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

(8:34 a.m.)

CHAIRMAN DAUM: Good morning and welcome. I would like to begin by asking committee members, old and new, and temporary voting members, all those people at the table really, to introduce themselves.

Dave, if you're up for it, we'll start up at your end, please.

DR. STEPHEN: David Stephens, Emory University and other places in Atlanta.

DR. KATZ: Sam Katz from Duke University.

DR. HAMILTON: Holli Hamilton, DMID, NIH.

DR. GLODE: Mimi Glode, pediatric infectious disease, University of Colorado.

DR. OVERTURF: Gary Overturf, University of New Mexico.

DR. FAGGETT: Walt Faggett, D.C. Department of Health, Private Practice Pediatrics, Washington, D.C.

DR. GRIFFIN: Diane Griffin, Johns Hopkins School of Public Health.

DR. WHITLEY: Rich Whitley, University of Alabama at Birmingham.

DR. DIAZ: Pam Diaz, Chicago Department of Public Health.

DR. GOLDBERG: Judy Goldberg, New York University School of Medicine.

DR. MARKOVITZ: David Markovitz, University of Michigan.

DR. PARSONNET: Julie Parsonnet, Stanford University.

DR. DECKER: Michael Decker, Aventis Pasteur and Vanderbilt University.

DR. KOU: Jingyee Kou, FDA.

DR. PRATT: Douglas Pratt, FDA, Office of Vaccines.

DR. GOLDENTHAL: Karen Goldenthal, FDA.

CHAIRMAN DAUM: I'm Robert Daum from the University of Chicago.

DR. SACHS: And I'm Jody Sachs with the FDA, the Executive Secretary for VRBPAC.

CHAIRMAN DAUM: There are a number of people at the table for whom this is their first meeting, including, of course, Dr. Sachs, who has taken over the Executive Secretary role from Nancy Cherry. Tough shoes to fill, but Dr. Sachs is up to the task and I have no doubt will be steering us through with the same aplomb as Nancy Cherry used to do.

In fact, we'll now turn the floor over to her, please, for a conflict of interest statement.

DR. SACHS: Thank you.

I want to welcome everybody, and I'd like to read the conflict of interest statement for the record.

The following announcement addresses conflict of interest issues associated with the Vaccine and Related Biological Products Advisory Committee meeting on May 21st, 2002. The Director of the Center for Biologics Evaluation and Research has appointed Dr. Mimi Glode, Holli Hamilton, and Dixie Snider as temporary voting members for the discussions during this meeting.

In addition, the Senior Associate Commission for Communications and Constituent Relations has appointed Dr. Richard Schwartz as temporary voting member.

To determine if any conflicts of interest exist, the agency reviewed the submitted agenda and all financial interests reported by the meeting participants. As a result of this review and based on the FDA draft guidance on disclosure of conflict of interest for special government employees participating in an FDA product specific advisory committee meeting, the following disclosures are being made.

Dr. Richard Schwartz has been granted a waiver under 18 USC 208(b)(3) and under 21 USC 355(n)(4), Section 505 of the Food and Drug Administration Modernization Act for stock in competing firm valued you at $5,001 to 25,000. Dr. Schwartz may participate fully in the discussions of the safety and efficacy of Prevnar for acute otitis media indication.

We would like to note for the record that Dr. Michael Decker is participating in this meeting as an industry representative acting on behalf of regulated industry. Dr. Decker's appointment is not subject to 18 USC 208. Dr. Decker is employed by Aventis.

In the event that the discussions involved specific products or firms not on the agenda and for which the FDA's participants have a financial interest, the participants rare reminded of the need to exclude themselves from the discussions. Their recusal 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 any current or previous financial involvement with any firm or products you wish to comment upon.

A copy of the waiver addressed in this announcement is available by written request under the Freedom of Information Act.

And I also would like to ask as a courtesy to the committee discussion and your neighbors in the audience please put your cell phones and pagers on silent mode. If you need to use your cell phone, please step out in the hall.

