**Anti-Infective Drug Advisory Committee**

**FOOD AND DRUG ADMINISTRATION**

**CENTER FOR DRUG EVALUATION AND RESEARCH**

**"Safety and Efficacy of 1-Day and 3-Day**

**Dosing Regimens of Azithromycin**

**Suspension (New Drug Application 50-710,**

**Pfizer Inc.) for the Treatment of**

**Otitis Media"**

November 7, 2001

Holiday Inn

8777 Georgia Avenue

Silver Spring, MD

Proceedings By:

CASET Associates, Ltd.

10201 Lee Highway, 160

Fairfax, VA 22030

\(703\) 352-0091

PARTICIPANTS

CHAIRMAN

Reller, Barth, MD

EXECUTIVE SECRETARY

Thomas H. Perez, MPH, R.Ph.

MEMBERS

Chesney, Joan P.MD

Christie-Samuels, Celia, DC., MD., MPH, FAAP

O\'Fallon, Judith R., PhD

Leggett, Jr., James E., MD

Wald, Ellen R., MD

Cross, Alan S., D

[Consumer Representative]{.underline}

Ebert, Steve, Pharm, D.

FDA

Moledina, Nasim, MD

Alexander, John, MD

Janice Soreth, MD

Goldberger, Mark, MD

CONSULTANTS

Mary Glode, MD

Richard Gorman, MD

GUESTS

Celia Maxwell, MD.

Jane L. Burns, MD

Jan Patterson, MD

Celia Marchant, MD

OPEN PUBLIC HEARING PARTICIPANTS

Michael R. Jacobs, MD

Ron Dagan, MD

CONTENTS

[PAGE]{.underline}

Call to Order, Introductions - L. Barth Reller, MD, Chair 1

Meeting Statement - Thomas H. Perez, MPH, Exec. Sec. 1

Welcome and Introductions - Janice Soreth, MD, Acting

Director, Division of Anti-Infective Drug Products 6

Design of Clinical Trials of Antibiotic Therapy for AOC

Colin Marchant, MD 8

Pfizer, Inc. Presentation:

The Bacterial Pathogenesis of Acute Otitis Media

Edward J. O\'Rourke, MD, Prof. of Pediatrics, Harvard

Medical School 27

Azithromycin in the Treatment of Acute Otitis Media

Michael W. Dunne, MD, Vice President, Clinical

Development, Infectious Diseases, Pfizer Global

Research and Development 36

FDA Presentation

Azithromycin for AOM - Nasim Moledina, MD, Division

of Anti-Infective Drug Products 99

Open Public Hearing 114

Discussion of Questions and Vote 151

Clinical Trials of AOM - John Alexander, MD, Division

of Anti-Infective Drug Products 198

[P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
[E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
[N]{.underline} [G]{.underline} [S]{.underline} 8:00 AM

DR. RELLER: Good morning. Welcome to the Anti-Infective Advisory
Committee meeting, the principal topic, safety and efficacy of 1-day,
3-day dosing regimens of azithromycin suspension for the treatment of
otitis media.

We will begin today\'s meeting with an opening statement from our
Executive Secretary, Tom Perez. MR. PEREZ: Good morning. The following
announcement addresses conflict of interest with regard to this meeting
and is made part of the record to preclude even the appearance of such
at this meeting.

Based on the submitted agenda for the meeting and all financial
interests reported by the Committee participants it has been determined
that all interests and firms regulated by the Center for Drug Evaluation
and Research present no potential for an appearance of a conflict of
interest at this meeting with the following exceptions.

In accordance 18 USC 208(b)(3) full waivers have been granted to Dr.
Steve Ebert and Dr. James Leggett to participate in the discussions of
the new drug application 50-710 for the treatment of otitis media.

In accordance with 18 USC 208(b)(3) general matters waivers have been
granted to all participants with the exceptions of Dr. Steve Ebert, Dr.
Ellen Wald and Dr. Mary Glode to participate in the general matters
discussion of clinical trials of acute otitis media.

Drs. Ebert, Wald and Glode are excluded from this discussion. A copy of
these waiver statements may be obtained by submitting a written request
to the agency\'s Freedom of Information Office, Room 12A30, Parklawn
Building.

With respect to FDA\'s invited guests, Dr. Colin Marchant and Dr. Jan
Patterson have reported interests which we believe should be made public
to allow the participants to objectively evaluate their comments.

Dr. Marchant would like to disclose that he serves as a speaker for
Bristol-Myers Squibb; Glaxo, Smith, Kline, Roche and Wyeth Ayerst. He
consults for Aventis(?) Biovel(?) Bristol-Myers Squibb, Glaxo, Smith,
Kline, the Robert Wood Johnson Pharmaceutical Research Institute and
Wyeth Ayerst. He is, also, an investigator on research contracts, grants
received from Bristol-Myers Squibb, Glaxo, Smith, Kline and Wyeth
Ayerst.

Dr. Patterson would like to disclose that she serves as a speaker for
Wyeth Ayerst, Merck and Aventis. She is a consultant to Pfizer, Merck,
Fusisawa(?) and Schering Plough. She, also, serves on the Clinical
Anti-Infective Advisory Boards for Pfizer, Wyeth, Ayerst and
Estraseneca(?).

In the event that the discussions involve any other products or firms
not already on the agenda for which an FDA participant has a financial
interest, the participants are aware of the need to exclude themselves
from such involvement, and their exclusion will be noted for the record.

With respect to all other participants we ask in the interests of
fairness that they address any current or previous financial involvement
with any firm whose products they wish to comment upon.

Thank you.

DR. RELLER: Thank you, Tom.

Next, I would like to have the members around the table introduce
themselves briefly and their position. We will start with Dr. Mark
Goldberger at my far right.

DR. GOLDBERGER: Mark Goldberger, the Acting Office Director for
Ode-4(?).

DR. SORETH: Janice Soreth, Acting Division Director for Anti-Infectives.

DR. ALEXANDER: John Alexander, medical officer in the Division of
Anti-Infectives.

DR.MOLEDINA: Nesim Moledina, medical officer for anti-infectives.

DR. WALD: Ellen Wald, Chief of Infectious Diseases at the Children\'s
Hospital of Pittsburgh.

DR. LEGGETT: Jim Leggett, Infectious Diseases, Providence Portland
Medical Center in Oregon Health and Sciences University.

DR. O\'FALLON: Judith O\'Fallon, statistician at the Mayo Cancer Center.

DR. CHRISTIE-SAMUELS: Celia Christie, Professor and Chair, Pediatrics,
University Hospital of the West Indies, University of the West Indies,
consultant in pediatric infectious diseases, epidemiology and public
health.

DR. CHESNEY: John Chesney, professor of pediatrics at the University of
Tennessee in Memphis and Infectious Disease Division.

DR. RELLER: Barth Reller, Division of Infectious Diseases, Director of
Clinical Microbiology, Duke University Medical Center.

MR. PEREZ: Tom Perez, Executive Secretary for this Advisory Committee
meeting.

DR. EBERT: Steven Ebert, Infectious diseases pharmacist, Meriter
Hospital and clinical professor, University of Wisconsin, Madison.

DR. CROSS: Alan Cross, professor of medicine, University of Maryland,
Division of Infectious Diseases.

DR. GORMAN: Richard Gorman, pediatrician in private practice and a
member of the Pediatric Advisory Subcommittee.

DR. GLODE: Mary Glode, I am professor of pediatric infectious disease at
Children\'s Hospital, University of Colorado.

DR. BURNS: Jane Burns, pediatric infectious diseases, University of
Washington.

DR. MAXWELL: Celia Maxwell, Assistant Vice President for Health Affairs
and associate professor of medicine, Howard University.

DR. PATTERSON: Jan Patterson, infectious diseases at University of Texas
Health Science Center, San Antonio and hospital epidemiologist for
University Health System in South Texas Veterans Health Care System.

DR. MARCHANT: Colin Marchant, pediatric infectious disease, Boston
University and Tufts University School of Medicine in Boston.

DR. RELLER: Dr. Janice Soreth, Acting Director of the Division of
Anti-Infective Drug Products will give an introduction to today\'s
meeting.

Janice?

DR. SORETH: Thanks, Dr. Reller.

Members of the Committee, invited guests, colleagues in industry and
FDA, ladies and gentlemen, we have a full agenda today. So, I will keep
my comments brief.

First, I would like to recognize several of our Advisory Committee
members who are completing their term with us and rotating off the
Committee.

I would ask you please to come forward and accept a certificate of
appreciation from us. They are Dr. Celia Christie, Dr. David Soper and
Dr. Joan Chesney.

Could you step forward, please?

Perhaps Dr. Soper is not here yet, and Drs. Barbara Murray and Wittner
are, also, not here, but rotating off the Committee.

We very much appreciate your active participation on the Committee, and
we fully recognize that in giving us your considered and critical
thoughts you add to already full calendars and long days.

As you rotate off the Committee I would simply add that we welcome your
comments on the experience as we are always open to your suggestions in
improving the process.

Second, I would just like to comment briefly on today\'s agenda. We will
begin with Dr. Colin Marchant whom we have invited to speak on the dual
aspects of clinical trial design in acute otitis media, an issue that we
periodically revisit. We will then have presentations from the sponsor,
Pfizer and from the FDA on azithromycin on the specific data that were
developed for single dose or a 3-day treatment regimen for children with
acute otitis media conducted in studies that fully correspond to our
current guidance document for developing a drug for acute otitis media.

The open public hearing will then follow and three speakers have come
forward to present. After lunch we will resume Committee discussions of
and voting on the specific data that speak to the efficacy and safety of
azithromycin in various treatment regimens for acute otitis media.

Finally, we will round out the day with an FDA presentation that comes
back to acute otitis media clinical trial design issues or lessons
learned as it were from half a dozen or so meetings that we have had int
he past 5 years on acute otitis media either as a general comment on
guidance for design or on specific drug products seeking a claim of
acute otitis media.

It is not the intent of the last part of today\'s meeting to come to any
final conclusions. Rather it is intended to serve as a prelude to a
future public meeting with an opportunity for all industry, academia and
the public to participate where the focus would be on the guidance
document itself and whether and how it might be revamped or improved.

Dr. Reller, I turn it back to you.

DR. RELLER: Thank you, Dr. Soreth.

Next we will look forward to hearing Dr. Marchant\'s presentation.

Dr. Marchant?

DR. MARCHANT: Good morning. Today I will talk about the design of
clinical trial and antibiotic therapy for acute otitis media, and my
remarks will be of a general nature, and I will not address the
particular application before you today.

My remarks are based on our formulation of the issues of clinical trials
and I think they are pertinent to the question of comparative trials of
acute otitis media.

I won\'t discuss the obvious issues that we should randomize patients or
we should do double-blind trials but rather I am going to focus on the
issues of the outcomes we chose in these trials and the implications
that result from choosing various outcomes.

Of course, we could use a clinical outcome of symptomatic improvement or
a combination of the two, symptomatic and where the clinician examines
the eardrum or some combination of these.

The bacteriologic outcome which refers to actually doing a
tympanocentesis has shown that there is eradication of the organism from
the ear and there can, also, be other combinations of this such as a
combined bacteriologic/clinical one where you look at clinical
improvement and then do a tympanocentesis to ask in cases where they
have found where they have eliminated the organism and then finally is
to look at the time of the outcome. It could be during therapy, at the
end of therapy or after therapy.

The timing of the outcome is varied, often symptomatic improvement or
persistent symptoms have been typically measured at 48 to 72 hours. The
trials that did bacteriologic outcome typically were at 4 to 6 days and
some trials have looked at symptomatic outcome at that same time. Other
trials have looked at end of therapy measuring typically symptomatic
outcomes but often measuring events that have occurred throughout this
time period and then there is the last outcome which was the test of
care where they also consider events that happen after therapy,
recurrences here as your outcome.

To decide how they should study acute otitis media in terms of its
clinical response in the face of effective therapy or therapy that you
would like to be effective placebo-controlled trials are often very
instructive as to what the natural course of disease is and may help you
in planning these.

Also, studies which followed clinical outcomes with bacteriologic
outcomes are also very instructive in telling us how we should plan
these trials.

So, I am going to review some of the data in the literature that speaks
to this. This is a randomized placebo-controlled trial done in Denmark
looking at children primarily older than age 3 with severe earache. They
measured a pain score. They were randomized to placebo or penicillin and
you can see here that in the first couple of days there is a significant
difference in favor of antibiotic treatment. This was done back in the
eighties. So, penicillin shouldn\'t be so shocking, but you can see
there is a difference here, but if you will notice out at day 4 or 5
there is no difference between the treatments. If you are asked whether
antibiotics are effective here, you come up with the answer that no,
they are not.

If you ask the question here, you will come up with the answer that yes,
they are. So, the timing in relation to how the disease behaves is very
important.

Final placebo controls, one of the ways the administration was to have
been done is a trial done at the University of Pittsburgh. The trial was
done in the early 1980s, comparing amoxicillin, placebo and various
combinations of myringotomy. The Pittsburgh trial divided the otitis
media in to severe and non-severe based on high fever and marked earache
and symptoms.

One of the outcomes they looked at was initial treatment failure at
typically 48 hours after starting therapy.

The group did not feel they could do a pure placebo-controlled trial in
the severe group. So, they made these three comparisons, and you can see
that amoxicillin and amoxicillin and myringotomy turned out pretty
similar results, but the placebo and myringotomy there was a larger
failure rate and a difference here depending on whether you make this
comparison or that comparison of about 12 to 14 percent.

So, in the severe group you see a spread in that sort of range, between
10 and 15 percent.

In the less severe arm of the trial they compared amoxicillin with
placebo. Now, instead of a 10 to 15 percent difference in terms of this
initial treatment failure you see a difference of only about 4 percent.
So, the severity of the disease that you are looking at will determine
what your response rate may be.

Also, look here that they were able to show that amoxicillin has a lower
rate effusion at 14 days, but that by 6 weeks the difference is washing
away. Why? Because recurrences of therapy occur equally in those that
received amoxicillin and those that received placebo and what this
should suggest to everybody in terms of a scientific experiment; that is
what this is, is a randomized scientific experiment is that this outcome
here really has nothing to do with whether you have treated or not
treated.

