, then to the results.  This is the only slide I=m going to show about local reactions, but it very well represents the whole picture.  This is tenderness.  Local reactions after Pnc CRM vaccines were more common than after hepatitis B vaccine, but on the other hand they were less common than after either the Hib combination that was given concomitantly with the first, second and third dose of the study vaccine.
Fever was more common in the Pnc CRM group after vaccination than in the control group, and this may be a little bit confusing to look at the rate of proportion of those with fever increases dose by dose and then suddenly drops, but I can remind you of the concomitant vaccine which was here, DTB Hib, whole cell DTB Hib combination and here IPB, so that explains it.
There were 160 SAEs, serious adverse events, or related unexpected adverse events in the Pnc CRM group, and 194 in the control group.  None of them was assessed by the investigators to be probably or definitely related to the study vaccines, and ten were considered to be possibly related to the study vaccines.
And, this is what they were, there were altogether six events in the Pnc CRM group, four of them were skin reactions.  They were not serious adverse events, did not result in hospitalization, but were considered unexpected by the investigators and were, therefore, reported in this category.  There was one event with a case of independent neurologic symptoms, which was a child hospitalized because of excessive crying, had at the same time fever and the child had just received DTB Hib combination and Pnc CRM vaccine, had also local reaction on the DTB Hib site.
This one other reason was a transient neutropenia case.
Here are some of the more severe serious adverse events which were not considered to be in any way related to the study vaccines.  There was one death in the Pnc CRM group which was caused by intestinal obstruction due to congenital malformation.  There was one hypotonic hyporesponsive episode in the control group and one invasive bacterial infection in the Pnc CRM group.  This was caused by C a non-vaccine serotype for invasive bacterial infections in the control group.  Two of these were pneumococcal infections caused by vaccine serotypes, one pneumococcal disease caused by a non-vaccine serotype and one meningococcal meningitis.
Okay.  Now, I=ll move on to efficacy.  First of all, we looked at AOM, acute otitis media, regardless of etiology, how many episodes there were overall.  In the Pnc CRM group there were 1,251 acute otitis media episodes, and in the control group 1,345 episodes, which means that the vaccine reduced the number of any AOM episodes by six percent, and the difference between Pnc CRM and control group is not here statistically significant.
Okay.  Then we looked at culture pneumococcal acute otitis media, irrespective of serotypes, and there were 271 episodes caused by pneumococcus in the Pnc CRM groups and 414 in the control group.  The vaccine efficacy against pneumococcal acute otitis media was 34 percent and this time the difference is statistically significant, 95 percent confidence intervals are from 21 to 45 percent.
This was our primary endpoint, acute otitis media due to vaccine serotypes, and this is our primary analysis which is the per protocol analysis. The per protocol follow-up period started 14 days after the third dose. And, during this follow-up period we had 107 AOM episodes due to vaccine serotypes in the Pnc CRM group and 250 in the control group, and, thus, the vaccine efficacy against acute otitis media due to vaccine serotypes is 57 percent, 95 percent confidence intervals are from 44 to 67 percent.
These are the results for the same endpoint analyzed by intention to treat, and the intention to treat follow-up period started on the day of the first vaccination, and here the efficacy looks very similar, it=s 54 percent.
We also looked at vaccine efficacy by dose, so from dose one to dose three, et cetera, and there seemed to be some efficacy already after the first dose, it increased after second dose, and reached kind of steady state after the third dose.  So, the endpoint is acute otitis media due to vaccine serotypes.
And, this is the summary of the efficacy results, vaccine efficacy against acute otitis media due to vaccine serotypes, 57 percent, pneumococcal acute otitis media overall 34 percent, and any acute otitis media six percent.
And, the FinOM study group concludes that heptavalent pneumococcal conjugate vaccine Pnc CRM is safe, it causes more local reactions than hepatitis B vaccine, but significantly less than DTB Hib combination.
There were fewer serious adverse events in the PRC CRM group than in the hepatitis B vaccine group, and there was no apparent association of any severe events with Pnc CRM vaccine.
We also conclude that the vaccine is efficacious against culture confirmed serotype specific acute otitis media and culture confirmed pneumococcal acute otitis media.
Thank you.
CHAIR GREENBERG: Thank you, Doctor Kilpi.  
We have time for a few questions, if there are any.
I=m sorry, Doctor Kim?
DOCTOR KIM: Can you somehow elaborate the phases of protection against acute otitis media following vaccines?  So, what is the sort of postulated mechanisms of protection against acute otitis media?
DOCTOR KILPI: You mean how the infection that is actually here kind of superficial can be prevented by a vaccine.  Well, the assumption is that the antibodies affect also the mucosal surfaces, but we don=t know about that yet.  We have collected saliva samples to assess that.
CHAIR GREENBERG: Doctor Daum?
DOCTOR DAUM: I have two questions for you.  The slide went up and down quickly, and I may not have read it right, and apologize if I=m wrong, but I thought I saw some efficacy estimates after various numbers of doses, and I thought that the first two doses had very wide confidence intervals, which had wide overlap with zero.  And then, I thought you said that the vaccine already had efficacy after one or two doses.  Did I misunderstand?
DOCTOR KILPI: I said the vaccine seemed to have efficacy.
DOCTOR DAUM: Not to mince words here, but do you want to revise that statement?  I can go on to my second question, I guess.
CHAIR GREENBERG: Why don=t you go on to your second question.
DOCTOR KILPI: Yes, it=s not statistically significant after dose one and dose two, between the interval, no, but the trend I think is very beautiful.
DOCTOR DAUM: The second question is, as I recall this trial initially had more than one pneumococcal vaccine in it.  Can you clarify that for us and tell us what happened to the others?
DOCTOR KILPI: The vaccine had C the trial had three arms throughout, and there were two conjugate vaccines involved, and the evaluation of the third arm, which was another pneumococcal conjugate vaccine, that has not yet been done.
CHAIR GREENBERG: Doctor Stephens?
DOCTOR STEPHENS: Was ear tube placement looked at as an endpoint in this study?
DOCTOR KILPI: It was not an endpoint in the analysis plan or in the protocol, and we are going to do the analysis, but it has not been yet done yet.
CHAIR GREENBERG: Okay.
If there are no other questions, I think we can move on and, Doctor Pratt?  Okay, excuse me, I=m  sorry, I=m moving too quickly.
Questions, comments, summary and presentation of questions.
Yes, Doctor Pratt, you are up, Doctor Pratt.
Ah, Doctor Black?
DOCTOR BLACK: Thank you, Harry.
I just wanted to make one quick comment in response to Doctor O=Brien=s question, in terms of race specific efficacy.  We did, during the brief lunch, look at the case split in African Americans, and the per protocol analysis the case split is 11 and the control group zero in the pneumococcal group, and in the intent to treat analysis that=s 13 in the control group and one child who was partially vaccinated with one dose in the pneumococcal group.
DOCTOR O=BRIEN: Thank you.
CHAIR GREENBERG: What I=d like you to do, Doctor Pratt, is just go over these questions again, and then we=re going to have an opening to public hearing, where people in the audience who wish to make a statement can, and then we will return to these.
DOCTOR PRATT: Okay, sure.
Questions for the committee are these, do the data provide sufficient evidence of efficacy against invasive disease for Prevenar, as it was studied in the efficacy trial that is, after administration at two, four, six and 12 to 15 months of age?  If not, what additional information should be requested?