And with that, I'd like to turn over the meeting to our Chair, Dr. Daum.

Thank you.

CHAIRMAN DAUM: And those that have just turned their cell phones and pagers off, we thank you.

I think we'll try and zip right along here and turn to business at hand. The first item for discussion today is an open session. We are discussing the role of Prevnar for an acute otitis media indication.

And we will begin with a two-part, as I understand it, sponsor's presentation, beginning first with Steve Black, which will give us a Prevnar update.

Welcome, Dr. Black.

DR. BLACK: Good morning. I've been asked to give an update on an ongoing post marketing, Phase IV study that we're conducting within Northern California, Kaiser Permanente, of the Prevnar vaccine, and I'll give you an update which includes an interim analysis on safety and results regarding the changes in epidemiology that we have observed of pneumococcal disease in our population.

The post marketing study that I'm going to describe to you, let me give you a little bit of background on that. The vaccine Prevnar was licenses in February of 2000, as you know, and post marketing surveillance began in our population very shortly thereafter with general availability of the vaccine in April.

And the vaccine is being given now routinely to children concomitantly with other vaccines.

What I'm going to describe to you this morning in terms of safety is a second interim look on data through December 31st, 2001. There was an earlier interim look through December of the year prior to 2000, which has been submitted to the FDA, and they've had time to review, and this, I should say in fairness to them, has only recently been submitted to them for their review.

Following the review of the safety, I'll talk to you about the impact of the vaccine and present what we think is exciting data on the changes of epidemiology that we've seen, which includes data through the end of the first quarter of this year.

Okay. So this shows you what happens if you keep tinkering with slides, but what I will show you here is that there are two cut points. One is December 2000 and December 2001, and what you can see here is that as of 2000 in the post marketing study or what you can't see -- I'll read it to you -- is that there were about 22,000 first doses given, whereas through December 2001 there were 54,000 first doses given, and there were only 85 fourth doses in the initial look, where there's 17,000 in the second look. So there's substantially more data there.

So back to visible slides now. The way this is set up, and since this is a post marketing study is that there is no control group, and what we're doing is comparing rates of medical utilization within a defined time window, exposure window following vaccine to a control period in the same individuals.

And the exposure window is 30 days for hospital ER and clinic, and there's an additional window in the clinic of three days that we've used to evaluate possible allergic reactions, for example.

And the control period in these comparisons that I'm going to describe to you is 31 to 60 days following vaccine for all settings.

Also what I'm reporting on here is the subset of children who received the first dose of vaccine at less than 120 days of age. In other words, catch-up and children who started late are not included in this analysis.

And the way we did this is we extracted all diagnoses for medical utilization in the clinic, emergency and hospital, from automated databases that exist at Kaiser Permanente and then rate comparisons were made for all diagnostic categories in the ER and the hospital, and for pre-identified clinic diagnoses as specified in the protocol for the clinic.

In addition, because of concerns expressed regarding a possible association of seizures with receipt of vaccine, we have conducted a review of seizure outcomes using medical record review, and I'll report that separately to you.

To give you an idea, not that you need to read this, this just gives you an idea of the number of diagnoses that were reviewed in the emergency hospital and clinic. These were basically, as I said, for the ER and the hospital all diagnoses, and it's important to be aware of this number because the statistics that I'm going to be describing to you are not adjusted for multiple comparisons.

And I hope there isn't too much information over here on the right. We'll try to capture that, but what this shows you are the diagnostic categories with elevated risk in this comparison.

This is a hospital setting, an emergency setting, and clinic setting, and then which series: the primary series or the booster dose? And for this analysis the primary series was analyzed as a unit, all three doses together rather than looking at each dose separately.

And what we see here is the outcome and then the rate ratio with a confidence interval and part of the P value here.

And what you can see is really there are two groups of diagnoses. These three, GE reflux, pyloric stenosis, and formula intolerance as a diagnosis.