Let us explore that further because this is part of the test of cure
outcome. Let us look at studies with bacteriologic and clinical
correlations. This is a study by Dr. Leibowitz and Dr. Dagan that was
presented at ICAC(?) last September. It is the third of three trials
that basically show the same idea though because this has a larger
number of patients that previous studies it shows it more closely.

What are we looking at here? This is a group of patients treated with
antibiotics with tympanocentesis during therapy and that result was
sterile but then on stopping therapy the first week, the second week,
third and fourth weeks afterwards there was a clinical recurrence of
otitis media that again there was a tympanocentesis to determine what
the bacteriology was. This refers to infections as determined by the
species, whether it was Pneumococcus or Hemophilus or by pneumococcal
serotype or electrophoresis typing of the organisms and for Hemophilus
influenzae they either beta-lactamase(?) positive or negative.

What this shows you is that even in the first week the majority of
patients had more infections, more relapses of their infection. Those
appear at least to be relapses and relapses of the bacteria of pharynx
or relapses because the bacteria had persisted in the ear. We have now
clinical data to address that situation. The previous data I showed you
recurrences occurred at the same rate only in drug and placebo and if
you look at a lot of the clinical trials that have looked at this
clinical recurrence after therapy, they are the same regardless of the
drug that you use. So, here is what you might say about clinical
recurrences. They are not reduced by antibiotic therapy. They occur in
the patients and new infections are more common than relapses.

So, in clinical trials we are going to be counting as failures the event
that don\'t appear to have any relation to antibiotic therapy.

Let us now move on to the clinical bacteriologic correlations in double
tympanocentesis studies looking at patients where the organism is
eradicated for the ear versus those where it persists and look at
clinical success defined as symptomatic outcome at the time of the
second tympanocentesis.

You see that those that eliminate the bacteria have a much higher cure
rate than those where you do not. You will, also, notice that there are
some here that still fail therapy despite the fact that you have
eliminated the bacteria and other studies suggest that those patients
have persistent viral infections that might be responsible for these
persistent symptoms.

You will, also, notice now that probability of failure clinically is
much higher when bacteria persist. This is data that my colleagues and I
did in Cleveland since then using a slightly different approach.
Dr.Degan and colleagues did another study, again, looking at
bacteriologic eradication, failure here in bacteriologic eradication,
then at the clinical status not at days 4 to 6 but between days 4 and 6
and day 10, but they are finding the same thing, and that is you are
more likely to fail if you don\'t kill those bacteria by day 4 to 6 than
if you have eliminated bacteria from the ear.

So, now, I would like to pursue the implications of this. This is the
data from Cleveland. The first two lines are the data I just showed you
two slides ago in pie diagrams. If you kill bacteria 93 percent success
rate. If you don\'t, 62-1/2, but in clinical studies where you don\'t do
a tympanocentesis you will, also, be looking at non-bacterial otitis
media and a response that right there was 80 percent. You can use these
data to calculate the clinical behavior of the disease at various levels
of bacteriologic efficacy of the drug which led to us describing the
Pollyanna phenomenon.

Here is what it shows. Here is efficacy on this axis. Here is
elimination of bacteria from the ear and each line adjoins the
corresponding clinical response that you see clinically. A perfect drug
looks worse than it is. A drug that eliminates bacteria 90 percent of
the time looks worse than it really is, and not all drugs of inferior
efficacy, down here at the bottom here, the yellow line which is the
placebo rate calculated from Dr. Virgil Highley\'s(?) study all the less
active drugs will look better than they are and in this and subsequent
slides I am going to represent drugs that appear worse than they are and
drugs appearing better than they are on the right. The predominant
effect is to conclude that drugs with poor activity actually work well.

So, now I am off to design issues. Now, we have looked at double
tympanocentesis study, single tympanocentesis study measuring clinical
efficacy and in the single clinical efficacy you saw on the previous
slide. This has very precise implications in terms of the ability of you
to do a clinical trial and detect a difference if a difference is there
whereas a difference between, well, a difference between say one drug
and the other versus a narrow difference it takes fewer patients to show
a difference in the clinical trial.

Let us look at that. So, here what I am going to show you is this. If we
compare a drug with 90 percent efficacy with drugs that are 30, 40, 50,
60, 70, 80 percent efficacious and lump your different trial designs and
use the sample size required to look at that for the bacteriologic
outcome less than 100 percent patients are required until you get up to
trying to detect a difference between 80 and 90 percent.

If you look at the clinical outcome in bacterial otitis media that is a
serotype study now you are able to tell the difference between say 70
percent and 90 percent is approaching 2000 patients and if you look at
clinical outcome with no tympanocentesis extremely large numbers of
patients are required.

For those of you, I know there is at least one statistician in the
audience, all the sample size calculations that I am doing today I am
showing you sort of a significance of .05, a power of .9 as the
universal method for calculating sample sizes and all sample sizes are
for a two-limb trial with half the subjects in each limb, and so now in
subsequent trials I am going to try to draw down and simplify the
question.

Various levels of bacteriologic efficacy, 90 percent is about as good as
you get with most trials in the literature. We will call this a good
drug. Here is the placebo related to approximately that of 30 percent
and looking at 50 and 70 percent.

So, I am going to focus our attention on those sorts of differences in
bacteriologic efficacy.

So, now I am just going to show you exactly the same graph that I showed
you before, but now I am just looking at the three different standards
compared to a 90 percent drug and I am going to continue to do that.

The only thing I did was I changed the scale here and topped it out at
2000 patients because nobody has ever down a trial larger and there is
really no point until somebody does of talking about achieving larger
sample sizes.

You can see that the clinical outcomes are way off the chart and not
feasible. The argument that I am putting forward and have put forward in
the literature has been based on the data from Cleveland that my
colleagues and I generated. Perhaps that data is very specific to the
particular patients that we studied.

So, now, I am going to look at other data in the literature and make
similar calculations. So, when I take the Pittsburgh trial I use these
standards. They looked at amoxicillin in the early 1980s and we will
assume it is about 90 percent efficacious in terms of bacteriologic
eradication. That is what the studies would tell you and here is the
effusion for outcome, for example. Here is tap water. That is the
placebo group and here is their response rate, and all I have done is
proportionately calculated these two numbers in between for the fair
drug and poor drug standards.

So, now, if we look at the outcomes in the Pittsburgh trial, what do
they look like? Here is the bacteriologic standard. Here is the outcome
of severe otitis media. They actually looked at myringotomy but that is
using a 14 percent difference, and you can see that with the fair drug
you can\'t tell the difference. With the poor drug you need above 600
patients.

If we look at the middle ear effusion outcome it appears here and if we
look at their clinical outcome in non-severe otitis media which was 78
percent of all otitis media you will have a very tough time telling the
difference between tap water and a good drug.

So, now we will turn to the test of cure outcome. Here is another one of
these Pollyanna graphs,the same bacteriologic outcome here, symptomatic
response. Now, when you start to calculate these recurrences against
therapy you will see what happens. You progressively make excellent
drugs in order that other drugs look worse and worse while your fair
drugs still look better than they really are compared to the
bacteriologic eradication rate.

I have used a range of numbers here because the recurrence rates are
going to vary by the population you look at and your exact time points
but that is a pretty wide spread.

What are the sample size implications of that?

There is your bacteriologic standard. Here is your clinical outcome and
as you add in the clinical occurrences after therapy in test of cure
outcome you just make it harder and harder as you have a higher
recurrence rate to show the difference between two drugs.

So, it makes everything look the same. I would now like to turn to some
other outcomes. I draw your attention here to the data from Cleveland.
We looked at bacteriologic response here and clinical response there
whereas Dr.Degan looked at bacteriologic outcome here and clinical
response anytime in this interval.

So, during this time after they did the second tympanocentesis the
otolaryngologist in this study would evaluate the patients in terms of
their symptoms and in terms of the examination of the middle ear, and if
they were failing therapy another therapy was described. So, the outcome
of failure could occur anywhere from this visit to this visit at the end
of therapy. So, that allows us to look at end-of-therapy outcomes
particularly the strategy of doing a tap and a tap of failure.

So, here is bacteriologic efficacy, and here we have the bacteriologic
outcome in clinical failures the tap and tap of failures. You can see
that yes, it has narrowed again but it is a little bit better than just
doing a clinical outcome in bacterial cases, and again, this is all
using Dr. Degan\'s data and if we look at the test of cure outcome using
approximately a 15 percent rate which is what he found in his studies,
no difference between those where the bacteria were eliminated and those
where they weren\'t and a rate of about 15 percent.

Again, you can see it driving down. So, you can see that the choice of
clinical trial design is going to determine where your efficacy is set,
but it is, also, going to have an effect on the narrowness of the
difference in the size of the trial.

So, here are the outcomes with Dr.Degan\'s trials.

Bacteriologic, a tap and tap of failures study does a little bit better
but it requires still quite large numbers at the 70 versus 90 percent,
the fair drug standard and again using the test of pure outcome is going
to drive the sample size higher.

So, how important are these? Well, I have talked about a good drug, fair
drug, poor drug, tap water. Using the relationship between clinical
response and bacteriologic outcome if you treat 1 million children, 1
million prescriptions how many children would have persistent symptoms
on day 3 to 6 who otherwise would have been asymptomatic if you had a
perfect drug if you eliminated bacteria from the ear? Well, we won\'t
achieve that standard, but here is the good drug standard, 20 percent.

Well, the difference between a good drug and a fair drug is 40,000
children per million prescriptions having persistent symptoms because
they got a drug that was less effective than a good drug, and if we go
down to tap water the difference is 140,000 minus 20,000 which comes out
to 120,000 children who remain symptomatic per million prescriptions who
otherwise would be better.

So, now to just draw down the see the numbers as they go by you I am
going to look first at the tap water standard and study designs using
initial bacteriologic diagnosis. How many patients do you need? You can
see that the bacteriologic outcome and the tap and tap of failures do
pretty well, clinical outcomes less well. Test of cure obviously drives
the sample size from here up to here.

This is the number of patients you analyzed because about 25 percent of
otitis media is non-bacterial. This is the number of patients you must
recruit. So, this is the work that must be done by the investigators, by
the sponsor of the trial, etc.

What about the clinical outcomes now, no tympanocentesis, again the tap
water standard? The best we can do comes from the data from the
Pittsburgh study with severe cases of otitis media and we are a little
under 500.

I now go to data I didn\'t talk about before and that is Dr.Rich
Rosenfeld, an otolaryngologist who is trained in epidemiology who did a
meta analysis in his book, evidence-based otitis media or something to
that effect, and the best outcome he could come up with in terms of its
effect on the disease was clinical resolution in 7 to 14 days and using
that calculation again we are all seeing a sort of neighborhood, and if
we take non-severe cases we are approaching 2000 patients just to tell a
difference between a good drug and tap water.

Moving up to the poor drug standard we see now that tap and tap of
failures is still feasible but getting tougher, clinical outcomes going
up for bacterial cases. The sample size is almost all in the thousands
here for the poor drug standard and if we move to the fair drug
standard, well, this is potentially feasible with a bacteriologic
outcome but this is now getting extremely difficult and the clinical
outcomes are really out of sight.

So, I am going to draw some conclusions because most trials are only
300, 400, 500 patients, 100, 200 patients and so forth, most trials that
use bacteriologic diagnosis and clinical outcome have been too small to
distinguish between a good drug and tap water and all have been too
small to distinguish between a good drug and a fair drug.

Most trials using clinical diagnosis and a clinical outcome have been
too small to distinguish between a good drug and tap water.

Data do not support the use of a test of cure outcome as a
scientifically valid outcome in clinical trials of antibacterial drugs
for acute otitis media.

Now, the sort or recommendations from this. Clinical trial data in
support of licensure of antibiotics for otitis media should at a minimum
at least show efficacy, that is distinguish between tap water a good
drug.

I think the FDA is already heading in this direction, but again, I
encourage that they should convene experts to examine the design of
antibiotic trials for otitis media using scientific data and scientific
principles as opposed to professional consensus and revise the guidance
for industry accordingly.

The problem with the tympanocentesis studies is basically that they are
difficult to do at least in the United States. That difficulty relates
to the fact that it is a painful procedure and people are reluctant to
do two tympanocenteses and if you look at the literature on how we
relieve pain in children for this procedure there are no good studies.
There is no good data. There is no standard of care and really in order
to do these studies which not only enlighten us in terms of relative
drug efficacy but allow us to, also, look at the relationship between
the MIC of the organism and eradication and so forth to do these we
really need studies looking at systemic or topical analgesia or
anesthesia and I suggest that industry might want to become interested
in seeing that go on, and because the bacteriologic outcome is not
universally accepted and certainly not universally loved mobilize a way
to make clinical trials better using clinical outcomes by more sensitive
outcomes, enriched populations and these should be investigated in
rigorous studies but I caution everybody that large numbers of subjects
are likely to still be required if we are going to distinguish between
one drug and another.

So, I thank everybody for their attention, and I thank the agency for
inviting me to address you today.

Thank you.

DR. RELLER: Thank you, Dr.Marchant for that presentation. That will give
new and enlarged insights into the discussion that we have this
afternoon on the topic of future approaches to clinical trials for
guidance to industry and investigators that we will cover after the
discussions this afternoon.

We now turn to the topic of the rest of this morning\'s deliberation and
the content that will be assessed by the Committee in their vote just
after lunch and I at this time would like to introduce the Pfizer
presentation about azithromycin and treatment of acute otitis media.

Dr. Michael Dunne, please?

DR. DUNNE: Thank you, Dr.Reller.

Good morning. My name is Michael Dunne, and I am an infectious disease
clinician that is responsible for clinical development of anti-infective
products at Pfizer.

We appreciate the opportunity this morning to discuss with you the data
that support the use of azithromycin given either as a single dose or
over 3 days for the treatment of acute otitis media.

I will be presenting an overview of the relevant preclinical data
followed by discussion of the clinical trial data that supported the use
of azithromycin with the shorter courses.

First, we will begin though with a presentation by Dr.Edward O\'Rourke.
Dr. O\'Rourke is assistant professor of pediatrics at Harvard Medical
School and a Director of Harvard Medical International.