Number two, do the data provide sufficient evidence of safety for Prevenar?  If not, what additional information should be requested?
Three, please discuss the data regarding con current use of Prevenar with other vaccines administered according to the recommended schedule of infant and childhood immunizations.
And, number four, please identify any issues that should be addressed by post-marketing studies.
CHAIR GREENBERG: Thank you, Doctor Pratt, and, committee members, as you listen to the open public comments I=d like you to cogitate on these questions and formulate your thoughts in a very clear way.
Do we have anybody in the audience who wishes to make a public statement?  Could you please identify yourself?
DOCTOR CLASSEN: My name is Bart Classen, I=m a vaccine researcher, and today I=m going to talk to you about our data that was published two weeks ago in the British Medical Journal, suggesting that the haemophilus vaccine C haemophilus influenzae B vaccine is likely to cause insulin-dependent diabetes.  The reason this is pertinent to today=s discussion is that we=ve heard from several people that the haemophilus influenzae B vaccine is very similar to what is in the pneumococcal vaccine, in that they are both conjugated polysaccharide vaccines.  The difference is the haemophilus influenzae B vaccine is a single vaccine, it=s against a single capsular strain of organisms, whereas the pneumococcal vaccine that we=re discussing today is really seven different vaccines, it=s against seven separate strains, capsular strains of pneumococci.
We are going to talk about insulin-dependent diabetes, which is an autoimmune disease.  It=s a marker for other autoimmune diseases, but it is relatively easy to study compared to other autoimmune diseases.  The theory, or this data is that as you stimulate the immune system you are going to increase the risk of autoimmunity.  We were able to follow up on a large prospective clinical trial in the haemophilus influenzae B vaccine in Finland, essentially, all children in Finland over a two-year period were put into this study, it=s 114,000 children, which would range by having either received four or one dose of the haemophilus vaccine.  And, because of the design of the study the control group were the children that were born in the two years prior to the study.
And, this is some of the data. It=s important to note that the data that Doctor Black said that were only about two years follow-up, and the curve was essentially identical at two years, they separate starting around three and a half years, and you get really nice separation around seven years.
And, this is the data with ten-year follow-up.  There are an extra 58 cases of diabetes in the group that got four doses versus the group that got no doses, and then there are about 36 extra cases per 100,000 in the group that got one dose.
What we want to do is get some additional data support causality, and so we did some subgroup analysis looking at the five to nine year old children.  And, as you can see here, there is an increase in diabetes, about an extra 32 cases per 100,000 in the groups that were five to nine, versus the group that didn=t get vaccine.
And, here=s the temporal data.  This is the instance of diabetes in Finland year to year from 1967 through 1995, and what you see is in the five to nine year old period it had been stable for about ten years or more, until the group that got the vaccine entered this age group and then the instance of diabetes shot up quite dramatically.  The incidence also had shot up after the measles, mumps, rubella vaccine had been added, and after a more potent pertussis vaccine had been added as well.
But, the take-home message with the haemophilus vaccine is that we had a very straight incidence of diabetes until the haemophilus influenzae B vaccine group reached this age group.  This is strong support for causal relationship.
Other data that support a causal relationship is that in other areas of the world, where the haemophilus vaccine was added, we=d expect that we=d see a rise in diabetes, in fact, that=s what we saw.  Several centers now in the U.K. have reported rises in diabetes following the haemophilus influenzae B vaccine.  This is Oxford, which is one of the first regions in the U.K. to give the haemophilus influenzae B vaccine, and, again, it was started around 1990 in Oxford, and then there=s a delay, as we saw in Finland, and then we see this rise in diabetes.
And, in the United States, probably the best diabetes registry is Pittsburgh, and we see that post introduction to haemophilus influenzae B vaccine in the zero to four year olds we see this more than doubling of the risk of diabetes.  
Risk benefit, well in the Finnish study we saw that this early vaccine, the Connaught vaccine, which we were studying the PPRD, was associated with 58 cases of diabetes per 100,000. Now, if that vaccine were 100 percent effective, 100 percent effective, it is supposed to prevent seven deaths and brain damage in seven of 26 kids.  So, you can see that the adverse events, when we are looking at only one autoimmune disease, diabetes, is several fold greater than what the benefit is.
Now, again, the pneumococcal vaccine is really seven vaccines, so you could expect to see that the adverse reaction would go out significantly more and the benefit of the pneumococcal vaccine is expected to be less than the benefit of the haemophilus vaccine.  So, the benefit would be substantially less.
Now, in the early PPRD vaccine which we studied, it was associated with about 58 cases of diabetes per 100,000.  We have a birth cohort in the U.S. of about 4 million kids, if we immunized all the kids for a ten year period, ten birth cohorts, we=d expect an extra 24,000 cases of diabetes.  Now, I said that we studied the PPRD, which was one of the first generation conjugated haemophilus vaccines, as the more potent second generation conjugated haemophilus influenzae B vaccines entered the market in Finland the extra risk of diabetes increased to about 100 cases per 100,000, so this would translate to about 40,000 children, extra cases of diabetes in this country, if we immunized ten birth cohorts.
Now, again, the pneumococcal vaccine is seven vaccines, so if we immunized ten birth cohorts we may have, in fact, an extra 280,000 cases of diabetes, that=s a quarter of a million people, assuming that there was a direct correlation between one vaccine and seven vaccines.  This is a tremendous risk to society.
Now, the Food and Drug Administration is guided by the U.S. laws, and the U.S. laws are written in Code of Federal Regulations, which say that vaccines must demonstrate safety before being put on the market.  We=ve proved that the haemophilus influenzae B vaccine has never been demonstrated to be safe.  We, in fact, proved that the pneumococcal vaccine, which you=ve heard about today, has not demonstrated safety either.
Now, Jean-Pierre Allain is a famous French, or infamous French public health official, who gave HIV positive blood products to hemophiliacs.  He, and about three other public health officials, went to jail for this, for blatant disregard to the law.
From his actions, maybe 400 people have died.  The issue is that when we are looking at giving the pneumococcal vaccine to everybody in the country, you know, all the children in the country, we are looking at mortality that may exceed 250,000 individuals, so clearly it=s potentially much worse than what Jean-Pierre Allain has done.
And, my last slide, one of the reasons the French were very upset with their public health officials was that, first of all, there were ways of testing blood products for the contamination of those viruses, and there were also ways of inactivating viruses in blood products.  Well, the same way with vaccines, there are ways of testing vaccines for their ability to induce diabetes, as we discussed, and there are also ways in which vaccines can be given without increasing this risk, and this is just one possible mechanism, the CDC=s own data showing that immunization starting in the first month of life is associated with a decreased risk of diabetes in both groups, both studies, two separate studies, compared to when the hepatitis B vaccine was given at eight weeks of life.  So, this is just proof of point that, in fact, we don=t need to just blindly give children vaccines and expect, well, we are preventing pneumococcus, we must be doing good things.  In fact, if we take our time we can find ways of having both worlds, preventing infections, as well as not inducing the risk of autoimmunity.
That=s all I have to say, thank you for the time.  Any questions, I=d be more than happy to answer them.
CHAIR GREENBERG: Thank you, Doctor Classen.
For the record, can you identify your affiliation?
DOCTOR CLASSEN: I am President of Classen Immunotherapies.
CHAIR GREENBERG: Thank you.
We have another C well, first, are there any questions?
If not, we have out next C thank you very much, Doctor Classen C we have our next open hearing speaker, Ms. Newby.