The rate ratio is here indeterminant because there were no cases in the control group, and then these febrile illness in the emergency room, in the clinic, and fever related diagnoses, which was a predefined diagnostic category in the clinic also showed up, and this entity is basically febrile seizures plus fevers. Febrile illness is pretty much driven by the febrile illness as you can see.

Next slide. Oops, that's me.

Okay. So these are the diagnostic categories with decreased risk. To give you an idea, there are actually more of them than the ones with increased risk, and we really attribute this to the multiplicity of comparisons rather than any protective effect for otitis media, for example, because remember the control period here is in the same children. So that wouldn't really make physiologic sense.

So we looked at these, and the elevated relative risk in a little bit more detail, and this is one of these, febrile illness in the emergency room after the booster dose, and this is the n, the number of events here, and this is the days since vaccination, and the 30-day exposure window.

And what you can see here is what we look for in this type of analysis when we see something that we might think might be physiologic, and that is a clustering of events at one time period, and we see these are eight to ten days following receipt of these vaccines.

If you remember, the booster dose is given concomitantly with MMR in the vast majority of these children, actually more than 90 percent, and we attribute this to the well described fever associated with MMR at this same time interval rather than the fever that we described in telephone interviews where we were actively looking for this and during the trial with Prevnar which was seen earlier on. So we're not really seeing that blip here.

Similarly, in the clinic, we see the same thing with the same time clustering of these events for febrile illness in the clinic and only after the booster dose.

In contrast for GE reflux, what we really see is not that. We see really pretty much a uniform distribution of these events spread out over this time window, and similarly for pyloric stenosis the data is much more sparse, but there really is no time clustering of the event or interpretation either.

Similarly, with formula intolerance as well.

So although seizures did not show up as a positive analysis in these reviews that I showed you, we had planned before doing this interim analysis report to do the seizure review, and let me describe that to you.

What we did is attempted to identify all possible seizure events in automated data by looking for seizure, possible seizure, epilepsy, spasm, shaking or suspicious movements, and those were then reviewed in a manner that was blinded as to whether they were in the exposure window or the control window by trained medical record reviewers using a standardized instrument, and they were classified as definite, probable or possible seizures or the other category was not seizures at all. There was a group of children who were there for maintenance or for assurance or for other things that were really not acute events.

But acute events were classified in one of these categories. Based upon what the physician wrote in the chart, if they described a definite seizure event or one was described then that was classified as definite, and if the physician's interpretation was that this was a probable seizure, then we took that at face value.

But if it was something that was included as part of a broader differential and they really weren't sure, and there were no confirmatory tests, and no medication was given, we thought it was less likely and that was classified as possible.

So a priori before doing the analysis we had decided we would want the definite and probable seizures together as a group and then analyze them as events, and those were classified as febrile or afebrile based upon, one, whether it's two possible criteria.

One is if it said they were febrile on the chart, we counted it as febrile, or if there was actually fever recorded by one of these two criteria, and our physicians are a little schizophrenic as to which temperature scale they use. So we had both criteria.

And these are the results for seizure, and I'm sorry this is complicated, but if you slide and dice things enough, this is sort of what happens. This is the hospital setting again, the emergency setting, the clinic, and then the series for this comparison, primary and boosters, primary and booster, primary and booster, and then the outcome, afebrile seizures or febrile seizures.

This is the exposed rate. This is the control rate, and then this is the rate ratio with a confidence interval, and then the P value.

To make a long story short, seizures were uncommon in either window and there was no statistical difference for any of these rate ratios. And furthermore, as you can see, there are a fair number that are below one, a fair number that are above one, and there is really not even any suggestion of a pattern here. So we found that quite encouraging in terms of the safety of the vaccine.

And we also looked at, to give you an idea of what these look like, these are emergency visits for febrile seizures after the primary series.