Dr. O\'Rourke will give us an overview of acute otitis media
specifically focusing on the influence of Streptococcus pneumoniae and
Hemophilus on the presenting signs and symptoms, the clinical course of
the disease and the secondary complications of acute otitis media.

Dr. O\'Rourke?

DR. O\'ROURKE: Good morning. Thank you for the opportunity to speak with
you today. I am going to talk about otitis which I think all of the
pediatricians in the room understand is the most commonly diagnosed
bacterial disease in children and the most common reason that
antibiotics are prescribed at all.

It, also,is one of the major reasons that we have problems with
antibiotic resistance in pediatrics because of the rate at which this
diagnosis is made, either correctly or incorrectly and the treatment
habits of our pediatricians. When we talk about tracing therapy for
otitis media we certainly want to think about what the reasons are that
we are treating and which are the pathogens that we should focus on, and
in selecting therapy on a rational basis there are several bits of data
that we would like to have to understand how to focus. One would be the
prevalence of pathogens, both patients who are untreated and those who
are presenting after an antibiotic failure.

We would, also, like to know whether the clinical severity of acute
otitis media relates to the pathogen.

Dr. Marchant showed us that some patients have severe disease and may be
easier to make an impact on their outcome than those with mild disease.

We would, also, like to know whether untreated infections resolve by
themselves and whether that varies by pathogen, where is a risk of
complications and whether that varies by pathogen.

We see here a commonly displayed summary of the bacteriological data
from Pittsburgh in the 1980s showing that Streptococcus pneumoniae is
the most common bacterial pathogen, Hemophilus No. 2, then Moraxella
catarrhalis.

In this particular summary of data there were a fairly large number of
patients included without bacterial isolates and if we look at data more
recently from the same institution we see that in data where there are
fewer non-bacterial pathogens in fact Streptococcus pneumoniae is even
more prevalent in relation to the other pathogens in otitis media.

If we look at data from the nineties looking at either untreated acute
otitis or persistent otitis media, this data from New York we see again
a fair number of patients with no pathogen, Streptococcus pneumoniae
clearly more prevalent than Hemophilus influenzae, Moraxella or Group A
Streptococcus.

In patients with persistent otitis media again Pneumococcus is the No. 1
bacterial pathogen although there are a large number that do not have
pathogens isolated. Hemophilus influenza and Moraxella come up second
and third.

Now, with this question of what organisms are isolated from patients who
have been treated and failed therapy we see that there is a difference
between studies that are reporting data from the 1980s and before and
those reporting in the 1990s, and fundamentally what we see is that in
the 1980s beta-lactamase producing organisms, Hemophilus influenzae or
Moraxella were the most likely organisms to be isolated from patients
who failed therapy.

Here we see drug-resistant Strep limo(?) and there are some intermediate
resistant strains reported but those would likely be different than some
of the strains down here in the 1990s where we start to see much higher
rates of truly resistant Streptococcus pneumoniae presenting and a
fairly stable picture with regard to Hemophilus and Moraxella.

One of the studies that I just alluded to was from Kentucky in the
mid-nineties and actually on the prior slide may have been misreported,
but here is an example of pathogens isolated from the middle ear after a
few days of antibiotic exposure that is those who are failing therapy,
those who are symptomatic at approximately 2 to 3 days and therefore
being re-evaluated with a tympanocentesis and we can see that
overwhelmingly Pneumococcus is the organism that is isolated in that
setting, that beta-lactamase producing organisms count for only 11
percent of the isolates in this study from Kentucky.

What about the issue of self-resolution? The classic study here is
Harry\'s study from Alabama in the 1960s and his data show that
Pneumococcus actually only infrequently resolves by itself within 3 to 6
days. Hemophilus resolves by itself about half the time. Moraxella more
recent estimates suggest probably resolves by itself 70 or 80 percent of
the time.

So, we see that Pneumococcus here is the on least likely to resolve by
itself.

Are there different clinical syndromes associated with these different
pathogens, that is to say are some more likely to be severe than others
and should those perhaps be the focus of our therapy?

Rodriguez and Schwartz in the Washington, DC area studied 224 episodes,
evaluated with tympanocentesis and clinical scoring, and they found that
a characteristic of a proportion of isolates that were found, that is
Pneumococcus No. 1, Hemophilus No. 2, Moraxella No. 3. They found
interestingly that if you look at the patients with more severe
presentation, that is fever greater than 38.3 with either red or yellow
bulging tympanic membrane that 41 percent of the cases of Streptococcus
pneumoniae fit into this category. Only 1.6 percent of those caused by
H. flu and only 2 percent of those caused by Moraxella fit into this
category of bulging TM with fever giving actually a positive predictive
value of this clinical syndrome of 94 percent for etiology by
Streptococcus pneumoniae.

There is no difference in that study in pain score. However, Harry,
also, did a study like this back in the sixties, 858 episodes evaluated
by tympanocentesis and clinical findings at presentation, found that 34
percent of the patients\' middle ear fluids grew Streptococcus
pneumoniae, 20 percent middle ear fluids grew Hemophilus. Severe pain
was seen in 41 percent of those with Streptococcus pneumoniae versus 17
percent of those with H. flu, fever over 101 in 30 percent with Strep.
pneumonia, 13 percent with H. flu, severe pain and temperature greater
than 101, 12 percent of Strep. pneumo and only .6 percent of those with
H. flu and mild or no pain and a temperature less than 100, 13 percent
with Strep. pneumo, 26 percent with H. flu.

So, it is pretty clear evidence that these two organisms while certainly
overlapping Hemophilus was more of a pest than a real pathogen in this
disease.

Just more evidence supporting the idea that these organisms produce
different syndromes comes from evaluating inflammatory mediators. This
is IL6 isolated from middle ear fluid by pathogen. Streptococcus
pneumoniae is in this first column, Hemophilus influenzae here and
Moraxella catarrhalis here. You see clear evidence that higher rates of
inflammatory mediators are seen with Streptococcus pneumoniae than the
other two organisms.

In fact, in animal studies with Hemophilus influenzae it has been shown
the peak of inflammatory mediator with this particular organism occurs
before clinical symptoms can be detected, that is the inflammation is
already resolving at the time that clinical symptoms are apparent.

Perhaps the major reason that we can justify treating acute otitis media
is the prevention of suppurative complications. The treatment of otitis
certainly can have some effect on pain, but that is more evident in
those with severe disease than with mild disease as Dr.Marchant showed
us with mild disease when used to treat 25 people who are going to
actually benefit from therapy, but with suppurative complications as a
consideration perhaps treatment can be justified.

Pneumococcus if we look at the most common or most severe and important
of the suppurative complications of acute otitis media is acute
mastoiditis and this is the rank order of pathogens with regard to their
rates of isolation in acute mastoiditis. Pneumococcus is No. 1 in
virtually every study reported around the world in the last 20 years.
Drug-resistant Streptococcus pneumoniae is being increasingly reported
in many of these studies although there are some studies that show while
Pneumococcus is No. 1 that the rate of pneumococcal resistance is not
going up quite as fast as we feared.

Group A Streptococcus interestingly has replaced Hemophilus influenzae
as the No. 2 pathogen, remarkable because it is really the No. 4 on the
list of causes of acute otitis media. Staphylococcus aureus and
Pseudomonas come in in the three and four slots reflecting probably more
chronic disease than truly acute, but I think what is notable is that
Hemophilus influenzae is reported most often as not occurring at all or
in studies that are done looking at children in the 1970s and 1980s up
to about 5 percent.

One of the interesting points here, however, is that in the seventies
and eighties we were not using the Hemophilus influenzae B vaccine and
very few of these studies differentiate the Hemophilus influenzae that
they report as being either typable Type B or non-typable disease.

There are occasional reports of non-typable H. flu as an etiologic agent
but they are really quite rare. To my knowledge Moraxella catarrhalis
has not been reported as a cause of mastoiditis at all. In summary,
Pneumococcus i clearly the major focus if we are worried about
suppurative complications of otitis media and Hemophilus influenzae is
literally reportable as an etiology.

If we consider then that Streptococcus pneumoniae is behaving as
suppurative pathogen in this disease acute otitis media what is
different about Hemophilus? It is an organism that commonly colonizes
the nasopharynx. So it is present in children normally in the day care
age group. It is typically thought the non-typable H. flu as opposed to
type B. It is typically thought to lack the ability to invade in normal
hosts. It is almost never the cause of bacteremia or meningitis for
example.

H. flu otitis is more likely to follow viral infection than any other
bacterial organism and therefore giving the impression that perhaps even
more than with the other organisms it requires some viral infection to
damage the host before Hemophilus can impose disease, again, a similar
point here that otitis prone children are more likely to be colonized
with H. flu reflecting again the fact that Hemophilus influenzae is the
No. 1 pathogen associated with otitis media with effusion as opposed to
acute otitis media, and as we ponder this, along with some recent data
looking at the role of Hemophilus for example in bronchitis, chronic
bronchitis, its ability to attach to non-ciliated epithelial cells and
to macrophages and remain viable may explain some of the role of this
organism in both otitis media and other diseases, and a question comes
up whether its intracellular location shields it from some antibiotic
therapy or whether simply the fact that it is part of a virtual biofilm
relatively metabolically inactive allows it to escape complete
eradication and then recur.

In summary if we look at the relative importance of these two major
pathogens in acute otitis media since Streptococcus pneumoniae is the
No. 1 isolate occurring 30 to 50 percent of bacterial isolates,
Hemophilus influenzae the No. 2, 15 to 30 percent in the US,
Streptococcus pneumoniae is the No. 1 cause of treatment failure in the
1990s, Hemophilus the No. 2 cause. The rates of drug resistant Strep
pneumo are rising faster than the rates of beta-lactamase positive
Hemophilus influenzae. Strep pneumo fails to resolve on its own without
appropriate antibiotic therapy about 80 percent of the time versus 50
percent of the time for Hemophilus. Streptococcus pneumoniae is
associated with a severe acute otitis media syndrome versus a less
severe syndrome for Hemophilus and more of a chronic otitis media with
effusion syndrome. Streptococcus pneumoniae is an invasive pathogen with
the potential to do real damage and long-term morbidity whereas
Hemophilus influenzae is a non-invasive opportunist which may cause
temporary morbidity and there are virtually no suppurative complications
other than an occasion perforated tympanic membrane associated with
Hemophilus influenzae in the normal host, and this organism is more
likely to recur after therapy.

Thank you.

DR. DUNNE: Thank you, Dr. O\'Rourke.

Why should physicians choose to use azithromycin for treatment of acute
otitis media? First, it is bactericidal against the pathogens
responsible for this disease. It has a pharmacokinetic profile suited
for the treatment of infection. It reaches effective concentrations in
the middle ear. It is used to sustain concentrations in white blood
cells. A complete course of therapy can be given in a single dose and
shorter courses of therapy will optimize compliance.

Azithromycin is a well-tolerated antibiotic. The side effects have been
well described and are generally gastrointestinal in nature. It is
recommended in treatment of children who are penicillin allergic and
post approval the oral suspension has been prescribed over 40 million
times.

Clinical efficacy equivalent to comparators has been demonstrated first
with the 5-day dosing regimen and now extended to 3-day and single-dose
therapies.

The single-dose therapy though has additional features of interest.
Giving the dose all at once allow for higher peak drug levels earlier in
the course of infection. As azithromycin concentrates in white blood
cells delivery of the regimen early in the course of therapy takes
advantage of the period of maximum neutrophil recruitment to the site of
infection. Based on in vitro data entry into white blood cells, uptake
per se is increased with elevated temperatures. The single dose
maximizes the rate of compliance and minimizes the burden on the care
giver.

The focus of today\'s presentation will be around the pivotal clinical
trials that support the use of the single and 3-day dose for treatment
of acute otitis media. Before we get to that data, however, we will
briefly review some relevant preclinical information.

The development program that generated azithromycin was focused on
finding a macrolide that was more acid stable than erythromycin.

That goal was achieved by insertion of a nitrogen into the macrolide
ring. The consequence of this nitrogen insertion was to add a second
basic site to the compound and it is the positive charge at these two
sites here and here that is responsible for the propensity of
azithromycin to accumulate within cells.

At extracellular pH a small percentage of the compound exists in a
neutral form here. This neutral form is more easily able to traffic
through cell membranes.

Once exposed to the lower pH in acidified vacuoles more of the drug
becomes proteinated leading to accumulation within this space here. This
accumulation within cells that have acidified vacuoles such as
neutrophils and monocytes is important in a disease such as acute otitis
media, given the infiltration of these cells into the middle ear during
the course of infection.

This is an H&E stain of a cross section of the mucosa of infected middle
ear. The lumen is here. The mucosa down here.

One can see the infiltration into the mucosa by neutrophils. Presumably
it is through this infiltration to the middle ear space by neutrophils
that azithromycin is delivered to the site of infection.

It is, also of interest to note the extent of the tissue involvement in
this disease process. Evidence that azithromycin accumulates within the
middle ear space comes from a number of pharmacokinetic studies in which
levels were measured within the middle ear.

In the study by Skaglione, this top study here one can see that the
distribution between cells in the extracellular compartment is similar
within the middle ear space to what we see in the blood.

In general these levels exceed the MICs for sensitive pathogens
responsible or acute otitis media. The in vitro microbiologic profile of
azithromycin has been extensively looked at over the last 10 years.

In a recently published study the MIC 90 to Streptococcus pneumoniae for
over 4000 organisms was found to be 2 micrograms per ml.

Similarly in over 3000 isolates of Hemophilus influenzae the MIC 90 was
2 micrograms per ml. For Moraxella catarrhalis the MIC 90 was found to
be less than 0.12 micrograms per ml.

While MIC 90 for Moraxella and Hemophilus has not changed over the last
10 years the MIC 90 for Streptococcus pneumoniae has been increasing.
There are two major mechanisms of resistance used by Streptococcus
pneumoniae against macrolides. The first works through an efflux pump.
The MIC 90 for 70 isolates of Streptococcus pneumoniae harbored in a FA
efflux pump was found to be 8 micrograms per ml.