MS. NEWBY: Hello.
Thank you for letting me speak today.  My name is Carla Newby, and I serve as the General Manager for the Meningitis Foundation of America.  I=m speaking today in support of this vaccination, not only on behalf of the Foundation, but also as a mother whose son died from pneumococcal meningitis.  One year and one week ago, October 28, 1998, I was forced to watch my youngest child, an only son, die from pneumococcal meningitis.  Jacob passed away only one month before his 7th birthday.
As you well know, the only way to determine for sure if a patient has meningitis is to perform a spinal tap.  That=s a problem.  Some doctors refuse to do spinal taps.  At best, it seems the doctors often delay the order of a spinal tap.  Either way, the necessary antibiotic treatment is often delayed.  The tragic result is that children commonly suffer lifelong disabilities, or in the case of my son and many others die from this disease.
In my role at the Meningitis Foundation, I hear the same story over and over again from parents throughout the country, from parents who have had their young babies die from pneumococcal meningitis, as well as from parents of school-aged children and even young adults, the children who suffer this disease and the parents who bear the heartache for the rest of their lives are from all walks of life, rich, poor, middle class, all ages and all races.
My son Jacob was an all American kid.  He had no special medical problems.  He had none of the special conditions that would have made his doctor think that he should receive the existing pneumococcal vaccination, but he still got pneumococcal meningitis and we watched him die.
Prevention of pneumococcal disease is clearly the answer to avoid these tragedies.  The vaccination you are considering today offers promises of preventing pneumococcal disease in millions of children.  The clinical trials have demonstrated how effective it can be in protecting children against the most serious forms of pneumococcal disease.  I strongly urge you to support and approve this vaccination, and that you do everything possible to make it available to children as quickly as possible.
All of us have heard the complaints about the number of vaccines our children now receive.  Maybe those people have complaints C have never experienced first hand the tragedy of a loved one suffering from a serious disease that could have been prevented from a vaccination.  Believe me, none of us who understand the devastation pneumococcal disease can cause will ever complain about too many shots. We want to do everything humanly possible to prevent disease from destroying our children and our lives.
Pneumococcal disease is serious, deadly and crippling.  We absolutely must do everything we can to prevent children from getting it.  The hardest thing I=ve ever had to do was to tell my son it was okay to stop fighting and to let go.  Please do everything possible to ensure that another parent never has to say those words to their child.
Thank you for your time and attention.
CHAIR GREENBERG: Thank you, Ms. Newby.
Any questions?
Okay.  I think we are going to move on, Doctor Pratt, to the C are there any other people in the audience who wish to make a statement?  Okay.
What I think we should do is go through these one by one and sort of talk them through, and see what questions we have and how close to a consensus we have.
So, the first question is, do the data provide sufficient evidence of efficacy against invasive disease for Prevenar as it is studied in the efficacy trial, in as you know, two, four, six and 12 to 15 months, and if not, what additional information should be requested.  So, the first question really is, one, do you think there=s sufficient evidence of efficacy, and I=ll take any comments the panelists want to make.
Doctor Ferrieri?
DOCTOR FERRIERI: I assume you=d like us to just open this up and then we can move on to more controversial questions, perhaps.
I think that the data provided were very compelling in demonstrating efficacy against invasive disease against the pneumococcal serotypes in the vaccine given under the conditions of the efficacy trial.
CHAIR GREENBERG: Not a highly controversial statement in my mind.
Does anybody else on the panel have any other point of view?  Many of you on this panel have, obviously, been engaged in vaccine trials, and it is rare for any of us to have 17 and zero numbers.
Dixie?
DOCTOR SNIDER: Well, I don=t think this is a highly controversial question, but, perhaps, it is important to say that the evidence, of course, is very strong for protection against invasive disease caused by the vaccine serotypes. The issue of any cross protection against other serotypes is not very substantial at this time, and at this point it looks very good in the one northern California Kaiser study with regard to the lack of replacement, but, obviously, that is something of concern.
There is also the issue that I=m sure most people in the room, if not everybody in the room is aware of, and that is that we don=t have the same serotypes around the world and, therefore, what data are available for the U.S. at this particular time are not necessarily applicable to other countries and may not be applicable to the United States at some point in the future.
CHAIR GREENBERG: And, of course, what Dixie says is absolutely true, but it, in fact, is true about all existing vaccines as well, where there=s always the possibility of change in the pathogen.  That=s one of the uncertainties that we have.
Any other comments?
Well, since there aren=t, I=m going to now then simply poll the committee members.  I=m open to more discussion of this, if there is any, but if there=s not I=ll start with you, Doctor Daum.
DOCTOR DAUM: I think this is a giant step forward for the health of children, and I vote yes on question one.
CHAIR GREENBERG: Doctor Kim?
DOCTOR KIM: Again, I guess this has been addressed by others, that this disease is certainly particularly invasive diseases due to pneumococci, namely, meningitis, is a very serious disease, with a considerable mortality and morbidity, based on the data presented today I will support the license of this product.
CHAIR GREENBERG: Doctor Snider?
DOCTOR SNIDER: Yes, the data are sufficient.
CHAIR GREENBERG: Doctor Stephens?
DOCTOR STEPHENS: This is an important breakthrough vaccine, and I think the data was compelling.  I would add a couple of caveats.  I think we haven=t heard much about the efficacy of this vaccine in high-risk groups, which is an important area and subject.  I think there are a number of unanswered questions regarding the efficacy, long-term efficacy of this vaccine, which have not been addressed.  But, I think in essence my response is yes to question one.
CHAIR GREENBERG: Ms. Fisher?
MS. FISHER: I think the evidence is compelling that is protective against invasive disease.  I wouldn=t say it is compelling in terms of the other otitis media, et cetera, but that=s not what we are considering today.
I would like to know more about mechanism, I=d like to know more about interference of maternal antibodies, but for question one only.
CHAIR GREENBERG: We are only dealing with question one at the moment for the rest of the people here.
Doctor Estes?
DOCTOR ESTES: I think the data was quite convincing, and my answer to this question is yes.
CHAIR GREENBERG: Doctor Hartigan?
DOCTOR HARTIGAN: I also think the data was convincing and my answer is yes.
CHAIR GREENBERG: Doctor Ferrieri?
DOCTOR FERRIERI: I=m very enthusiastic about licensure.
CHAIR GREENBERG: Doctor Glode?
DOCTOR GLODE: Yes, I think the data provide sufficient evidence for efficacy.
CHAIR GREENBERG: Doctor O=Brien?
DOCTOR O=BRIEN: Yes.
CHAIR GREENBERG: And, for the record, I also say yes, and would simply second my colleagues in saying that this seems to be an extremely exciting breakthrough for a disease that can have a devastating effect.
So, we=ll move on to the next question then. Do the data provide sufficient evidence of safety of Prevenar, and, if not, what additional information should be requested?  And, I=d like to hear some comments from the committee about safety.  We=ve seen a fair amount of data, I would say it=s complicated data, and it=s multi factorial and there=s all sorts of analysis of it, so what are your thoughts and what further information do you want, and what do you think?
Doctor Snider?
DOCTOR SNIDER: Well, first of all, as we all know from recent experience with rotavirus, we never have sufficient evidence surrounding safety before we are in a position to be licensing vaccines.  And so, it=s important to continue to look at safety data after licensure to look for uncommon events.