There isn't really any clustering of this, surely not within the first few days where fever is observed with Prevnar.

And after the booster dose, this is not statistically -- there is no statistical clustering here, but we do see that there are more of these events at the same time period where we saw fever in the emergency room as well.

And, again, if there's anything here, we would probably attribute that to the fever of MMR rather than Prevnar.

So a summary of the safety analysis to date, and I would like to emphasize that this is ongoing and not the final results by any means, is that our analysis showed an increased rate of utilization for febrile illness following the booster dose, and the timing of this fever suggests a relationship to concomitant MMR.

Other events observed with an increased risk, including GE reflux, pyloric stenosis, and formula intolerance, were not felt to be physiologically likely. The analysis, as I said, and data collection are ongoing.

And furthermore, the results are consistent with the first interim analysis which the FDA has had more time to review, as well as with pre-licensure data from our own infancy trial.

So that's the safety data I wanted to share with you, and now I'd like to share some exciting information; at least we think it's exciting vis-a-vis what's happening with disease epidemiology in our population since introduction of the vaccine.

Again, Prevnar was still licensed in February of 2000, and general use began in April. For the evaluation of effectiveness case ascertainment, it's important to emphasize here it was for the whole Kaiser population. One, children and adults, and both vaccinated and non-vaccinated.

So unlike the efficacy trial data we showed you where we're comparing a vaccinated/unvaccinated group, we're really looking here at the population dynamics as a whole and the effectiveness of that vaccine program.

And to look at this effect, we compared the disease risk in the two years since vaccination compared to prior years, as you'll see. All isolates, Strep. pneumoniae from normally sterile sites were identified from laboratory databases, and then the isolate was sent to Dr. Robert Austrian for serotyping.

The medical records of all the infected children have been reviewed to ascertain and confirm vaccination history and history of any underlying disease.

And then we calculated age specific disease incidence. So this is the graph I would like to show you, and I will remember if we come back next year to move things over to the left here a little bit because we won't be able to see this.

But let me orient you to this slide. This is the incidence in cases per hundred thousand person-years ranging from zero to 120 at the top, and these are years at the bottom. Each dot is a year, and the years are unusual in that they began in the second quarter of each year.

And the reason we did that is that's when the vaccine program began. So we wanted to be able to make the comparison of comparable.

And what we see here in this yellow line is children less than two years of age, and we see that prior to introduction of the vaccine to general use, the disease incidence in this group ranged between 80 and about 110-plus cases per 100,000 person-years and then falls off to virtually nothing here, less than ten disease incidents during the year beginning in the second quarter of 2001 and ending in the first quarter this year.

Similarly for children under one, the disease incidence as you know is somewhat less, ranging between 50 and almost 100 here and then falls off quite dramatically. You can see this fell off more steeply because that's where the vaccination program began, and for children under five, we see this as well.

There are five cases total that we saw during this year as compared to about 120 during years prior to introduction of vaccine. Only one of those children was vaccinated, and that child was partially vaccinated.

One of the concerns has been that we might see replacement. It's commonly said nature abhors a vacuum, and there's been a concern that other serotypes would come in and causae disease.

I guess I'd better hurry before something happens here. That's okay. I'd rather live with it this way than lose the whole thing.

What that shows in blue is the same graph that I just showed you in the different age groups, and then below these are non-vaccine serotypes, and what you can see is that, one, the incidence is lower as we all know, and if anything, there is a downward slope to the graph although that trend is not statistically significant, but there's clearly no suggestion of replacement for invasive disease up until this point in time.

And this is something that is actually quite new. This is something that we just presented at the pneumococcal disease meetings in Anchorage a couple of weeks ago, and what we did here is used the same surveillance mechanism to look at disease in older children and adults, and this is the age group here. This is the rate in the five years prior to introduction of vaccine, and this is the rate in the two years after the percent reduction, and part of the P value here.