The other mechanism is coded by an erm(?) d-methylase. Among 65 strains
carrying the resistance mechanism for erm-d-methylase, among 65 strains
carrying the resistance mechanism for erm-d-methylase the MIC 90 was
greater than 128 micrograms per ml.

There has been identified an association between resistance to
penicillin and resistance to macrolides. Among 1200 isolates of
Streptococcus pneumoniae susceptible to penicillin the MIC 90 to
macrolides was 0.25 micrograms per ml.

Among isolates with high-level penicillin resistance the MIC for
macrolides increases to 32 micrograms per ml.

Presented here is similar information examined in a different manner.
Among isolates susceptible to penicillin only about 3 percent were found
to be resistant to erythromycin. For isolates demonstrating high level
resistance to penicillin as many as 61 percent were found to be
resistant.

The phenomenon of cross resistance is seen across other antibiotics
including another beta-lactams F-furoxine(?) trimethaprim(?) sulfa and
to a lesser extent with tetracycline.

This list of antimicrobials, also, tracks with age such that isolates
obtained from younger children are more likely to be resistant than
those obtained from those over the age of 13. For example, 63 percent of
isolates obtained from children under the age of 2 were susceptible to
erythromycin in this series compared to 80 percent with isolates takes
from those over the age of 13.

Resistance to antimicrobials including macrolides has been increasing
over the last 10 years. Presented here are data from eight published
surveillance studies examining pneumococcal resistance to either
macrolides or penicillin, and the penicillin break points are given here
in these studies. These red squares here are non-susceptible isolates.
The green squares are those that are high-level resistant.

In 2001 in vitro resistance to macrolides is seen in up to 25 percent of
isolates with high-level resistance to penicillin in up to 20 percent.

In general macrolide resistance in the US has been associated with the
efflux pump mechanism.

These isolates were obtained from a variety of sources. So a range of
resistance rates can be seen in any one year surveyed. Generally
resistance to community-acquired respiratory tract isolates is higher
than that obtained from steroid sites.

Now, focusing on susceptible isolates, in vitro experiments demonstrate
bactericidal activity of azithromycin against Pneumococcus.

In this time kill experiment Streptococcus pneumoniae is exposed to
azithromycin at 2 and 8 times the MIC. After 24 hours of incubation
there has been a 3 to 6 log reduction in the quantity of organisms in
culture consistent with a bactericidal effect.

Similarly bactericidal activity has been seen for azithromycin against
Hemophilus. In this time kill experiment Hemophilus influenza is exposed
to azithromycin at the MIC and at 4 times the MIC. After 24 hours in
incubation there has been a 4 and 6 log reduction in the quantity of
organisms in culture again consistent with bactericidal activity.

We now move to in vivo data derived from animal models, specifically the
chinchilla model of acute otitis media. In this experiment presented at
ICAC last year by Franz Bable from Steve Pelton\'s group chinchillas are
infected with non-typable Hemophilus influenzae.

Starting 2 to 4 days later they undergo tympanoscopy as well as
tympanocentesis at various time points with bacterial cultures as well
as drug levels.

Dosing is started on day zero with either 30 milligrams per kilo or 120
milligrams per kilo orally each day for 5 days.

Drug levels from the middle ear are presented here. Peak levels are seen
at day 5. Total middle ear fluid levels which would include any
intracellular as well as extracellular drug are 9.6 micrograms per ml on
the 120 milligram per kilo dose and approximately 3 micrograms per ml on
the 30 milligrams per kilo dose.

These total middle ear fluid concentrations are within the range of
levels obtained from children getting a 30 milligram per kilo dose. The
extracellular levels from a 30 milligrams per dose are lower than that
of the total levels you can see here. These are the extracellular
levels. These are the total levels,

Not shown here the serum levels seem with the 30-milligram-per-kilo dose
most closely to approximate the serum levels seen with a
30-milligram-per-kilo dose given in children.

Quantitative bacterial cultures from the middle ear were performed. One
can see it on day 3 no significant reduction in bacterial counts was
observed compared to controls. By day 5 the mean counts on the
30-milligram-per-kilo dose were approximately 2 logs lower than control
while those from the 120-milligram-per-kilo dose were 5 logs lower.

Bacterial eradication continued through day 11. Between this slide and
the next one there are three points to be made. The first is that at
doses at least in the range of what could be seen in children there is a
significant antimicrobial effect of azithromycin against Hemophilus
influenzae and that effect is observed as a dose response.

The other two points focus on methodology. The second point is that the
timing of the culture significantly affects the impression of
antimicrobial effect. For example, if day 3 in this experiment was the
only time point looked at one could conclude that neither regimen has
activity.

In contrast at day 5 one could conclude that the 120-milligram-per-kilo
dose is very potent and the 30-milligram-per-kilo dose while not fully
clearing the infection has been effective enough to reduce the
concentration of organisms by 2 logs.

The third point to be made is done by contrasting these findings with an
analysis of the same data looked at in a qualitative fashion. Here is
the same information on antimicrobial effects. It is reported as
cultures being either positive or negative. Now, one could interpret the
day 5 data as reflective of a 50 percent failure rate for the
120-milligram-per-kilo dose and a 95 percent failure rate for the
30-milligram-per-kilo dose, a very different picture of antimicrobial
activity from what was previously demonstrated.

So, the sensitivity of the test methodology must be considered in
forming an interpretation of antimicrobial activity in these kinds of
settings.

We turn now to the clinical program where we will start with an overview
of the data at the point of use of azithromycin as a
30-milligram-per-kilo dose now given over 5 days, a 5-day regimen.

These were the pivotal studies that supported the 5-day program. In the
two comparative studies patients given azithromycin had a clinical cure
rate similar to the children taking the comparative agent. There were
two studies that identified pathogens at baseline.

The clinical success rate at day 30 for the 56 children with
Streptococcus pneumoniae identified at baseline was 71 percent. With 47
with Hemophilus influenzae identified at baseline it was 64 percent and
for the 26 children with Moraxella catarrhalis it was 73 percent. The
results of the smaller comparative study were similar.

Of the 975 patients who received azithromycin 7.2 percent developed an
adverse event related to drug compared with 23 percent of the 827
children who received amoxicillin/clavulanate. The most common adverse
event seen was diarrhea at 12.6 percent for children getting amoxicillin
and clavulanate; vomiting and abdominal pain were also seen.

We will come back to these side effects later when we compare them to
the shorter courses of therapy with azithromycin.

Based on the animal experiments and pharmacokinetic properties of
azithromycin it appeared that the total dose and not the duration of
dosing might be most relevant to treatment outcome. Given this
background and the ongoing medical need for therapies which could
improve compliance rates we undertook a program to reduce the dosing
duration for treatment of acute otitis media to under 3 days and then to
a single dose therapy.

I would just like to point out that the regulatory implications of this
program were not to gain an indication for acute otitis media as that
was previously established with the 5-day program but rather to adjust
the dosage and administration section of the label to allow for 5, 3 or
1 day of dosing.

Now, for orientation the actual daily dosing of these regimens is
provided here. The 5-day dosing regimen is given at 10 milligrams per
kilo on the first day and 5 milligrams per kilo each day from days 2 to
5.

The 3-day dosing regimen as given as 10 milligrams per kilo each day for
3 days and the single dose regimen provides the entire
30-milligram-per-kilo dose in a single administration.

The program to study these shorter dosing regimens follows the 1998 FDA
guidance on the design of studies for acute otitis media. These
guidelines require one statistically adequate comparative study with
clinical end points and a test of cure visit 2 to 4 weeks after
conclusion of therapy.

In addition there should be one non-comparative trial with
tympanocentesis at baseline to identify pathogens of interest and
clinical cure rates for these pathogens should be clinically acceptable
to find as comparable to a labeled comparator drug.

The program had pivotal and supportive studies. The pivotal studies in
support of the single-dose program were study R-0581, a double-blind
randomized comparative clinical trial and study 1015, a non-comparative
study with tympanocentesis at baseline.

There was one comparative double-blind randomized clinical trial in
support of the 3-day dosing. It was agreed that microbiologic data from
the single dose program could support the 3-day program given the data
already available from 5-day dosing.

There was one Phase II supportive trial that served as a pilot study and
it compared azithromycin as a single-dose therapy with 3 days of dosing
with azithromycin with ceftriaxone given intramuscularly. Patients had a
baseline tympanocentesis in this study as well.

We will start by reviewing the single-dose program. The best place to
start to understand comparability between all the studies in this single
dose program is to look at who was included in the trials. We will do
that by reviewing the inclusion and exclusion criteria for the
single-dose program overall.

Now, this is a busy slide, but I will draw your attention to the most
important points. First you will see that there are four columns at the
top. The three columns on this side are the pivotal studies in the
program. This column provides a reference point for the 1998 FDA
guidance specifically in this slide on the symptoms consistent with
acute otitis media.

All three studies allowed for enrollment of children down to 6 months of
age. Ninety-eight percent of the children in study 1015 had either ear
pain or fullness. Seventy-seven percent of the children in R-0581 had
ear pain. Ninety-three percent had either ear pain or a history of fever
and 96 percent of the children had ear pain in study 95001. So, all of
these children appear to have symptoms consistent with acute disease.

Presented here are the inclusion criteria for signs of tympanic membrane
disease. Over 90 percent of the patients had at least one abnormality in
study 1015. The majority had more than one. All patients in both 1015
and R-0581 were to undergo electroacoustic reflectometry and have
acoustic gradient angle of less than 70.

Ninety-nine percent of those in R-0581 and 87 percent of the children in
1015 had that finding. The majority of the remaining children in 1015
had a perforated eardrum. So, they couldn\'t undergo that test. All of
the children in 95-001 had a bulging eardrum at entry.

Recent antibiotic use was exclusionary in each study. Though not
specifically indicated in every protocol no child was enrolled with
typanostomy tubes present or who had otitis externa.

The primary end point was clinical cure. The primary time point for test
of cure was day 28. In addition to cure and failure the assessment of
improvement at day 28 was collected in study R-0581 and 95-001. As a
result the comparison of clinical success which is the sum of cure plus
improved was, also, analyzed for these studies at the day 28 time point.
This clinical success assessment was made at the end of therapy visit in
all the studies and is examined as a secondary end point.

The population of patients analyzed for clinical efficacy at day 28
included patients who took at least one dose of study medication, had a
diagnosis of acute otitis media and returned for a visit at day 28.

Anyone who received a concomitant antibiotic for failure was carried
forward as a failure. The population evaluated for bacteriologic
response included all the clinical efficacy population who also had a
pathogen of interest isolated at baseline.

The assessment of cure was defined as complete resolution of specific
signs and symptoms of acute otitis media. Following recent guidance for
the two more recent studies, 1015 and R-0581 the presence of a middle
ear effusion per se did not preclude an assessment of cure. So, some
residual signs of effusion did not prevent the investigator from calling
that patient a cure.

So, we will focus on the pilot study first. Study 95-001 was the first
study designed to assess the activity of azithromycin given as a single
dose for the treatment of acute otitis media. It compared the
single-dose regiment with azithromycin given for 3 days with
ceftriaxone. This was a prospective single center study performed in
Costa Rica. The patients were screened and randomized to azithromycin as
either a single dose or a 3-day dose or to ceftriaxone. Each of the
azithromycin regimens was given with a placebo oral suspension to match
the other.

Ceftriaxone was given intramuscularly at 50 milligrams per kilo as a
single administration. There was no blinding for ceftriaxone as it was
not felt appropriate to give placebo injections to the other groups.

In an attempt to blind this regimen though the physician assessing the
clinical response did not administer the study drugs.

Typanocentesis was performed at baseline. Follow-up occurred at typical
intervals through day 28.

Sixty-six children were randomized to each regimen. All of these
children were available for a safety assessment and all but three were
included in an assessment of efficacy at day 28. Approximately one-half
of the children had no organism identified at baseline.

The mean age of children enrolled was 2.4 years and roughly 40 percent
were under the age of 2. The distribution of demographic characteristics
was comparable among the treatment regimens.

The mean duration of symptoms of acute otitis media prior to
randomization was 1.5 days for those given azithromycin as a single
dose, 2.4 days for those given a 3-day dose of azithromycin and 1.7 days
for those given ceftriaxone.

Analgesics or antipyretics were used during the course of the study to a
similar extent by children on each regimen. Symptomatic medications for
respiratory tract infections were infrequently used throughout the
observation period. The clinical success rate at day 14 was similar on
each regimen as you can see here.

At day 28, again, there were similar success rates and cure rates,
success on this line, cure here. Provided for reference is the 95
percent confidence interval on the difference in outcome between the
single dose azithromycin and ceftriaxone.

Clinical outcome was, also, stratified by age. Clinical cure rates at
day 28 were similar between regimens for each group. As is typically
seen the cure rates for children less than the age of 2 are lower than
those for children over the age of 2.

Fifty-seven of the 60 Streptococcus pneumoniae isolates obtained during
the study had susceptibility testing performed. Forty-six of those were
susceptible to azithromycin and 11 were resistant. All isolates were
susceptible to ceftriaxone.

All isolates of Moraxella catarrhalis and Hemophilus influenzae were
susceptible to both azithromycin and ceftriaxone. Of patients in whom
Streptococcus pneumoniae was identified at baseline the clinical cure
rate at day 28 was 85 percent in the 20 patients receiving a single dose
of azithromycin, 94 percent for the 17 patients receiving 3 days of
azithromycin and 83 percent for the 23 children receiving ceftriaxone.

Of patients for whom Hemophilus influenzae was identified the cure rate
was 88 percent in the eight patients receiving a single dose, 69 percent
in the 13 patients receiving 3 days of azithromycin and 89 percent in
the nine children receiving ceftriaxone. There were only two patients
where the Moraxella catarrhalis was identified.

Coming now to safety, 11 percent of children given a single dose
treatment of azithromycin had a treatment-related adverse event compared
with 9 percent of those given 3 days of azithromycin and 9 percent of
those given ceftriaxone.

Similar rates of diarrhea were seen on each treatment regimen with rash
more common in the ceftriaxone-treated group and vomiting at 5 percent
more common with the single-dose therapy with azithromycin.