Here, I think we really have a lot more data, though, on common events than often we have had, because, as was pointed out, of the place that this study was done and the kinds of record systems they have, and the kinds of research infrastructure they have and so forth.  And so, if anything, I think there=s more safety data here than we have gotten in the past.
As has been pointed out, there=s some confounding here because of the fact that another C the control was another experimental vaccine.  It was good to be able to see some of the vaccine safety data link data prior to the use of either one of the vaccines to let us know that some of those uncommon events were in the ballpark of what were observed before.  Otherwise, we wouldn=t be able to say over an average two-year follow-up period that some of these things were not of concern, or had as much assurance about that.
I think the issue which was raised around diabetes, about long-term effects, is something we are all sensitized to, and we recognize the need to look properly at long-term events, potential long-term adverse consequences of vaccines.  And, that=s challenged not just with this vaccine, but for many other vaccines that are already licensed, as well as new ones that come before us.
So, I was not, with regard to safety, was not particularly surprised that when seven vaccines were given compared to one vaccine, in essence, that there were more local reactions or more systemic, but non-serious, reactions.  And so, I felt that the safety profile given, particularly given comparisons to what has proven to be used in the past as a standard of care, such as DTP was actually let, the overall profile was better than whole cell DTP, given the fact that we were providing benefits against or protection against seven serotypes was a reasonable tradeoff with regard to safety.  So, I personally was comfortable with that.
But, that=s, I think, additional information on that, on even the local reactions, would be useful to continue to collect.
CHAIR GREENBERG: Thank you, Dixie, for your usual good and well-balanced answer.
Any other comments on safety?  Now, safety is a very important issue, remember you are always weighing safety and efficacy, and that=s the issue that we are dealing with.  Do we have any other C I=m just going to step in while the committee collects their thoughts and just say that I also just couldn=t be happier with the venue where this trial took place, and the database and accessibility of being able to do multiple comparisons, and I think we should all just take our hats off to the Kaiser team that put this together, because they sure overwhelmed me.  I have too many comparisons in my mind at the moment to really figure it all out, but there certainly is access to an awful lot of data, which I think sets the bar for future studies.
Any other questions about safety?  If not, I am going to start over there in the right-hand corner again with my colleague, Doctor Daum.
DOCTOR DAUM: It was much better yesterday morning when I sat up there.
I=m very comfortable with the safety profile data that I saw today that the safety and effectiveness ratio comes way down on the effectiveness side.  I am mindful of Doctor Snider=s comments, and agree with them, and believe that the long-term, post-marketing assessment needs to be in place.  I believe it is in place.  There are mechanisms for capturing these things, and that we might need to revisit this, but for right now I=m very enthusiastic, the short-term safety data we saw today were impressive, and this is a safe vaccine.
So, I think, yes, the evidence is sufficient.
Doctor Kim?
DOCTOR KIM: Well, I guess there=s no absolute answer to this question, unless there is a continued monitoring of potential adverse effects or other unanticipated side effects that may occur following licenses.  So, with that in mind, the data presented on localized systemic reactions appear not to differ from that we have seen with the other licensed vaccines.  So, with that, I would support, the safety data appears to be, you know, acceptable.
CHAIR GREENBERG: Doctor Snider?
DOCTOR SNIDER: I think I=ve already answered it, but, yes, I think the data C
CHAIR GREENBERG: For the record.
DOCTOR SNIDER:  C for the record, I think the data are sufficient on safety, as I already indicated.  I think additional information should continue to be collected, as it relates to local and system reactions, but more importantly long-term events need to be evaluated using good scientific methodology, with attention to any confounding and to all of C hypotheses being met.
CHAIR GREENBERG: Doctor Stephens?
DOCTOR STEPHENS: You can never be sure about the long-term safety of any product, but I think the data do provide sufficient evidence for safety as we now view it.
CHAIR GREENBERG: Ms. Fisher?
MS. FISHER: There=s not enough known about the safety of this vaccine, especially when U.S. data shows that local systemic and neurological reactions are more frequent in the pneumococcal vaccine group than in controls.
The fact that the whole cell DBT vaccine was used extensively in this trial, and an experimental meningococcal vaccine was used to control further clouds the safety picture.
There is no biological mechanism data that has been presented to this committee regarding adverse events, and we don=t know if the addition of this vaccine to the routine schedule will cause ultimately an increase in autoimmune or neurological disease in children and young adults.
The fact that the ACIP committee has recommended this vaccine for universal use in all children, before this vaccine has been licensed, is highly inappropriate, because it means that policymaking has preceded the scientific evaluation by this committee of this vaccine, and it means that when we vote for licensure we vote for basically mandatory use of this vaccine, because once a vaccine is recommended for universal use by ACIP it is put into the mandatory schedule.
And, this happened with rotavirus vaccine, and now with this vaccine, and I would hope that it would never happen again, because it does not instill confidence in the public in the integrity of the licensing process.
CHAIR GREENBERG: Doctor Estes?
DOCTOR ESTES: I share the words that have been said earlier in terms of the need for long-term follow-up, but I think that the data that were presented today do provide good evidence of safety for this vaccine.
CHAIR GREENBERG: Doctor Hartigan?
DOCTOR HARTIGAN: The data seem to me to provide sufficient evidence, even though it was an experimental control, but long-term follow-up should be looked at.
CHAIR GREENBERG: Doctor Ferrieri?
DOCTOR FERRIERI: Well, I share other opinions here that have been stated by the majority, that the data presented certainly suggests that this is a safe vaccine.  Anticipating questions from parents who want to know what might happen if my child gets the vaccine, and you might say, well, at the very least there may be C he has a very high chance of not having any side effects, on the other hand the worst scenario is that the patient, your little baby, may develop a very high fever, be listless, irritable, have a painful limb with diminished appetite, and might even need to be hospitalized.  And, I use this example in order to stimulate conceivable studies that could be done to examine the possible beneficial value of non-steroidal anti-inflammatories given prior to complex vaccines like this, examining whether there=s any attenuation of immunogenicity.
I recollect seeing a small paper several years ago, perhaps, seven or eight years ago, not with the polysaccharide vaccines, but with routine DTWPE and, perhaps, something else showing certainly one can attenuate fever and other local side effects.  And, I=d like to, as we move forward with the complexity possibility that we will even have a more expanded repertoire of this pneumococcal vaccine, then I think we are asking for more and more side effects, adverse events, not life threatening necessarily, but they can diminish the credibility and interest of parents in having their children vaccinated.
So, I think it=s obligatory for us to examine whether there=s a safe way of ameliorating some of these reactions.
CHAIR GREENBERG: Doctor Glode?
DOCTOR GLODE: Yes, I think the information presented this morning provides sufficient evidence of safety, again, with the caveat that events that would occur at a rate of one to 50,000 that would be serious we won=t know about, except for very stringent and careful post-marketing surveillance. And, I don=t know if things have changed and if there=s currently a mechanism by which manufacturers are scheduled on a regular basis to present post-licensing data, but I=m concerned about rare serious adverse reactions that occurred at a significant rate of one in 50,000, as well as the long-term follow-up for other chronic conditions.
CHAIR GREENBERG: Doctor O=Brien?
DOCTOR O=BRIEN: I think the data certainly were supportive of this vaccine being safe.  I share Doctor Glode=s caveat that we really do need to be sure that we look at potential adverse reactions.  I=m less concerned, I know the rotavirus vaccine is being brought up as a concern rightly, but this is a different kind of vaccine, and the prototype more like it is the Hib vaccine, which has proven to be quite safe.  So, I have more assurance on that basis.