And what we can see in yellow are shown the two age groups where there's a significant -- or three really if you count this -- age groups where there's a significant reduction in the disease, really quite strikingly dramatic, something we would not have predicted in the 20 to 39 year old age group, a 58 percent reduction in invasive disease in this age group.

Now, most of these have not been serotyped. So this is really all serotype disease. Over age 60 we see a 14 percent reduction, which is also significant, and then over age five we see an 18 percent reduction.

It's important in fairness to say that over age 60 there have been changes in terms of the polysaccharide vaccine coverage in our population which could account for part of this. We estimate there's been about an eight to ten percent increase in coverage over that time period.

But that's not true in this younger age group which we attribute this to the fact that this is the age of the parents of the children who are being vaccinated, and the children it is known -- contact with young children is a risk factor for pneumococcal disease, and we believe that this is entirely suggestive of the fact that herd immunity is operative here and is protecting these individuals.

So, in summary, we've observed a dramatic reduction in basic pneumococcal disease in childhood within our population. The magnitude of the reduction in the first year, which was much greater than the vaccine coverage, and the reduction observed in adults suggests herd immunity effect.

We've not observed any evidence of serotype replacement for invasive disease, and I'd like to say also that Dr. Cindy Whitney of CDC has results from the ABC surveillance program which are consistent with the disease reduction in adults and older children that I've shown you.

Thank you very much.

CHAIRMAN DAUM: Thank you, Dr. Black, for that update.

We have a few minutes for committee questions, if there are, or discussion points. Dr. Katz?

DR. KATZ: Steve, you mentioned the concomitant administration of MMR. Was varicella given at the same time also?

DR. BLACK: Yeah, varicella vaccine, the uptake for varicella vaccine is quite high in our group, and we looked at MMR. There's more than 90 percent of that concomitantly. Usually varicella is given at the same time, but it isn't always. We have not looked at it, but I would guess from past observations we had made it was about 80 percent.

DR. KATZ: The reason I asked is there is some indication that when you give MMR and varicella concomitantly you even further increase the febrile response.

DR. BLACK: At that same interval.

DR. KATZ: Thank you.

DR. BLACK: Actually we'll look at that. that's interesting. Thank you.

CHAIRMAN DAUM: Dr. Faggett and then Dr. Snider.

DR. FAGGETT: Steve, thank you. Those are very exciting reports. A question relative to the experience of Prevnar in the sickle patient. They were probably included under your febrile illnesses, but do you have any information on specifically how the vaccine was tolerated by sickle patients?

DR. BLACK: Yeah, we've not done specific studies on the safety of Prevnar in sickle cell patients. However, the Prevnar vaccine is being routinely used in both younger children with sickle cell disease and in older children as well, and our surveillance does include children with sickle cell disease, and we've not seen during the last two years because they were not surprisingly targeted for early immunization any cases in children with sickle cell disease.

CHAIRMAN DAUM: Dr. Snider?

Steve, I have one question. The adult data you showed on the last slide are pretty interesting. You mentioned that you haven't yet broken them down by vaccine serotypes and non. Will you be able to do so? Do you have the isolates?

DR. BLACK: No. We started collecting data at the first of this year. We're now -- Dr. Austrian, since the case load in children is reduced, is now willing to do serotyping of adults, and so beginning the first of this year, we're now serotyping all ages, but don't have that historically.

Dr. Whitney at CDC, however, does have serotype data from ABC and I think is analyzing that currently and will be reporting it soon.

CHAIRMAN DAUM: I have on other question. In the very nice curves you showed of what's happened to disease in your area since the vaccine was introduced, you broke down the data between vaccine serotypes and non-vaccine serotypes.

How would that look for the non-vaccine serotypes which did appear to be trending down? If you removed the related vaccine serotypes -- excuse me. The serotypes that are not in the vaccine but are related to those in the vaccine from that analysis.

DR. BLACK: Okay. Let me try and rephrase your question. What you're looking for are the non-cross-reacting serotypes.