There had been a concern that giving the entire dose of azithromycin all
at once would result in an unacceptable GI side effect profile. The
adverse event rate seen here though was encouraging and supported the
clinical development program for single-dose therapy.

We turn now to study R-0581. This study was designed to collect
comparative clinical data for the single-dose regimen. It was a
multicenter randomized double-blind comparative study of azithromycin
given at a single dose and amoxicillin/clavulanate each with matching
placebos.

A history and physical exam was performed at baseline. The first dose of
study medication was given in the clinic and patients were asked to wait
for 30 minutes. Any patient who vomited during that time was redosed.
Patients were contacted by phone between days 3 and 5 at which time data
relevant to adverse events, compliance and clinical symptoms was
collected.

At days 12 to 16 and again at days 28 to 32 patients returned to the
clinic where data relevant to adverse events and clinical response was
obtained.

One hundred and seventy-five patients were randomized to each study
regimen and 173 in each group had a safety assessment. One hundred and
fifty-one patients treated with azithromycin and 154 treated with
amoxicillin/clavulanate were included in the efficacy analysis at day
28.

The mean age of children randomized to azithromycin was 2.7 years and to
amoxicillin/clavulanate it was 3.4 years. Approximately 40 percent of
the children enrolled were under the age of 2.

Regimens were balanced with respect to age, gender and race. The
duration of symptoms of acute otitis media prior to randomization was
3.4 days for those given azithromycin and 3.9 days for those given
amoxicillin/clavulanate.

Approximately 80 percent of the children had a prior history of acute
otitis media. Analgesics and symptomatic medications for treatment of a
respiratory tract infection were used during the course of the study to
a similar extent by patients one each study regimen.

The clinical success rate at day 14 was similar on each treatment
regimen as seen here. The clinical success rates at day 28 were, also,
similar with a lower limit on the 95 percent confidence interval on the
difference of minus 10 percent given here. The lower limit on the
difference in cure rates was minus 7 percent.

Clinical outcome stratified by age was, also, examined. The cure rates
at day 28 for children above or below the age of 2 were similar for each
regimen. Again, as expected cure rates for children under the age of 2
were lower than for those children older than 2.

Ninety-nine percent of children randomized to azithromycin took their
study medication compared to 83 percent of those
amoxicillin/clavulanate.

Turning again to safety 17 percent of the children receiving a single
dose of azithromycin reported an adverse event related to drug compared
to 23 percent of those randomized to amoxicillin/clavulanate.

Diarrhea and rash were seen more frequently in children given
amoxicillin/clavulanate and vomiting was seen in 4 percent of children
on either regimen.

Study R-0581 confirmed and extended the efficacy of a single dose as we
had seen previously in the pilot study. We will now review study 1015.

Study 1015 was designed to obtain clinical outcome information according
to the pathogen isolated by tympanocentesis at baseline. It was a
prospective open-label multicenter non-comparative trial.

History, physical exam and tympanocentesis were performed at baseline.
The first dose of study medication was given in a clinic and patients
were asked to wait for 30 minutes. Any patient who vomited during that
time was redosed.

Patients were contacted by phone at day 5 at which time data relevant to
adverse events was collected. At day 10 and again at days 24 to 28
patients returned to the clinic where data relevant to adverse events
and clinical response was obtained. The primary efficacy end point was
clinical cure at day 28 by baseline pathogen.

Organisms isolated by the local laboratory were sent to a central lab
for confirmation. Two hundred and forty-eight patients were enrolled in
the study and all of these were included in safety assessments. Two
hundred and forty-two patients were assessed for clinical outcome at day
28. Approximately one-half of the patients had an organism identified at
baseline.

The mean age of children enrolled in the study was 3.4 years.
Thirty-five percent of those enrolled were under the age of 2. The mean
duration of symptoms of acute otitis media was 2.5 days and 72 percent
of the children had at least one previous episode of acute otitis media.

Analgesics were used during the course of study in 63 percent of the
children and symptomatic therapies for respiratory tract infections were
used in 19 percent.

The clinical success rate at day 10 was 89 percent. The clinical cure
rate at day 28 was 85 percent. This is all patients enrolled. The
clinical cure rate for children over the age of 2 was 89 percent and it
was 77 percent for those under the age of 2. Again, we see that children
under the age of 2 had a lower success rate than the older children.

Eighty-eight percent of 76 children with Streptococcus pneumoniae
isolated at baseline were cured at day 28. Sixty-four percent of 44
children with Hemophilus influenzae isolated at baseline were cured at
day 28 and all 10 patients with Moraxella catarrhalis were cured.

I would like to focus a little bit more on the isolates of Streptococcus
pneumoniae identified in the study.

Of 76 patients with Streptococcus pneumoniae identified at baseline 67
isolates had susceptibility testing performed. Presented here is the
number of isolates distributed by the baseline MIC.

The break point for resistance to azithromycin is 0.5 micrograms per ml
which would make these 12 isolates resistant.

The resistant isolates sort into two groups, those with an MIC of 8 and
those with an MIC of greater than 256 micrograms per ml.

We have some additional data on this group of 12 organisms. There were
seven isolates that had an MIC of 8 micrograms per ml. All of these were
susceptible to clindamycin and all had the mef-A gene identified by PCR,
both characteristics of organisms that have an efflux pump mechanism of
resistance.

All five of the isolates with an MIC greater than 256 micrograms per ml
were resistant to clindamycin and had the erm B gene identified
consistent with ribosomal resistance.

Presented here is the clinical outcome by baseline MIC for 66 patients
that had clinical outcome data available. Four of the 12 patients with
these resistant isolates failed therapy. You can see there are four
right here. We did note that this child here had a resistant isolate
recovered on therapy. So, I would, also, like to review this one
patient.

This is an outline of the patient\'s clinical course. He presented with
an abnormal reflectometry score in the left ear and tympanocentesis of
that ear revealed Hemophilus influenzae and Strep. pneumoniae with an
MIC of 8.

On day 4 because of persistent symptoms he came back to the clinic where
the left ear had improved. However, the right ear was now found to be
involved. Tympanocentesis and culture of that ear revealed Streptococcus
pneumoniae but now the MIC was greater than 256 micrograms per ml. The
child\'s therapy was then switched.

In order to determine if this was the same organism, this Streptococcus
pneumoniae was the same or not but simply had a higher MIC we did pulsed
field gel electrophoresis on these two isolates and that is presented
here. This is the strain an MIC of eight. This is the strain with an MIC
of greater than 256 micrograms per ml, and these two strains of Strep.
pneumoniae were determined to be clonally distinct which raises the
possibility that the child\'s failure on therapy was a consequence of a
superinfection with a less-sensitive organism. Because of the cross
resistance seen between penicillins and macrolides in Strep. pneumoniae
we performed an assessment of clinical outcome by baseline penicillin
susceptibility.

Forty of the 65 isolates were susceptible to penicillin as shown in the
top left of the table, these 40 over here. Thirty-eight of the 40, 95
percent were assessed as cured at day 28.

Just to note all of these 40 isolates were, also, susceptible to
azithromycin. Here in the left-hand column on this side there are 16
isolates with intermediate resistance and 12 of the patients with these
isolates were clinically cured.

In the middle nine isolates demonstrated high-level resistance to
penicillin and six of the patients with these isolates were clinically
cured.

I would like to focus some more attention on these nine isolates now in
the next slide.

These nine isolates were analyzed according to their macrolide
susceptibility as seen in the bottom table there. Three of the isolates
were susceptible to azithromycin and all three of the patients with
those isolates were clinically cured.

An interesting thing to note here is that all of the isolates with the
erm B phenotype demonstrated high-level resistance to penicillin. So,
there was a complete correlation between those two.

Now, I should, also, note that these data are updated from what you have
in your briefing document on Page 25. Now, safety. In this
non-comparative study 12 percent of patients receiving azithromycin
experienced a treatment-related adverse event. The most frequently
identified event was vomiting seen in 6 percent of the patients. In this
study of single dose of azithromycin the clinical outcome assessed in
patients with infections due to the key pathogens responsible for acute
otitis media was comparable to that seen with the 5-day regimen.

Okay, so now we will move from the single dose program to the 3-day
program, and we will start with study 1014. The purpose of this study
was to collect comparative data on the activity of azithromycin given
over 3 days for treatment of acute otitis media.

This was a randomized double-blind multicenter study where patients were
given either azithromycin for 3 days or amoxicillin/clavulanate at 45
milligrams per kilo per day divided b.i.d. for 10 days with matching
placebo.

Children were enrolled down to the age of 6 months. Ninety-seven percent
of the children had either ear pain or fullness. The majority of
subjects had more than one of the typical signs of tympanic membrane
disease. Ninety-eight percent of the patients had an electroacoustic
reflectometry exam with an acoustic gradient angle less than 70 at
baseline..

Recent antibiotic use and the presence of tympanotomy tubes were
exclusionary criteria and no child was enrolled with otitis externa.

A history and physical exam was performed at baseline. Patients were
contacted by phone at day 3 to 5 at which time adverse event data and
compliance data were collected.

At day 10 and again at day 24 to 28 patients returned to the clinic
where data relevant to adverse events and clinical response was
obtained.

The primary end point was clinical cure. The primary time point was day
28 at which time a clinical assessment of cure or failure was obtained.
Clinical efficacy at day 28 was analyzed for patients who took at least
one dose of study medication, had a diagnosis of acute otitis media at
baseline and returned for that visit.

Patients who used a concomitant antibiotic for failure were counted as
failures and carried forward as such.

Cure was defined as complete resolution of the signs and symptoms of
acute otitis media. The presence of a middle ear effusion would not
necessarily preclude an assessment of cure.

One hundred and eighty-eight children were randomized to azithromycin
and 185 to amoxicillin/clavulanate. All of these children were included
in the safety analysis. One hundred and eight-two children given
azithromycin and 180 given amoxicillin/clavulanate were included in the
efficacy analyses at day 28. Symptoms prior to enrollment for children
on either regimen was 1.2 days. Over 80 percent of the children had a
previous episode of acute otitis media.

Analgesics were used by approximately half of the children on either
regimen at any time during the study and 40 percent used symptomatic
treatments for respiratory tract infections.

Clinical success rate at day 10 was similar on each regimen given here.
Clinical cure rates at day 28 were equivalent with a lower limit of the
95 percent confidence interval on the difference of minus 5.

Clinical outcome stratified by age was, also, examined. The cure rate at
day 28 for children above or below the age of 2 was similar on each
regimen. Again, as expected cure rates for children under the age of 2
were lower than for children over the age of 2..

Ninety-nine percent of children assigned to azithromycin completed their
treatment regimen compared to 89 percent of those given
amoxicillin/clavulanate.

Eleven percent of children taking a 3-day regimen of azithromycin had a
treatment-related adverse event compared to 20 percent of those taking
amoxicillin/clavulanate.

Diarrhea and rash were seen most frequently in those on
amoxicillin/clavulanate. Vomiting was seen to a similar degree on each
regimen.

In this comparative study the 3-day regimen of azithromycin demonstrated
comparable safety and efficacy to amoxicillin clavulanate.

I would like now to present a summary overview of the four studies that
I just presented. As we have seen in the three comparative studies
azithromycin was demonstrated to be as effective as the comparator as
defined by the lower limit of the confidence bounds and the difference
in cure rates.

The similarity in efficacy rates was, also, seen in the more
difficult-to-treat subpopulation of children under the age of 2 and the
same conclusion can be drawn from an assessment in this subpopulation at
the earlier end-of-therapy time point.

An 88 percent clinical cure rate was seen in the 76 children from whom
Streptococcus pneumoniae was isolated at baseline, a 64 percent cure
rate in the 44 children from whom Hemophilus was identified at baseline
and all of the children from whom Moraxella was identified.

Similar results were seen in the smaller comparative study. Presented
here are safety data from the comparative pivotal studies for the single
and 3-dose regimens as well as the 5-day regimen submitted in the
original application.

The comparators have been pooled across all the studies.
Treatment-related adverse events were seen in 14 percent of patients
given a single dose of azithromycin, 10 percent of those given the 3-day
dose and 8 percent of those given the 5-day dose. This compares to a 22
percent adverse event rate in those given the comparator drug.

Diarrhea was the most frequently observed in the comparator regimen.
Vomiting was seen in 1 percent of those given the 5-day regimen here, 2
percent of those who got the 3-day regimen, 5 percent of those who got
the single-dose regimen and 4 percent of those who got the comparator.

Now, there is a progressively higher rate of patients with adverse
events in the 30-milligram-per-kilo dose of azithromycin as the duration
of dosing shortens.

This was not unanticipated. The gastrointestinal side effects are dose
proportional and the 30-milligram-per-kilo dose on day one with the
single-dose therapy delivers more drug than the 10-milligram-per-kilo
dose on that same day, but given the shorter duration of dosing on the
single dose the likelihood of experiencing related adverse events on
subsequent days would decrease. Therefore we thought it was, also,
important to consider not just the number of patients with adverse
events but the actual number of adverse events accounting for the
duration of each event as well.

For reference we see the total number of patients that had an adverse
event here. You saw that in the previous slide.

Noted below, however, are the number of related adverse events
normalized for patient year of exposure. What one sees is that while
more patients getting the single dose had a side effect, mostly on the
first day of dosing, the number of event days of side effects was not
higher than on the other regimens.

In review of the clinical data there are a few topics that were of
additional interest to us and merit some further discussion.

These topics include the effect of vomiting on day 1 on the clinical
outcome of children assigned to the single-dose therapy, a comparison of
outcome at day 28 for published studies and empiric therapy with acute
otitis media with azithromycin as well as a by-pathogen outcome
assessment at day 28 and a look at outcomes at earlier time points than
day 28, including the use of other measures to assess clinical response.

We wanted to assure ourselves that there was no negative impact on
clinical outcome for patients assigned to the single-dose therapy who
subsequently vomited. A total of 52 children, 10.7 percent assigned to
single-dose therapy vomited at some point during the observation period
which goes out to 30 or 35 days after dosing.