CHAIR GREENBERG: For the record, I think also that safety has been demonstrated. I would simply like to say that it is a daunting task to ensure, in anyone=s lifetime, that the long-term effect of a vaccine is totally understood.  When you immunize a child, presumably you have a 70-year approximate time frame in which some adverse event could be associated with that vaccination.  And, scientifically how to get at that is very, very hard.  I think we all need to think about better ways to do it, but at the moment it is a very C you have to weigh that with the fact that there are children dying from pneumococcal meningitis.  And so, I feel that the preponderance of the data says this is safe, but I think we really need to think about how better to understand possible long-term consequences.
Can we have the next set of questions?
Well, here=s the one where you really have a lot of interactions, so please discuss the data regarding concurrent use of Prevenar with other vaccines administered according to the recommended schedule of infants and childhood immunization.  So, just to put this, you saw lots of data put up there with many interactions, and the question really is, do we know enough, or do we know sufficient amounts to say that this vaccine can now be incorporated into general use, and we feel comfortable that we are going to muck up what we currently have.
Dixie, so far you=ve just cut right to the chase.  You are hot, do you want to continue?
DOCTOR SNIDER: Oh, so that=s the reward I get.
CHAIR GREENBERG: Yes, never volunteer.
DOCTOR SNIDER: Well, I thought the data were  somewhat concerning, mostly because there are a lot of comparisons, and the type one polio is an example, or polio is an example, because the type one, responses to type one was lower, but then when I went back and looked the response to type three was higher.  So, I don=t know what to make out of that, and I was glad Karen made her comment, that with regard to the actual C the absolute responses of the participants, there doesn=t appear to be any reason for major concern.  But, this clearly is an area, another area, where we need to continue to look at this, and I=m not sure whether the data are available or embedded in this study to tease more out, or whether additional studies need to be done. 
But, overall, I=m reasonably sure that there are not any monsters in here, in terms of there being interference which would lead to an increased susceptibility to disease, but have some concerns because of the small amount of data and the lack of clinical endpoints, as opposed to immunologic endpoints.
So, I think it=s something we need to continue to give some attention to.
With regard to the safety of the concurrent use, which is another issue, I think that we do have this confounding effect of, as has been pointed out in shifting around from whole cell to acellular pertussis, there are also, with the confounding, trying to look in this trial C I mean, the ethical reasons for giving the other experimental vaccine were laudable, it=s just that from a scientific standpoint it makes it a little bit more difficult to figure out what=s going on.  So, that confounding makes the data difficult to interpret, a little bit more difficult to interpret.
So, bottom line is, I think that what was outlined as appropriate concurrent administration is probably okay on a population basis, but I would like to see more data in the future on that.
CHAIR GREENBERG: Doctor Ferrieri?
DOCTOR FERRIERI: One of the questions that will be asked by primary care physicians is the influence on the haemophilus conjugate vaccine and its antibody responses, and the data that has been presented suggests that there may be some attenuation when the pneumococcal vaccine is given with DTaP and the haemophilus vaccine versus the control group without the pneumococcal, but the titers are still extremely favorable and eons beyond what one would need for protection against haemophilus influenzae type B.  But, the numbers are small, and so I would echo the need for expanding studies of this kind to examine responses to the other vaccines administered in any post-licensure phase.
And, the other point raised by someone else here earlier, I think, is an important one.  We don=t have the data we would like on other products, other than the HbOC, and so we know that many healthcare systems that contracts are put out that are based on price only, without consideration of compatibility of one vaccine with another or scientific medical rationale, but it=s strictly bottom line contract.  And so, I think careful thought must be given to this and studies done to demonstrate that there is no modification of either product in the face of some other haemophilus product, haemophilus conjugate.
CHAIR GREENBERG: Other comments?  Doctor Daum?
DOCTOR DAUM: Thank you.  I think that we haven=t begun to deal with the probably more difficult part of this question, and that=s what happens when combination vaccine research begins with the pneumococcal conjugate being a component of a putative new combination vaccines.
And, that might be a more difficult issue to deal with.  We don=t have data today to need to deal with that, except that I would encourage the manufacturer to proceed with development and assessment of combination vaccines, including this new vaccine, as quickly as they are able in an effort to keep the number of injections down that children need to receive.
In terms of vaccine components given separately, one is always faced with a conundrum when one analyzes the data, because you can do a correction for multiple comparisons, and thereby make a demonstration of significance more stringent, but the price of that, of course, is to miss real comparisons which shook out at a less stringent level.  So, I=m actually glad the data were presented the way they were today, so that we can discuss and assess all possible interactions and decide whether the statistically significant ones are clinically important.
My view is that most of these in combination vaccine research that I=ve done myself and seen others do, that many of these so-called significant interactions, in fact, represent alpha errors and don=t hold up to repeated study.
And finally, although Doctor Ferrieri=s point is correct, that the fourth dose had raised some concerns about interactions with the Hib component, the primary series, the manufacturer now has data from two, and I think even three, trials, that the primary series, the Hib response was enhanced by children that received the pneumococcal vaccine at the same time.  That raises the possibility of doing some investigation to see if the actual milligram dose of these vaccines could be turned down without loss of effectiveness or deterioration in safety and, perhaps, these vaccines could be made available to more children around the world.
CHAIR GREENBERG: Ms. Fisher?
MS. FISHER: We have been given no data about what occurs at the cellular molecular level when you give this vaccine in combination with all these other vaccines.  If this vaccine were being licensed for use, voluntary use is one thing, but it=s going to be inserted into the mandatory schedule, all children ostensibly are going to be receiving it, which means what we basically have here is a post-marketing experiment, and I think that we need to know more about the biology of what occurs in the human body when you give this vaccine in combination with other vaccines, versus just simply clinical observations.
CHAIR GREENBERG: Doctor O=Brien?
DOCTOR O=BRIEN: I=d just like to follow-up on the Hib question, and note that I never heard any mention of any cases of haemophilus influenzae disease at all, in either control or vaccine group, both of which got CRM-related products.  Small scale, but if there was some problem we might have seen a case or two.  Was there any?
CHAIR GREENBERG: Doctor Black is going to address that issue.
DOCTOR BLACK: We have not had a single case of Hib disease since 1991, both before the trial and during the trial.
CHAIR GREENBERG: Doctor Glode?
DOCTOR GLODE: I was just going to say that I continue to be impressed as new vaccines are being studied with some unexpected immunologic outcomes that seem to happen in many vaccine trials, and I think this is one of them.  And so, with the Hib antibody response being enhanced with the early doses, but suppressed with the later doses, that still is disturbing to me.  And, although I accept Doctor Siber=s possible immunologic explanation for it, I think we could have support for that by studying some of the other Hib conjugates and, perhaps, shed a little light on that issue.
And, I am concerned as new combination vaccines are licensed, et cetera, that it will be very important to study this vaccine, because I just think some of these interactions do seem a little bit unpredictable and surprising us, and then we learn about it and can explain it.
CHAIR GREENBERG: Doctor Stephens?
DOCTOR STEPHENS: One issue that I=d like to address is the catch-up schedule which we haven=t talked about very much.  In the data from the catch-up schedule, and it=s not on our questions, so I=m not sure that we are being asked to judge that or not, but, you know, the data as I saw it was very preliminary, or the numbers were much smaller for the catch-up schedule and it seemed less defined.  And, certainly regarding question three, the potential interactions with other vaccines in the catch-up schedule, I think have not been addressed.