CHAIRMAN DAUM: Right. Thank you for that help.

DR. BLACK: We have a slide for that here. Let me see if I can find it. We also have a million other things.

Oh, you have that somewhere else? Okay. Sorry.

The numbers are smaller and so there's more noise in this, but let me show it to you.

Yeah, okay. So what we have here is, again, the same type of graph, but you'll notice that rather than going up to 120 or 40 here, this only goes up to 20, and again, with the same age groups, under one you can see actually now has a higher incidence of these. Under two, and then under five, and you know, the overall slope here is sort of downward, although I don't understand that, and this dot, this little blip at the end here is really in the same range as these.

So so far, you know, the numbers here are a lot smaller. So it's a little bit harder to interpret, but we don't think this suggests any evidence of replacement disease because the incidence levels here are very low, consistent with what we saw before.

CHAIRMAN DAUM: Thank you.

We'll take two more comments. Dr. Snider, then Dr. Stephens.

DR. SNIDER: Steve, could you tell us what the serotypes that are vaccine related that you're still seeing are? I mean, specifically people I'm sure that have read the material have some concerns about 19F, for example.

DR. BLACK: Yeah. So the question is, you know, is 19F -- do you mean in vaccinees or in -- yeah, we've really not seen -- I mean the cases of disease that we've seen in the last couple of years since the post marketing took place have not included 19F. There's a couple of fours and one 6B, and that's really about it.

So the concern that we and others had in terms of trying to understand the difference in response to 19F, we're really not seeing that translated into breakthrough disease up until this point in time.

CHAIRMAN DAUM: Dr. Stephens.

DR. STEPHENS: Regarding the effect in young adults, is there any evidence in your health care system of off label use of the conjugate or any increased use of the 23 valent polysaccharide in individuals who may be at risk?

DR. BLACK: Well, we're encouraging increased use in individuals, you know, over age 60. so that has gone up we estimate eight to ten percent over the time period.

The older individuals where we're encouraging its use is primarily hemoglobinopathies or people who are in that category.

There has been some use in older individuals where it's not indicated, but it's very small. There's four or five individuals for reasons that we can't understand who have obtained the vaccine. Four of them are pediatricians. So maybe that's it. They're enthusiastic and want the same protection for themselves. But they're really a handful. It's very, very small.

So it's not the case in the 20 to 40 year olds. We are going to be undertaking a case control study to look at risk factors and look at this in more detail, but that will take some time.

CHAIRMAN DAUM: Dr. Katz, one last.

DR. KATZ: One quickie. In all of those things that are flashing by when you were trying to find the right slide, one that stood out in my mind was sudden infant death syndrome. That's one that in your primary series you're running through the high risk area.

Can you reassure us about that one?

DR. BLACK: Yeah, let me see if I can find that slide.

DR. KATZ: I don't need a slide. Just tell me.

DR. BLACK: Okay. I mean, the rates that we have for that are not for the last year because the state death tapes lag. So as of the interim report that we did through year 2000, the SIDS rates were about half what the state rate was, and were pretty much identical to what they were in the clinical trial, which is about .2 per thousand.

CHAIRMAN DAUM: Thank you very much, Dr. Black.

We sometimes remember and are striving to meet various bars of vaccine safety and various tests and concerns, just how wonderful vaccines are, and it's very gratifying to see this kind of information after the introduction of a new vaccine.

We will move now on to the second part of the sponsor's presentation this morning, which is concerning acute otitis media, or AOM, and we will begin with Dr. George Siber, who will introduce the topic on behalf of the sponsor to us.

Dr. Siber, welcome.

DR. SIBER: Good morning. My name is George Siber. I'm Senior Vice President and Chief Scientific Officer of Wyeth Vaccines.

Is that going to go to right for us? We'll see.

In any event, during the next hour or so we'll present series of presentations on the data and rationale underlying our proposal for an indication for otitis media for the seven valent pneumococcal vaccine, Prevnar.