Thirty-six of these children vomited on the first day. So, there may be
concern about vomiting around the time of dosing on this first day. We
assessed outcome for those 36 children and compared that outcome to the
group that did not vomit on that day. Ninety-one percent of the children
who vomited were cured or improved at day 14 compared to 89 percent of
those who did not. At day 28 the rates were 85 percent and 81 percent.

Based on this overall measure of clinical outcome at least of the
patients in this program the children who vomited initially were not
disadvantaged.

The previous data presented information on a population basis. The data
presented here measure absorption on an individual patient basis and are
taken from PK studies in normal adult volunteers given a single dose of
2 grams or 3 grams of different formulations of azithromycin, four
formulations here in the first study, two formulations here, two
formulations over here.

Displayed in the red triangles here are the mean AUC for each group with
corresponding standard errors around it. The green triangles are
individual results from patients who vomited greater than 2 hours after
dosing, here, here, here and here and here, and the yellow from those
who vomited within 2 hours. So, that would be these two, this one, these
here, here, here.

The yellow triangles highlighted with purple dots are those that vomited
within 30 minutes. There are four of those, one, two, three, four.

One can see that the values for patients who vomited fall within the
standard error and are as likely to be above the mean as below
regardless of the timing of the vomiting post-dose.

These two sets of data provide some assurance that individuals that
vomit around the time of dosing are as likely to be clinically cured as
those who do not vomit.

We will now examine the clinical response at day 28 for any azithromycin
comparative study of empiric therapy for acute otitis media and then
look at the clinical outcome at day 28 for patients with either
Streptococcus pneumoniae or Hemophilus identified at baseline who were
treated with either azithromycin or any other approved therapy for acute
otitis media.

Presented here are the 95 percent confidence intervals on the difference
in cure rates for all studies either published or presented for
regulatory review with outcome data available at day 28.

The studies in yellow here at the top are the two studies that supported
the original 5-day dosing regimen. The study here, the 1014 study
supports the 3-day dosing regimen. The study, R-0581 supports the
single-dose regimen and there are a variety of other published studies
that have data available.

Now, in an analysis of studies that compared azithromycin to
amoxicillin/clavulanate, so any one of these that had
amoxicillin/clavulanate as the comparator totaled about 1800 patients,
as well as an analysis of all of these studies with about 2000 patients.

The point estimate of difference in outcome is small, and there are very
narrow confidence intervals around it.

Presented here is the 95 percent confidence interval on the point
estimate of success. So, this isn\'t difference in cure rates now. This
is just the point estimate of success for antibiotics that are approved
for treatment of acute otitis media that have clinical outcomes data at
day 28 for patients with Streptococcus pneumoniae identified at
baseline.

The data is presented as clinical success. These here are clinical cure
down here, and this is the as presented in the labels. For reference the
outcome of patients given a single dose or azithromycin is given here.
These vertical dashed lines just orient you around the upper or lower
limits of the 95 percent confidence interval on that point estimate.

Now, some caution should be taken in interpreting these data. Important
demographic variables like age, previous episodes of acute otitis media,
other things that are important in outcome are not taken into account in
looking at one drug versus another here.

These are simply the data as they appear in the label, but even so these
are data that have been used for regulatory decisions and are available
to treating physicians.

From these data the outcome at day 28 for children with acute otitis
media due to Streptococcus pneumoniae and treated with a single dose of
azithromycin is comparable to that of other regimens.

Presented here now are the 95 percent confidence intervals again on the
point estimate of success for all drugs approved for treatment of acute
otitis media that had data available in the product label on clinical
outcome at day 28 in patients with Hemophilus identified at baseline.

The data is presented again as clinical success and clinical cure and
again that is as shown in the labels.

For orientation this is the outcome of the single dose treatment here.
The dashed lines are the upper and lower 95 percent confidence limits.

Again, no attempt is made to adjust the outcomes by these other
important demographic variables. This is just as it is.

Given that caveat it would appear that the clinical outcome at day 28
for children with Hemophilus at baseline treated with azithromycin is
comparable to that of other approved therapies.

In addition to the information at the day 28 test of cure the data is
collected throughout the observation period that may be, also useful in
assessing clinical response. This would include various on-therapy data
such as the use of additional antibiotics for failure, the use of
analgesics or antipyretics to control symptoms and the results of
questionnaires aimed at the patient\'s impression, the parents\'
impression I should say of clinical outcome.

Presented here is a survival-type analysis focusing on the time to use
an additional antibiotic for failure. As a parent could bring a child to
the clinic at any time for reassessment it provides an additional
measure of the timing of clinical failure.

If I can draw your attention to the earliest time period here and
actually looking over the whole curve as well you can see that there is
no obvious difference in the time to antibiotic used for failure between
any of the regimens in this pooled analysis of the three comparative
studies that I reviewed this morning.

Alternatively the earliest response to therapy could be measured by the
use of medications to alleviate the symptoms of disease. Here I present
the percentage of patients using analgesics throughout the observation
period, in study R-0581 no difference in the use of analgesics was seen
and the use of these symptomatic medications had dropped to 2 percent by
about day 5.

Again, in study 1014 no difference in the use of these medications was
seen suggesting that gross differences in the symptoms of acute otitis
media among these regimens is unlikely.

In study R-0581 parents were asked at various intervals to assess how
sick overall their child had been. One could see at day 3 to 5 here the
parents felt that their children were improving at a similar rate
between those given a single dose of azithromycin and those given 10
days of amoxicillin/clavulanate.

Following guidance documents the test of cure visit for this program
occurred at day 28. Assessments of the day 10 to 14 end-of-therapy visit
though were also performed.

Presented here are the 95 percent confidence intervals on the difference
in clinical outcome for all clinical trials comparing azithromycin to a
beta-lactam that had an assessment of clinical outcome at days 10 to 14.

There are 5-day dosing studies again. These are the ones that supported
the original application, a 3-day study I reviewed this morning and
R-0581 here supporting the single-dose therapy. In general one can see
that the difference in success rates was small in each of these studies
and a pooled analysis of approximately 3200 patients comparing
azithromycin with amoxicillin/clavulanate and again here in analysis of
almost 4000 patients comparing all the patients in this program one can
see that the difference in success at day 14 was less than 2 percent
with very narrow confidence limits.

This is for us to examine the outcome of children treated with a
single-dose of azithromycin for acute otitis media due to Hemophilus at
the day 10 to 14 time point relative to other approved therapies.

Presented here is the 95 percent confidence interval on the point
estimate of success for antibiotics that are approved for treatment of
acute otitis media and clinical outcome data at day 14 for patients with
Hemophilus isolated at baseline.

For reference the outcome of patients given a single dose of
azithromycin is up here and again we have the dashed lines that give the
upper and lower limits of the 95 percent confidence interval. Again,
these are point estimates of success.

The same cautions we noted previously about comparisons between the
drugs are important. With those caveats, however, the outcome at day 14
for children with acute otitis media due to Hemophilus and treated with
a single dose of azithromycin is comparable to other therapies.

In conclusion then we find that the data presented this morning
demonstrate that azithromycin given as a single dose or over 3 days is
an effective empiric treatment for acute otitis media.

Adverse event rates were similar or lower than the comparator and are
generally limited to the gastrointestinal tract.

We believe that these shorter courses of therapy will optimize
compliance while easing the burden on the care giver.

Thanks for your attention. I would be happy to answer any questions.

DR. RELLER: Thank you, Dr. Dunne.

Questions for Drs.Dunne or O\'Rourke from the Committee.

Dr.Chesney?

DR. CHESNEY: Would you mind reviewing Slide No. 104 for us again,
please?

DR. DUNNE: Main body presentation No. 104, please?

I will go over this again. This is data taken from studies in adults. It
is pharmacokinetic data. It looked at different formulations of
azithromycin. They were given as 2 grams as a single dose or 3 grams and
there are different groups you can see in each study depending on the
formulation that they received.

These are the PK parameters that were collected and this particular
slide looks at area under the curve. The red triangles here are the
means, and there is a standard error bar around each of the means.

The green triangles here, so this one, this one, this one here, here,
here, these are individual values. They are individual AUCs for the
subjects that vomited at greater than 2 hours, right? Yes, greater than
2 hours post-dose.

The yellow triangles are the AUC measurements for the individual
patients that vomited within the 2-hour window, and then we highlighted
the ones that vomited even within 30 minutes and that is as you can see
there in the purple dots.

DR. CHESNEY: Those weren\'t levels drawn from the patients though?

DR. DUNNE: I am sorry.

DR. CHESNEY: Were those levels drawn from the patients?

DR. DUNNE: Yes. These are the individual patient\'s data. So, we have a
mean in red and in the individual patient in the yellow or the green to
give you a sense of where they fit in and our conclusion from this
particular slide here is that even if you vomit after getting the dose
of azithromycin you still see to be absorbing it, and you might ask how
could that be, you know, you gave them the drug and they are vomiting it
up; how does that work?

The first thing to think about is that the amount of drug that is
delivered either in this situation or actually in the pediatric trials
is very small. It is only 2 teaspoons, 10 cc\'s. It is actually very
hard to bring that back up. It actually lines the stomach wall.

Another thing that is important is that if it is treatment-related
vomiting that tends to recur when the drug has reached the duodenum the
distal parts of the duodenum. By the time a drug is there, the pyloric
sphincter will have closed if you start to vomit.

In other words by the time a drug is getting out to the place where it
is causing you to vomit you are already absorbing it and even if you do
vomit there is very little actual substance in there to come back up.
So, it all kind of fits together when we look at the PK data and the
clinical outcome data for us.

DR. CHESNEY: Just one more question along these same lines. Do we have
any pharmacokinetic data from children using the single-dose therapy?

DR. DUNNE: No, we don\'t have any PK data in children per se at the
30-milligram-per-kilo single dose.

DR. CHESNEY: Were any children redosed if they vomited within half an
hour?

DR. DUNNE: Yes, there were. There were eight children that were redosed
if they vomited within the 30-minute window.

DR. RELLER: Dr. Glode?

DR. GLODE: I had three short quick questions, I think. One would be in
the information we were given, the briefing document there is reference
to modified intention to treat analysis.

Could you just review what is modified in intention to treat?

DR. DUNNE: Yes. Actually let me put up the slide that shows kind of how
we analyzed the patients? They are all kind of the same. So let us put
up main slide No. 85, please?

Patients who were analyzed at day 28 had to receive a dose of drug. So,
if you randomized and then left the clinic you would not be included.

You had to have a diagnosis of acute otitis media at baseline. I think
just about everybody had that, but that was a rule and in this
particular study you had to have shown up, actually in all of the
studies you had to have shown up at the day 28 visit.

That means that the rule generally was that missing data was excluded
from this particular analysis.

DR. GLODE: Thank you.

Then, and please excuse me. You presented so much data that I may have
gotten this wrong, but it looked to me like the failure rate in the
Costa Rican study was 6 percent for the day 28 overall failure rate and
then in your subsequent studies that were done at multicenters in the
United States they are pretty consistently in the range of sort of 25 to
26 percent per single dose?

DR. DUNNE: Yes.

DR. GLODE: What do you think is the explanation for that?

DR. DUNNE: It is hard to know. That is a single center. So, within that
25 percent of the overall for the other studies there could have been
centers that were higher or lower around that. It is a single center
study.

DR. GLODE: My third question is that you said, \"And as expected the
failure rate in all these studies is much higher for children less than
2 than greater than 2.\" Why do we expect that?

DR. DUNNE: It has been seen in all of the studies that have used
whatever antibiotic in treatment of those children.

DR. GLODE: But what are the possible explanations or what has been
excluded? For example, is the rate of recovery of pathogens, bacterial
pathogens different? If you do a tympanocentesis on less than 2 year
olds versus older than 2 year olds, are we treating more non-bacterial
disease in those children? I mean just sort of biologic plausibility I
need an explanation.

DR. DUNNE: I think that you, I will just speculate here just for a
second. A respiratory tract infection, of course, can occur because of
host defense problems in addition to a particular pathogen that has come
and taken advantage of that host defense issue. I think the children
under the age of 2 are likely to have more host defense issues. The
angle of the eustachian tube is a little different. The antibodies they
may have to the various bugs are at different levels than the older
children. There are different developmental issues which may be playing
a role in the outcome of children under 2 rather than over 2. So, it
could be other epidemiologic variables which get folded in there as
well, day care center attendance, for example, other things that could
be important.

So, there is probably a collection of reasons.

DR. GLODE: And has anybody analyzed the tympanocentesis studies to see
if the rate of recovery of a bacterial pathogen is different in the
younger children than the older children? That would be of interest, and
that information is available, I guess, just could be analyzed that way.

DR. DUNNE: Let me just look and see for a second if we have something
along that line.

DR. RELLER: While Dr. Dunne is looking up this information, Dr. Marchant
had a comment to make.

DR. MARCHANT: There is a study in the brochure that the Food and Drug
Administration handed out by Carlin which shows that it is the exact
data that you are asking for and it shows that the patients that, in
patients whom you fail to eliminate the organism on average younger than
those where the organism, sorry. Patients who eliminate the organism are
older than patients who fail on average, the mean age.

So, young age is associated with failure to eliminate bacteria from the
ear, and there is parallel clinical data in other trials that show the
age effect on a clinical basis.

DR. DUNNE: I can just answer the one question. I think we will have to
go back and look that up for you specifically. We had outcome data by
bug. That is not the same question that you asked. So, we will have a
look at that and see if we can bring it back after the break.

DR. RELLER: Dr. Wald had a question.

DR. WALD: Specifically though, Colin, I think that the question is is
there a lesser frequency of recovery of bacterial pathogens in children
less than 2 years of age, and I think the answer is no.

DR. MARCHANT: Right.

DR. WALD: I think that is the answer to your question that frequency of
recovery of bacterial pathogens in children under 2 is not less.

I really enjoyed your presentation. I think you did a very nice job, but
there are two issues that really I find perplexing. In every study of
the epidemiology of acute otitis media children under 2 are the largest
age incidence group. Maybe two-thirds to 70 percent of all children with
acute otitis media are under 2. So, I am a little bit surprised that in
every one of your studies that this more-difficult-to-treat age group is
in fact under represented. That is sort of question No. 1, and question
No. 2 is that in the two tympanocentesis studies that were done the
recovery of bacterial pathogens was only 50 percent, and I think that is
a little bit less than we expect and my suspicion is that when children
are selected for tympanocentesis one is very stringent in applying
criteria because you really want to recover a bacterial pathogen.