And, just as a general comment, and I think I agree with most of the other comments that have been made, the issue of overall vaccine delivery and the issue of continued increasing antigen load in children, and the desire to look at development of alternative vaccine delivery systems.
CHAIR GREENBERG: I=m just going to make a comment here.  I think it was the manufacturer who mentioned the fact that attempts to study comparisons of various vaccines were looked upon as somewhat low level types of research for the VTUs, or at least somebody mentioned that the VTUs felt that the mundane questions of how to study multiple vaccine interactions was not appropriate for good scientists.
And, I would simply say that this committee seems to be daunted with this question on almost ever vaccine, and I personally would say that it=s a perfectly good thing to use the VTUs for, so our colleagues in the audience who are NIH and who have oversight on the VTUs, those tremendous assets represent one of the few places where you can really do comparisons here that are very, very hard to do in other ways, and I would suggest that people start thinking about that as one of the places to do research.
Any other C just a little editorial, that was just an editorial C any other comments?
Bill?
DOCTOR EGAN: Doctor Egan from FDA.
I forget the data exactly, but, perhaps, either the manufacturer or Kaiser could comment on the response to the Hib vaccine that was done from the initial trial, particularly, with regard to the percentage of seroconverters at the various levels, relative to the data that=s presented now for the pneumococcal arm.
CHAIR GREENBERG: I=m not sure they understand your C am I correct that the manufacturers aren=t understanding the question?  They are looking puzzled over there.
DOCTOR EGAN: Yes, I=m sorry, there was some concern about in the pneumococcal arm about the GMCs, the titers going down after dose four, and the percent of seroresponders, the 97 and 98 percent in the pneumococcal arm, do you recall what those numbers were from the initial study of the haemophilus vaccine?
DOCTOR SIBER: You=re really asking, Doctor Egan, from the original efficacy trials done at Kaiser?
DOCTOR EGAN: Yes, that=s correct.
DOCTOR SIBER: Those are not data we brought.  The best we can do is the control comparison in the one study that was controlled, which just suggested I think it was about 20 micrograms per ML.  Does anyone in this group have a solid memory that=s worthy of putting up here on the initial trials?  No?  Well, those are the data we are talking about right now, we are talking about in the control trial.  Wait a minute.  The question is, the original efficacy trial done at kaiser with HbOC, what were the levels with boosting in those trials, and the answer is, we would have to get back to you on that.
Dot says Midori=s memory, and she has vouched for a pretty good memory, is 16 to 22 micrograms geometric means, in the good old days.
CHAIR GREENBERG: Say it again, George.
DOCTOR SIBER: In the Kaiser study itself, the immunogenicity was done as part of the Hib efficacy trial, we were asked what the geometric mean antibody response was after the booster dose, and the memory of our staff, it is between 16 and 22 micrograms, but I would ask you to let us get back to you to confirm this, because this is memory.
DOCTOR EGAN: Yes, and the percentage at greater than one microgram.  My recollection is that these numbers here are actually higher.
DOCTOR SIBER: Forty-five might be a record.
CHAIR GREENBERG: Okay.
I have the request to make a comment from Doctor McInness from NIAID.
DOCTOR McINNESS: Doctor Greenberg, your editorializing forced me to my feet.  I=m puzzled by the comment that the VTU investigators sometimes are scientifically non-challenging.  In fact, I think for the record we have been involved in a variety of relatively extensive trials looking at what we call mix and match combinations, and I don=t believe that philosophy has changed in our partnering to find effective and safe vaccines.
So, I would extend my invitation earlier this morning to have some discussions on what might be possible in that framework.   Thank you.
CHAIR GREENBERG: Well, that=s the best possible outcome, and to the degree that I misinterpreted or misheard what was said earlier, I=m happy because that=s a terrific thing, and we really need the VTUs to address this issue, because it=s an important one.
Anymore C Doctor Ferrieri?
DOCTOR FERRIERI: I have a question for the sponsors, if they have any preliminary information from study 124-501 on the effect of the 9-valent vaccine on nasopharyngeal colonization with pneumococci, is there anything that we=re learning from that that would influence post-marketing studies of the 7-valent vaccine in terms of addressing the issue of the colonization, for example, with serotypes that are not in the vaccine, or the most basic question, does it influence nasopharyngeal colonization as Hib conjugate did for HIV?
DOCTOR SIBER: There are data published by Ron Dagan on this from a study in Israeli daycare centers, in which a majority of the children were enrolled into studies were they were randomized to either pneumococcal 9-valent vaccine or meningococcal c vaccine.
What the study showed was a variable reduction in the vaccine serotype, but the average was on the order of 40 or 45 percent, as I recollect, and that occurred rather quickly after immunization.  These were toddlers at one or two doses of vaccine.
And, a more gradual increase in the vaccine recipients of non-vaccine serotypes, there=s been lots of debate about whether that increase represents unmasking of non-vaccine serotypes, because we eliminated the vaccine serotypes, whether they are there in similar concentrations that were simply allowed to be cultured when you got rid of the dominant vaccine types, and that is not yet resolved.
Another effect that was observed is that the character of the antibiotic resistant stains was significantly reduced in children who got the pneumococcal vaccine.
There will be additional data which are not yet available that look at overall antibiotic use in that daycare center population, and overall morbidity in terms of doctors visits, otitis, and so forth, that are shaping up to be interesting, but they have not yet been presented by Doctor Dagan.
CHAIR GREENBERG: Doctor Pratt, do you feel you are getting a good answer here, since you don=t have a specific question I=m not sure you are getting a discussion.  Are you becoming informed on number three?
DOCTOR PRATT: Yes, I find the discussion useful.
CHAIR GREENBERG: Any other C I think I have a good idea so far C did I see another hand over here C of where the panel C anymore data for number three?
DOCTOR ESTES: I was on to four, I=m sorry, Harry, I didn=t realize we were through with number three.
CHAIR GREENBERG: Well, we are not quite yet, until everybody gives me the high sign that they think they are done with talking about three.  I think we are pretty done on three, so let=s go on to four, and this is good, I think we are making good progress.
Please identify any issues that should be addressed in post-marketing studies.  Now, of course, we=ve touched on a bunch of this, but I won=t C Dixie, I=ve trained him here, Dixie, I=ll let you go first.
DOCTOR SNIDER: Well, since you called on me last time, I thought I=d just volunteer this time.
Yes, a number of things we=ve already mentioned.  We=ve mentioned safety, particularly, long-term safety issues.  I think a number of us are still concerned about the concurrent administration issue, and we=d like to see more data on that.  Mention has been made about efficacy and safety, but particularly efficacy in other risk populations that were not included here.  Certainly, there are other health outcome data, notably pneumonia, that we haven=t seen data on yet, so somewhere along the way we=d want to look at that.  And, probably post-marketing it would be C even if you do it in a trial, this might be the way to really figure out how much pneumonia is due to these serotypes, and how much acute otitis media, for that matter.
We need to follow the serotypes, both in terms of the replacement issue and in terms of the vaccine serotypes that might be showing up.  I think it was some suggestion in 19f, I believe, that, you know, it may mean nothing, but the question is whether the current vaccine needs to be beefed up in any way to protect against any of the vaccine serotypes.