I'll give a brief introduction on otitis media epidemiology and background. Dr. Terry Kilpi, who is a senior researcher and the head of the Department of Vaccines at the National Public Health Institute in Helsinki, will discuss the FinOM trial that was conducted in Finland, and then Steve Black will come back and discuss otitis media from the Northern California Kaiser Permanente trial. And then I'll give brief conclusions at the end on impact.

First of all, a quick background on clinical manifestations of otitis media or rather of pneumococcal disease in general. This pie diagram shows you the major pneumococcal syndromes and makes the point that the pneumococcus is a very important if not the most important single pathogen contributing to major bacterial infections in U.S. children, causing 45 percent of meningitis in the first two years of age, a vast majority of bacteremia sepsis, and for these two Prevnar is indicated in the package insert, but also about 60 percent of pneumonias and as much as 40 percent of bacterial otitis media.

This shows you a pyramid which puts into perspective the relative frequencies of these syndromes. Fortunately the most severe of those syndromes are the least common, with about 1,400 cases in children under five years of age of meningitis, 17,000 of bacteremia, and estimated 71,000 for pneumococcal pneumonia.

But at the base of this pyramid and really a massive number is the five million estimated episodes of otitis media each year, and although clearly a much milder disease than the others, it certainly has morbidity and has a very tremendous impact on health care and antibiotic use and so forth.

With regard to the epidemiology of otitis media, these are actually data from the Northern California Kaiser Permanente trial and the control groups looking at the age distribution of otitis media, and which show several things.

One, that in boys, in blue, the rates are somewhat higher throughout follow-up period, here to 42 months of age, than in girls. And the peak incidence is very high, and this is otitis visits per 100 children-months between six and 18 months of age, but really continues throughout the follow-up period, declining slowly but steadily with time.

A somewhat more extended age distribution comes from these data, which plot the number of visits for otitis media to physicians' offices in thousands by year from zero to ten years of age, and you can see that the peak here is 4,400,000 visits, and again, a decline over time, but continuing to have as many as five to 600,000 visits per year even out to ages nine and ten years of age.

So to summarize the impact of otitis media, this is the most common reason for sick child visits. It is also the leading cause for prescribing antibiotics during childhood, and we believe that the use of antibiotics frequently contributes to the increasing antimicrobial resistance that we have seen in this country and elsewhere.

Complications of recurrent disease and effusions lead to tempanostomy tube insertions, and this is the most common reason why children have surgery that requires general anesthesia.

The direct and indirect annual costs have been estimated to exceed more than $5 billion per year in children under five years of age. That's for all otitis media.

And this just shows you, I think, what we all know, and that is during the '90s there has been a progressive increase, looking here at pneumococcal disease, an increased rate of resistance from the low digits, five percent or so, to over 30 percent at the end of the decade.

An interesting question is whether there will be an impact of Prevnar on this phenomenon.

Importantly, the serogroups that are most likely to be resistant to penicillin and other antibiotics are serogroups that are contained among the seven valent types of the vaccine, six, 14, 19, 23, and nine. And that's true not only in the U.S. but throughout the world.

And specifically in terms of coverage for otitis media, this is an example of a study by Ellen Wald's group in Pittsburgh reasonably recently looking at serotype distribution in otitis media and suggesting a coverage of the vaccine serotypes themselves of about 70 percent.

If you assume coverage for cross-reactive types, that goes up to 85 percent, and if you only selected antibiotic resistance, you would probably get up over 90 percent in this series in terms of coverage by the vaccine types and related types.

So at the moment, you my be aware that the package insert makes no mention whatsoever about otitis media with regard to Prevnar efficacy, and we are here today to propose that otitis media be included in the package insert and that the indication be that Prevnar is indicated for active immunization of infants and toddlers against invasive disease and otitis media caused by Strep. pneumoniae due to the capsular types included in the vaccine.