So, that makes me really worry about the studies in which there was no
tympanocentesis.

DR. DUNNE: I will start with the first question if I can make sure I
have got that clear. Why is there only say 40 percent of the patients in
these studies include children under the age of 2 whereas you might
expect 50 or 60 percent in the clinical population? Yes, it is an
enrollment into studies issue, and it may be that some parents with
children under the age of 2 are less likely to enroll their children in
a trial compared to what you might see in the community. I can say
specifically within the studies, again, enrollment was allowed under the
age of 2 and the investigators were free to enroll anyone that they
wanted to but these are the data that we kind of got.

On recovery of organisms, I think 50 percent recovery in these types of
studies is probably not far off from what is seen typically; certainly
in the studies that we have done it is not far from what has been
presented.

I wouldn\'t doubt that in other settings you might be able to get a
higher rate of recovery. Say in a clinical practice setting you know the
patients and there is more follow-up but the 50 percent mark is about
what we have seen in other studies that we have done.

DR. RELLER: Dr. Gorman and then Dr. O\'Fallon.

DR. GORMAN; As a pediatrician it is nice to see some recognition of host
factors. Knowing we stand in front of the Anti-Infective Committee the
microbiology discussion was very elucidating to me, but there are a few
other host factors involved, and I was glad to see that those were
mentioned at least briefly.

You had a lot of data about failures and successes over and under 2. Was
any of that failure or success related to the adverse event and
discontinuation of the medication, either yours or the comparator agent?

DR. DUNNE: So, to repeat the question \--

DR. GORMAN: The data showed that there was a higher failure rate in
children under 2. Was that related to the adverse events and the
discontinuation of medicine secondary to adverse events?

DR. DUNNE: For the patients who received azithromycin there was a 99
percent compliance rate. So, we wouldn\'t have seen failures due to
discontinuation of therapy in the azithromycin group. We didn\'t analyze
the data specifically to look at compliance with the
amoxicillin/clavulanate arms, for example, to see if that correlated
with failure or not. Typically you need fairly large sample sizes to get
a sense of compliance giving you efficacy correlations. So, I don\'t
think I can answer that fairly for you, but it wasn\'t an issue for the
azithromycin-treated patients if they altered their drug.

DR. RELLER: Dr. O\'Fallon?

DR. O\'FALLON: You set me up. My question right from the \"get-go\" has
been about how compliance was defined since compliance is obviously a
major issue for this particular application. In those two double dummy
type studies R-0581 and 1014 I read trying to figure out just exactly
what it meant. They say, \"The double dummy,\" but what we have here in
one case is 3 days of active treatment and the other one 1 day of active
treatment, and versus 10 days twice a day.

Now, how was that double dummy managed?

DR. DUNNE: You are right. You couldn\'t assess compliance during the
course of the study because it was blinded. You could only do that after
we had the data in house and we unblinded the data because the
compliance measures that we used for these particular analyses looked at
people taking their active study drug.

DR. O\'FALLON: That is what I was afraid of.

DR. DUNNE: Yes.

DR. O\'FALLON: Now, you are saying, let me just make it the worst case,
you have got the one shot drug versus the twice a day for 10 days drug
and now were the kids with the one shot getting a pill plus these two
dummy pills for 10 days?

DR. DUNNE: Yes, the regimen would be that everybody got that first
azithromycin dose either active or placebo right there in the clinic and
they would then start that same time point their b.i.d. for 10-day dose.

So, after they left the clinic they were taking their b.i.d. doses.

DR. O\'FALLON: Right, and half of them, the ones were getting, okay. So,
now, when we talk about compliance, now what are you talking about if
the kids on the one shot, the true active stopped taking their dose at 4
days, did they count as being compliant because they had their drug
whereas the ones who were on augmentin had to have all 10 days or 8 days
of it anyway, 9 days of it?

DR. DUNNE: Yes, that is an important point of the whole presentation.
Let me see if I can clarify that for you. The idea of those
presentations was to say, \"How likely is it that someone will take
their single dose versus how likely is it that someone will take 10 days
of therapy?\" That is kind of the question.

Now, there is a number of methods one can do to get at that. We chose
the method of looking at compliance with your active study drug. So,
basically the children who were assigned to augmentin retrospectively
now we can look back and see who they were. We looked at the number of
days that they took their therapy and if you were fully compliant you
were fully compliant. Obviously if you were not you were less compliant.

Now, we could do other analyses of course. You could look at the people
who were given azithromycin active and took placebo augmentin and see if
they took their placebo compliantly. That is another approach. I suspect
that because it was randomized you will see a similar outcome.

DR. O\'FALLON: You didn\'t show us that.

DR. DUNNE: Would you like to see that?

DR. O\'FALLON: Yes, you didn\'t show us that.

DR. DUNNE: We will do that for you.

DR. O\'FALLON: Because by definition the one drug is going to have 99 or
100 percent compliance.

DR. DUNNE: Sure. You know, it is an interesting question. How do you
study compliance? And how does otherwise somebody study that? It is easy
to just kind of walk beyond that in our data sets and say, \"Well, of
course.\"

Let us look at whether there really is a difference, and I think we see
that there is a difference.

DR. O\'FALLON: And the parents, that was the other thing. I had two
technical questions about what you asked, I mean what you were showing.
I couldn\'t absorb it quickly enough. The adverse events per patient
year, what is that?

DR. DUNNE: Okay, let us go into that. We have a few slides to help you
with that.

I will flip through my book.

DR. O\'FALLON: I didn\'t write down the number unfortunately.

DR. DUNNE: That is okay. We have it up here. Let us try looking at what
exactly it is. First let us look at what I showed and then we will go
back and see how did we get that.

Okay, so we will go to the main presentation and that is going to be
Slide 99. Okay, good.

The backdrop to all of this is the top line here looks at patients that
had an adverse event. So, if at any time after you randomize you had an
adverse event you raise your hand, yes, but it doesn\'t get at the
burden of side effects, how many did you have, how many days did you
have them? So it is a fair analysis of the subjects with the adverse
event. That is fair, but there may be more dimension to this when we are
looking at the same total dose but delivered in different ways. So, we
attempted to look at something that we actually don\'t normally do which
is total burden of side effects in this particular program.

Okay, now, let us go to the safety slide No. 17 please?

So, this is a kind of a basic sense of what we are doing. This is a
patient, for example, who had a vomiting adverse event on day 1 and day
2, nausea on day 1, 2 and 3 and a headache on day 3 and 4.

In that top line of the analysis they get a one. Yes, I had a side
effect. We miss all the other burden in here by doing that. So, what we
tried to do was basically add up the X\'s. That is the approach. You
look at the number of adverse events they had and the number of days
that they had that.

Now, in order to compare one arm to another we had different numbers of
patients and we had to normalize it to something. So, we just picked
patient years\' exposure, but how that works is you have a 30-day
observation period when you are in the studies.

So, we just normalize that 30; that is the same for 1, 3 and 5, and then
you just normalize that out to a year. That helps us deal with the big
N. Okay? Does that help enough?

DR. O\'FALLON: Yes, I see the concept, and I think it is a good
analysis, I would say. There are different ways to do it, but that is
good.

DR. DUNNE: Okay, thank you.

DR. O\'FALLON: And finally, one more thing. On Page 54, I guess I wrote
the page.

DR. DUNNE: This is of the briefing document?

DR. O\'FALLON: No, your presentation, No. 107 and this happened on the
other one as well. You keep just saying, \"Percent successful clinical
outcome,\" with a confidence interval on there, but I don\'t know which
way the difference is defined.

DR. DUNNE: Okay, yes.

DR. O\'FALLON: I cannot tell from this one. Other ones you showed but
these don\'t, and I don\'t know what that confidence interval is.

DR. DUNNE: I want to make sure I have the right slide for you.

DR. O\'FALLON: I have 107 and 108, either one of them.

DR. DUNNE: Let us put slide 107, say, for example? Yes, now, this is
very important actually. In the previous tonados(?) there we have the
difference in clinical outcome. So, it is the confidence interval on the
difference.

DR. O\'FALLON: But defined which way, which drug is first and which one
is second?

DR. DUNNE: Great. I will go back to that. Why don\'t we go back to that.
Let us just go back to Slide 106 then.

DR. O\'FALLON: That one it defines it.

DR. DUNNE: Yes. Okay, so, this is confidence interval on the difference.
The right side we favor azithromycin. The left side we favor comparator.

Now, we come to the next slide, 107, and we are switching things on you
now.

DR. O\'FALLON: That is what I was wondering because this doesn\'t look
good for you if you kept it the same way.

DR. DUNNE: Yes, what this is is the confidence interval on the point
estimate of success. So, it is not a difference anymore.

DR. O\'FALLON: Oh.

DR. DUNNE: It is just the point estimate of success and there is a
certain number of observations in that point estimate, and that gives
you a 95 percent confidence interval.

So, we just presented this for data for a quick reference about how
this, how our drug would look compared to what else is out there.

DR. O\'FALLON: But what is the 80 to 95 percent business? What does that
mean?

DR. DUNNE: Okay, yes. Those are the upper and lower limits of the
confidence interval on that point estimate. So, here is the point
estimate here. It is about 88 percent.The lower limit is down here, 81
percent. The upper limit would be something like 95 percent. So, it is
just for reference because otherwise there are lots of lines there. It
is hard to find the azithromycin single dose regimen. So, we just
labeled it out there for you.

DR. O\'FALLON: Okay.

DR. DUNNE: Okay?

DR. O\'FALLON: Yes, I will have to look at that.

Thank you.

DR. RELLER: We have a series of questions now. Dr.Christie and then
Ebert and Glode and Leggett, and then we have a break, and we can come
back if there be questions for Dr.Dunne in the discussion later, I am
sure he will be happy to answer those.

So, we will have the four queries on the table and then our break.

Dr. Ebert?

DR. EBERT: My question pertains to the end of treatment assessment.
Could you just review the difference between a clinical cure and a
clinical improvement as far as the criteria?

DR. DUNNE: Yes. Just to repeat your question, the question is what is
the difference between clinical cure and clinical improvement. The
protocol gives a lot of leeway to the investigator to make decisions
about improvement or cure.

Cure is complete resolution of signs and symptoms. So, they are all
gone, but as I pointed out there could be a little sign of effusion left
at any of those time points that would not preclude the investigator
from calling it a cure.

Improvement is something shy of that. There is not quite resolution to
feel comfortable that the child is cured. There may be a little bit of
irritability left. There is some kind of sign or symptom which they are
not happy is completely resolved, but it is better than baseline, and it
is certainly not worse.

DR. RELLER: Dr. Christie?

DR. CHRISTIE-SAMUELS: Thank you. Do we know anything about whether or
not the Hemophilus influenzae bacteria were typed and do we know
anything about rate of HiB vaccination usage in Costa Rica as compared
to here in the United States?

DR. DUNNE: Okay, so, two questions. Was the Hemophilus typed? Was it
non-type O; was it type B? I assume that is the question, and the second
was about vaccine, I am sorry, which vaccine?

DR.CHRISTIE-SAMUELS: Hemophilus influenza Type B vaccine. Is it used in
Costa Rica?

DR. DUNNE: In 1995, I am actually not sure. We will have to go back and
check that for you. I am not sure if that was \-- that data was not
collected as part of the program whether they had had Hemophilus
influenzae vaccination or not but we can check with the investigator to
see.

The other question was was the Hemophilus typed. No, we didn\'t do
specific typing for Hemophilus as part of the program. Presumably the
later cases, the ones in the more recent studies probably had a low
incidence of Type B, but we didn\'t actually do typing on those
Hemophilus.

DR. RELLER: Dr.Glode?

DR. GLODE: My question was just about that table 107. You have just
explained now clinical cure versus clinical improvement, but what is
clinical success?

DR. DUNNE: Clinical success is a combination of cure plus improved. Yes,
that is a little regulatory thing.

DR. RELLER: And finally,Dr. Leggett?

DR. LEGGETT: I have a question regarding Hemophilus influenzae and this
question of effusions and improved versus cure. Fifty percent of H. flu
isolates more or less revert spontaneously to sterility and yet the
statement is made on Page 4 of your briefing document and was made here
that they are, quote, difficult to cure.

What does that mean?

DR. DUNNE: I think the implication of that statement was not so much
that in the short term the organisms could not be reduced in burden or
there couldn\'t be some immediate cure rate, but it is difficult to
completely eradicate that organism and the infection due to that
organism.

So, in other words the overall success rate as you go farther out to day
28 later seemed to be a little lower for Hemophilus patients than it is
for Strep. pneumo patients for example.

So, ultimately as Dr. O\'Rourke kind of told us it may be more difficult
to ultimately clear away that infection.

DR. LEGGETT: I don\'t remember seeing in Dr. O\'Rourke\'s presentation,
and maybe you can give us the data, was the relapse rate or that
incidence of new infections higher for H. flu than it is for
Pneumococcus? Is that the proposed \-- and then how do we then wrap that
around the fact that Pneumococcus is much more likely to cause acute
otitis media than H. flu? I am having trouble with those concepts.

DR. DUNNE: I am trying to think of what I can help you with from the
data that we collected.

DR. LEGGETT: That is sort of a problem, isn\'t it?

DR. DUNNE: Yes. I am not sure that we have data within the program to
get specifically at the reasons for why it may be more difficult to
treat Hemophilus, why there might be a lower overall success rate within
the program. I will tell you we can go back and think about that and
bring it back to you.

DR. LEGGETT: My question is what caused, what was your definition
clinically of failure? Was it that the ear had to be red? Was it just
that there was an effusion? That is what I am getting at.

DR. DUNNE: I think we have a breakdown by who failed and who cured and
what their symptoms were. Maybe that would help a little bit.

DR. RELLER: We can go at ten-forty-five for the FDA presentation and
questions from the general audience we will take care of in conjunction
with the public presentation.

Thank you.

(Brief recess.)

DR. RELLER: The FDA presentation will be by Dr. Moledina.