The issue of catch-up has been mentioned and the proper dosing there, and I think we could open it up even further and say, how many doses, and when, we really don=t know, and there is suggestion from the data, as has been commented on, that you might get quite a bit of efficacy out of one initial dose in the series, but obviously we don=t know how long that might persist.
So, it will be interesting over time to look at pneumococcal conjugate vaccines to try to ascertain what C how many doses you actually need and what is the optimum interval between doses.  So, I think those are some of the things down the road we=d be looking at, not necessarily all of them that the manufacturing are doing, but these are some of the things that come to mind.
CHAIR GREENBERG: Doctor Kim?
DOCTOR KIM: You know, this is, I think, a serious C again, this is pretty much bottom line, but it is very, to me, important to document that invasive pneumococcal disease is, indeed, decreased and maintained throughout, you know, the coming years, make sure that there=s no C not only replacement with other serotypes, you know, or replacement by other pathogens in the community regarding invasive disease.
And, an additional comment, I think that needs to be done, which we touched several occasions, I mean, is regarding some of the immunologic profiles and the assay issues, and I think it is important to have some sort of a consensus or guidance from the FDA regarding the issues about protective levels of antibodies, which, you know, may differ depending upon the types of diseases, like invasive disease versus C again, I=m not still clear about the beneficial effect of this vaccine against otitis media, for example, and I think those types of issues continue to be very critically analyzed through the samples are variable from participants, I think those are extremely, to me, valuable resource to address some of those issues.
And, again, as you know, the assays ought to have some variations, so that if you are looking to some numbers, and those numbers happen to be within two-fold, I=m not sure I have any confidence in those numbers in providing some guidance to, let=s say, second, third generation vaccines to, you know, imply that those vaccines are, indeed, efficacious or not.
CHAIR GREENBERG: Ms. Fisher, then Doctor Daum.
MS. FISHER: I have a practical question.  If this vaccine is licensed and shortly put out on the market for use in all children, how is the FDA and the CDC, how are they going to determine when a child suffers this health problem following vaccination with this vaccine, in combination with all these other vaccines, if it is indeed due to the pneumococcal vaccine?
CHAIR GREENBERG: Well, I don=t think there=s C perhaps, there is somebody here who can speak for the CDC, but that=s a question directed at the FDA first.
MS. FISHER: Well, Dixie is from CDC.
CHAIR GREENBERG: Yes C no, no, but I=m letting the FDA, since this is an FDA meeting, take first chair in this response.
DOCTOR GOLDENTHAL: Thank you.
Well, I mean, that=s a very C you know, that=s a very complex C you know, it=s a very difficult question to answer, because when you are giving multiple immunizations attributing cause to one particular vaccine, or even to vaccination at all, can be difficult.  I mean, we have a staff that=s focused on post-marketing evaluations, and looking at VAERS data, and looking for trends or any troubling findings that may occur.  I think that a specific post-marketing study in the right setting may also be helpful to look for any unanticipated, you know, events, and maybe also detect any increase compared to background. 
But, you know, in a setting of a non-randomized evaluation, that can be difficult to do.
MS. FISHER: I mean in any given case, you know, a parent takes a child in, and the child suffers a seizure, or suffers high-pitched screaming, or whatever, I mean, it seems that we need to have a clear idea if we are going to attribute that to the vaccine or not, and it seems that biological mechanism work is the only way we are going to get at that.
CHAIR GREENBERG: Dixie, and then Doctor Ferrieri.
DOCTOR SNIDER: Well, with regard to looking at vaccine safety, I think people are aware that we do have the Bayer system and people hopefully are also aware of the limitations of that system.  Nevertheless, I think FDA and CDC, who work together with that system, would like to enhance it and make it better, and increase the participation in it among clinicians and parents.
There are also the large link databases, such as the vaccine safety data link, which we would very much like to get the resources to expand, because people, I=m sure, are aware of the fact that your ability to detect rare events increases as your sample size increases, and, therefore, we=d like to include other organizations in the vaccine safety data link.
I think it=s hard to get very specific about what one might do, depending upon C because it will depend upon what kind of event you are talking about, certainly all the events we look at we have to look at what is the temporal association, what is the biologic plausibility.  At times one can do special case control studies to evaluate putative adverse events, at other times it does take a special study set up prospectively to be able to adequately answer certain questions.
And, as many people know, we are engaged in establishing a number of studies, both retrospective studies, nested case control studies, and prospective studies, to look at several putative associations between vaccines and various adverse events.
CHAIR GREENBERG: Doctor Ferrieri?
DOCTOR FERRIERI: I=d like to address the issue of post-licensure bacteriological monitoring of pneumococcal isolates and present the fact that many academic institutions, many hospitals, medical centers, including university hospitals, do not routinely serotype pneumococci.  And so, who will be responsible for seeing that they are examined properly, that they don=t die in route?  Will there be a central bank to receive them, and will that be organized somehow?
So, I guess I would appreciate any comment from FDA, CDC or the sponsor about this.  We don=t want misleading information, and we do extensive pneumococcal typing in the laboratory I direct, but there are pitfalls in doing this, and one needs to be aware of that.
So, I think this is really important as we move forward, to understand the full protection or cross protection, et cetera.
CHAIR GREENBERG: Doctor Pratt or Doctor Frasch, are you going to take a crack at that, at answering that?
DOCTOR SNIDER: Well, Harry, I=d be glad to say, I mean, I think CDC plans to continue the ABC data collection that George showed, and certainly that would be one source for us to be able to continue to look at serotypes.
CHAIR GREENBERG: Does the sponsor have anything to add here?
DOCTOR FERRIERI: It=s a lot different in doing this for a study and doing it under very diffuse conditions with all comers, and what will be the practice?  Will FDA write something up, so that all physicians know that there=s interest in examining those isolates?
CHAIR GREENBERG: Doctor C
DOCTOR FERRIERI: Carl, what do you think about that? How do we make it not a problem?
DOCTOR FRASCH: Well, I think it=s FDA=s job to license, and then monitor the safety through the VAERS system, but I think it=s the CDC=s job to do the strain surveillance, you know, through Doctor Fraklan=s lab and so on.
CHAIR GREENBERG: Doctor Daum, and then Doctor Stephens.
DOCTOR DAUM: Just to add a couple of things, and try not to be repetitious to things that have been said before.  I think we need some studies directed at the performance of this vaccine in high-risk groups, specifically, sickle cell anemia patients and children infected with HIV, perhaps, asplenics.  I=m sure there are others that come to mind, but we need to know, need to be reassured that there can be bridging.
CHAIR GREENBERG: It was my impression that the manufacturer did show us a list of a fair number of immuno C of high-risk groups that studies were ongoing, which we=ll need to see that data, but I think those studies, or at least we saw a slide that said they were underway.
DOCTOR DAUM: Also, I think that the duration of the antibody response, which has been touched on, is an extremely important issue, because pneumococcal disease differs quite markedly from Hib, which has been analogous so far, and that pneumococcal disease also is a problem in adults.  And, it will be interesting to consider, at least, how long protection from a four dose series in early childhood can, in fact, endure, and how long is it capable of being boosted.
So, I would like to conceive and have performed some studies to look at that.
We also need to think about a vaccine that will protect against all cases of pneumococcal invasive disease, not just the percentage that we have captured in a 7 or 9-valent vaccine.  There may be some carrier priming and carrier immunity issues here that need to be explored and addressed, but buoyed up by the success of this first generation vaccine it might be fun to push that along as quickly as we can so the children aren=t getting any pneumococcal invasive disease.
I also touched on before, but would like to just reiterate under the umbrella of question four, that I think the vaccine community needs to explore issues of bridging to other pneumococcal conjugates as quickly as we can, because I think that there may be other candidates out there that may be useful, and we won=t know how to assess them.
I also will take up a theme that I touched on this morning in talking about post-marketing immunogenicity assessment.  I don=t know quite who should do it.  I don=t know what umbrella it should be done under, but I think that there should be some monitoring of the immunogenicity of randomly chosen lots that are put on the market to ensure performance is as good as it has been.  
And, lastly, this issue of carriage with respect to vaccine, which has been well documented and incredibly complete in some populations, and clearly in other high-risk populations been much less complete in terms of eradication, needs to be studied more.  And, I would encourage people who are doing research in this area to pursue this, I think it=s a very important issue.
CHAIR GREENBERG: Doctor Ferrieri, and I would encourage committee members now to really try to touch on things that haven=t been said before, so that we can give the FDA as broad a list as possible.  I think they=ve gotten a fair amount of input from us.
DOCTOR FERRIERI: As we=re winding down, I feel it=s very important to say something that FDA will not be able to control, but that has to do with allocation of resources and social policy.  I understand that this vaccine is going to be quite expensive per dose, and I want us to mobilize as a group of physicians and scientists to see that this, as well as other critical vaccines, are distributed to disadvantaged, economically disadvantaged, disenfranchised racial minorities, in particular, who are at highest risk of invasive disease.  And, as a single individual I can=t do anything about this, but I think we should reflect on this and see that there is appropriate use so that the kids of Bethesda and Chevy Chase are not the only ones in Maryland who receive this vaccine.
So, what about inner city kids in Baltimore, Atlanta, New York City, Chicago, et cetera.
CHAIR GREENBERG: And, I would just echo that, I assume that there are outer city kids in Bangladesh who sorely need this vaccine as well, and they are even further from it.
Doctor Snider?
DOCTOR SNIDER: I just wanted to respond to that.  I mean, I just want to call to people=s attention that actually we have a very peculiar situation in the U.S. with regard to that.  If the vaccine is licensed and the ACIP votes to include the vaccine in the vaccine for children program, there will be a mechanism for purchasing the vaccine for the poorest children.  Presumably, the richest will be able to purchase it as well, and it=s those in the middle that are most likely to be deprived of the vaccine, or have the most difficulty obtaining the vaccine.  And, it=s just an anomaly of our vaccine delivery system these days, as to who is most likely to have difficulty obtaining it, and not the poorest of the poor.
CHAIR GREENBERG: Well, we have a big list of things that you folks at the FDA, and the manufacturer, and the CDC have to do, and Doctor Stephens is going to add to that.
DOCTOR STEPHENS: At the risk of prolonging this a little bit, I had seven categories, most of which have been covered.  I do want to make a couple of points.  One is an issue we haven=t talked about, is individuals who may have received prior pneumococcal polysaccharide vaccine, and the potential effects or interference effects of that vaccine on this vaccine, an area that we haven=t touched upon, but certainly for high-risk groups that=s an area of some concern, given other data and other systems suggesting that there may not be C there may be less of a response in those particular individuals.
The other has to do with as an adult infectious disease individual, there is a clear need for this vaccine or a much improved vaccine in the adult population, in terms of the immunocompromised patients with serious pneumococcal disease, and certainly in the elderly, and I realize those studies are ongoing, but it=s an area of immense concern for many of us.
And lastly, an issue regarding, I participate as one of the sites for the ABCs, the CDC ABCs, and certainly those sites are ideal for looking at the impact of the introduction of a new vaccine.  We certainly saw the dramatic decrease in haemophilus influenzae B with the introduction of the vaccine in the Atlanta community, and I think it=s important to document the introduction of this vaccine in sites where there is very good active population-based surveillance, to look at overall efficacy, and to identify potential effects on herd immunity, which was certainly a major benefit of the haemophilus influenzae vaccine that we really didn=t anticipate when we began the studies.
CHAIR GREENBERG: Ms. Fisher?
MS. FISHER: I think also in any post-marketing surveillance there has to be attention paid over the long term to the increases in C possible increases in diabetes and other autoimmune disorders, asthma, with the addition of this vaccine to the routine schedule.
CHAIR GREENBERG: I=m just going to take a second here to underline what Ms. Fisher said, and I think it=s clearly time for the vaccine community to really figure out the scientific way how to deal with these long-term questions that are so hard scientifically to deal with, and to develop systems so that we can be ahead of the curve as opposed to behind the curve, in having databases that are robust that really enable us to answer these questions.
And, I think my advice to the FDA and the CDC is, perhaps, and maybe it=s already in place and I=m unaware of it, but it seems to me that there are real statistical problems and database problems, and all sorts of C yes, and money problems, excuse me, that deal with this.
On the other hand, being behind the cure also creates money problems, and it seems to me that it might be a good idea for people to come together and say, what is the best solution we can come up with now, and start instituting it so that, otherwise five years from now, and ten years from now, we=re going to have the same questions, and they are going to be very difficult to answer, because we won=t have good databases.  So, that would be, again, just editorializing.
Carl, I=m about to wind this down now, so make it brief.
DOCTOR FRASCH: I think I need to point out that Doctor Daum had made comments about not getting behind the game, shall we say, we=ve already had meetings regarding, through the WHO mechanism, one, how to get the pneumococcal conjugate vaccine out to the underprivileged countries.  We=ve met there this year.  We=ve already had another meeting regarding assay standardization and possible mechanisms to allow for a second pneumococcal conjugate vaccine or an improved pneumococcal conjugate vaccine, so we are not exactly playing too much catch up.
CHAIR GREENBERG: That=s heartening.
If there are no other new comments from the committee, I=d like to ask Doctor Pratt, do you feel you=ve gotten a full airing of the two last issues for which there wasn=t real questions?
DOCTOR PRATT: Yes.
CHAIR GREENBERG: Okay, and the manufacturers, I hope, have been taking notes.
Okay.  I=d like to thank the committee for being extremely active, and thoughtful, and also timely, and I=d like to thank the audience, and I=m going to call this meeting C oh, there=s an open public meeting, does anybody want to address the panel before I close the meeting?  Excuse me.
DOCTOR CLASSEN: Yes, I have one question.
Ms. Fisher brought this up, again, you know, do we have specifics on a plan of action to look at the effect of vaccines on diabetes?  I mean, we heard about, Doctor Black brought up that they had historical data on diabetes, but I think three or four different vaccines have changed since that time, the timing of the hepatitis B vaccine using the acellular pertussis vaccine versus the whole cell pertussis vaccine.  There is other changes as well.
So, it=s very difficult using the Kaiser database to look at the effect of vaccines on diabetes, and I was wondering if the FDA had some plan or specifics, that I guess Ms. Fisher alluded to.
CHAIR GREENBERG: So, any FDA C
EXECUTIVE SECRETARY CHERRY: This is not the time for questioning.
CHAIR GREENBERG: Okay, so we take that, the questions are over, I think the FDA has heard you, that they are well advised to have a specific plan to look at type one diabetes, and I hope the FDA is listening to me.  These questions will not go away until the FDA generates C the FDA, government or whoever, generates compelling data to show that there=s not a risk.  So, I think it=s important to get those databases in place.
Thank you, everybody.
(Whereupon, the meeting was concluded at 2:23 p.m.)