Dr.Moledina?

DR. MOLEDINA: Good morning. I am Dr. Nasim Moledina from Division of
Anti-Infective Drug Products and as you must have figured out by now the
discussion of topic today is single dose and 3-day treatment of
azithromycin suspension in pediatric patients with acute otitis media.

With that as a background I would like to sort of summarize what is
currently approved for acute otitis media as a 5-day regimen, not acute
otitis media as a 5-day regimen in adults and in children for the
indications for Zithromax and in adults for the 5-day dosing regimen it
has been approved for acute bacterial inflammation of chronic
bronchitis, pharyngitis/tonsillitis, community-acquired pneumonia and
uncomplicated skin and skin structure.

In children azithromycin 5-day dosing regimen has been approved in acute
otitis media, pharyngitis, tonsillitis and CAP and the indication reads
that it is approved for acute otitis media caused by the three most
common organisms, H. flu, M. catarrhalis and Strep. pneumoniae.

The dosing regimen is given as 30 milligram per kg total dose given as
10 milligrams per kg on day 1 and 5 milligrams per kg on days 2 through
5.

Basically I would like to give a background on how this drug was
approved as a 5-day treatment and you have already heard from the
sponsor that on day 30 for this 5-day approval. I would just like to
point out the end of treatment data which was on day 11 for the three
studies that were submitted in support of this, the original oral
suspension.

The first study was study 134 and just to give you an idea, the success
rate which now you know what success means, it means cure plus
improvement and day 11 was the end of therapy evaluation point where
azithromycin and the comparator both had a cure rate of 88 percent.

The 30-day data was already presented by the sponsor. So, I am not going
to go through those. When you look at the second study which was a
non-comparative clinical and bacterial study the success rate at the end
of therapy was 84 percent for azithromycin.

This study, also, had data collected where there was baseline
tympanocentesis done and this is for the end of therapy in this column
and you look at the patients with Strep. pneumo isolated at baseline, 82
percent were cured compared to 80 percent in the H. flu group and 80
percent in the M. catarrhalis group.

There was a study, 128, which was, also, a comparative clinical and
bacteriologic study. This was a study that was initially set up as a
comparative study but when our guidance came out the sponsor stopped the
study and put all the patients in a non-comparative trial. So, this did
not have too many patients enrolled in the study.

For this study when you look at the end of therapy treatment
azithromycin had an 88 percent cure rate. The basic data from the study
because this was a small study when you look at the Strep. pneumo at the
end of therapy treatment end point there were 86 percent of Strep.
pneumo cured versus H. flu 82 percent and 7 out of 7 M. catarrhalis were
cured.

So, this basically gives you an overview of how they approved the 5-day
regimen for otitis media in children. Was, as you must have already
found out from the presentation this morning that there is scarce PK
data in pediatrics, but when you look at the comparison of exposure
among azithromycin regimens, 5 day versus 3 day, basically the
conclusion drawn from studies that were submitted to FDA is overall
exposure associated with 3-day regimen is similar to the 5 day.

When you look at the 3-day regimen versus 1 day in adults all we can say
is overall exposure associated with 3 day may be similar to 1 day, but
we can\'t make any more conclusions than that.

In pediatric patients when you look at the 5 day versus the 3 day you
can see that the 3 day may be similar to the 5-day regimen, and we do
not have data from 3 day versus 1 day regimens in pediatrics. That
basically gives you an overall of what we have already approved.

I will now go to the pivotal studies and go over my slides rather
quickly because the numbers don\'t change. So, I will discuss the 1014
study which was the 3-day study first and then discuss the two 1-day
therapy study and touch a little bit on the supportive study.

Study 1014 as you know was a clinical only study which was a
double-blind multicenter randomized study comparing 10 milligrams daily
dose of azithromycin given for 3 days with a 10 day course of augmentin.

Three hundred and seventy-three patients were enrolled for 28 US sites.
The age group for entry was 6 months to 12 years and the mean age was
3.5 years.

I forgot to mention in the 5-day approval the cutoff age point for entry
was 2 years and above. So, in that 5-day study none of the children were
less than 2 years of age because that was the entry criteria. I forgot
to mention that.

When you look at the MITT population and look at end points at end of
therapy and test of cure, the success rates for azithromycin were 83
compared to 88 for the augmentin group and when you look at the test of
cure with it which was on day 20 to 32 apparently the cure rates flipped
and in the azithromycin group the outcome is better than what you see in
the comparative group, and I wanted to bring this to your attention.

When you look at the outcomes broken by age I may sound like a broken
record, but anybody who is less 2 years of age the outcome for
azithromycin is 75 percent compared to 85 in the augmentin group and
when you look at children more than 2 years of age the cure rates are a
bit higher than what you find in kids less than 2 years of age.

When you look at the test of cure visit you see the same thing. Children
who are less than 2 years of age had a lower cure rate than children who
were more than 2 years of age.

The second study is a clinical only study, 0581 which is a double-blind,
double-dummy, multicenter study comparing a single dose of azithromycin
with a 10-day course of augmentin.

In this study 350 patients were enrolled from nine US sites. The age
group for entry was 6 months to 12 years and the mean age was 2.7 years.

In this study, also, when you look at the end of therapy and the test of
cure the success rate at the end of therapy for azithromycin was 87
percent compared to 88 in the augmentin. So, it was similar and both
azithromycin and augmentin had similar performance as test of cure.

When you break the clinical outcomes by age groups, children who were
less than 2 years of age had a lower success rate than children who were
more than 2 years of age and that was at the end of therapy. This is at
the test of cure visit, and you see a similar pattern.

Study 1015 was a single tap open level non-comparative study which had
tympanocentesis performed at baseline and 248 patients were enrolled
from 22 US and Latin American study sites. The age group for entry was
similar to the previous two studies. The mean age in this study was 3.4
years.

When you look at the clinical outcome since this was a non-comparative
study azithromycin success rate at end of therapy was 89 percent
compared to cure rates at test of cure visit which was 85 percent.

When you break the clinical outcomes by age it is the same story. You
see here patients who are less than 2 years of age had a lower outcome
than patients who were more than 2 years of age, and this was at the end
of therapy. When you look at test of cure you see similar numbers.

This study had tympanocentesis done only at baseline and there were 42
H. flu, 10 M. catarrhalis and 76 Strep. pneumo isolated.

When you look at the end of therapy assessment the success rate which is
cure plus improvement 71 percent of H. flu had cured clinical outcome,
100 percent for M. catarrhalis and 92 percent for Strep. pneumo.

When you look at the clinical outcome at the test of cure visit 64
percent of H. flu were cured, 100 percent of M. catarrhalis and 88
percent of Strep. pneumo.

The sponsor gave you a detailed presentation about the resistance, but I
am just going to mention that 16 percent of Strep. pneumo isolates were
resistant to azithromycin and the success rate at the end of therapy and
test of cure was 10 out of 12 and 8 out of 12 respectively.

When you break these two most common organisms down by age, when you
look at the outcome at the end of therapy for H. flu patients who were
less than 2 years of age the success rate at end of therapy was 61
percent compared to 79 percent for children more than 2 years of age.

In the Strep. pneumo group it did not matter. Kids less than 2 and more
than 2 basically had the same outcome. When you look at the test of cure
in H. flu patients 53 were cured who were less than 2 years of age, but
72 percent who were cured were more than 2 years of age and for Strep.
pneumo the outcome was lower for kids who were less than 2 years of age
than who were more than 2 years of age.

So, basically it follows the same pattern.

Study 95001 was what the sponsor calls a pivotal study and was submitted
to the NDA as part of a supportive single-step study which was done in
one center only which compared a single dose of 30 milligrams
azithromycin to 3 days\' therapy, 10 milligrams daily with IM
ceftriaxone.

Clinical evaluations were made at end of therapy which was days 9 to 19
and follow-up on days 26 to 44. The mean age in that study was 2.5 years
and it ranged from 0.3 to 6.5 years. So, this study enrolled younger
patients.

When you look at the clinical outcome by baseline pathogen at end of
therapy for the two common organisms, as you know the sponsor presented
only two M. catarrhalis isolated in the study and both were in the 3-day
group. I wanted to concentrate on H. flu and Strep. pneumo.

When you look at the end-of-therapy evaluation the success rate for
1-day therapy for H. flu is 89 compared to 93 percent for the 3 days and
100 percent for ceftriaxone.

When you look at Strep pneumo, 95 percent for 1-day therapy, 83 percent
for 3 day and 100 percent for ceftriaxone.

So basically that sort of summarizes all the studies that were submitted
for this particular approval for 1 day and 3 day AZ. Just to sort of
summarize study R-058 was a single dose comparative study which was a
clinical only study, The study 1040 was a 3-day study which was also
comparative to augmentin and 1015 was a non-comparative single dose, and
it sort of gives you an idea of the cure rates ranging from 75 to about
85 percent, and bacterial outcome which was in the pivotal study where
you know the H. flu was like 44 patient who had isolated, 10 and about
76 Strep. pneumo the clinical outcome in those patients who had H. flu
isolated at baseline at end of therapy was about 68 percent compared to
like lower sixties. M. catarrhalis all 100 percent were cured and Strep.
pneumo had a better outcome at end of therapy and at test of cure.

So, this basically summarizes all the efficacy data that was submitted
by the sponsor and FDA had a chance to review the source data and verify
all the outcomes.

Just to make the discussion more complete we did go and look at the
literature and in your briefing package I had included articles by Degan
and others where two double-tap studies were done and we particularly
looked at this because both the studies used azithromycin. One study
used 3-day azithromycin and the other study used 5-day azithromycin, and
there were low bacteriological eradication rates for H. flu when tests
were done on therapy.

As I mentioned there are limitations of evidence from these publications
because FDA has really not had a chance to review the source data from
these publications.

One other published study that I didn\'t put in your briefing package
but I handed it out and it should be in your package was a study that
was done by Doern and others in Antimicrobial Agents and Chemotherapy
this year.

This study looked at all the clinical isolates of Strep. pneumo that
were obtained from 1999 to 2000. There were about 1531. This was more
like a surveillance study where it looked at all the isolates and
susceptibility of Strep. pneumo to several antimicrobial agents,
quinolones, cephalosporins, macrolides and there was a whole bunch of
them. Since the topic of discussion is azithromycin today from the
particular paper when you look at all the clinical isolates of Strep.
pneumo 25.7 percent of them were resistant to azithromycin, but when you
only took those isolates that were pain resistant which were like 329
isolates 77.2 were resistant to azithromycin.

Moving on to safety, all I need to do is point out a couple of ADRs that
are of particular interest to us. As of June 30, 2000 cutoff point 2590
patients in all Phase II to IV studies, this is regardless of
indications that they were entered and had received azithromycin and the
sponsor presented adverse reactions which were treatment related.

I am going to show you a different picture in which all adverse
reactions for all the otitis media studies, the numbers are the same,
the denominators. These are the studies that the sponsor presented,
also, but they presented the treatment related or what an investigator
thought was, the vomiting was due to the treatment. I am looking at all
adverse events since vomiting is really subjective.

So, when you look at all the patients with any sort of adverse reaction
reported and in vomiting with yellow bile it is the 1 day. The turquoise
is the 3 day and the red is the 5 day and this was taken from the
original NDA and the comparator. In this study the comparator was
ceftriaxone and augmentin.

When you look at this vomiting almost 10.5 percent of patients vomited
on day 1 whereas 6 percent on day 2 and a little more than 3 percent on
day 3.

When you look at this particular group of vomiting and break it down to
the days where these children vomited about 37 of 52 of the patients who
reported vomiting on a single dose vomited on day 1 whereas there is
only about less than 1 percent vomited in the 3-day group and about half
of the patients vomited who were receiving the 5 day and then of course
it decreases as you go out with 3, 4 and 5.

This concludes my presentation. I did not really go into detail because
we basically did not disagree with the sponsor\'s data, but I would like
to make the following acknowledgements, Dr. John Alexander and Dr.
Thomas Smith did the primary review with me and Dr. Makhene, Dr. Soreth,
Goldberger, Dr. Gavrilovic, Dr. Ross, and the project manager, Jose
Cintron and our statistician George Rochester and the team leader
Daphne. Mr. Harold Silver is our microbiologist and Dr. Sheldon. Dr.
Charles Bonapace is our biopharmacist and Dr. Pelsor the team leader for
biopharmacy. Dr. Andrew Yu is our chemist and Dr. David Katague is team
leader, our chemistry team leader.

All of them were good moral support for me and participated in putting
this presentation together. Thank you very much.

DR. RELLER: Questions for Dr. Moledina?

Dr. Chesney?

DR. CHESNEY: I had two questions. The first one I just wanted to
clarify. You said that the 5-day initial azithromycin studies in
children were done only in children over 2 or over 5.

DR. MOLEDINA: Over 2.

DR. CHESNEY: Over 2, and my second question is we have no
pharmacokinetic data at all for azithromycin in children?

DR. MOLEDINA: I think they have some data, but Dr. Bonapace can answer
that question.

DR. BONAPACE: The data we have in children consists of 5-day and 3-day
regimens. The 5-day regimen is 12 milligrams per kilo and sampled only
on day 5. We, also, have a 10 milligrams per kilo for 3 days sample on
day 3 and a 20 milligrams per kilo also sampled on day 3. So, we do not
have any information from the 1-day regimen in pediatrics.

DR. CHESNEY: Were those all in children over 2 years of age?

DR. BONAPACE: Most of the children were over 2 years of age, and there
may have been maybe one or more down around 1-1/2 years but most of the
children are over the age of 2, yes.

DR. RELLER: Other questions for Dr. Moledina?

Dr. Wald?

DR. WALD: So, does that mean that azithromycin is only approved for use
in acute otitis media in children over 2? Is that the current
indication?

DR. MOLEDINA: No, the current indication reads 6 months and over.

DR. WALD: But there was never any data evaluated on children?

DR. MOLEDINA: I think there was some data not for otitis media, for
other indications that children less than 2 years of age were enrolled
and I think when the labeling was done those things were part of the
whole package, and I looked at it. I was trying to go through the
history and went through the whole 5-day package to see because the
label is very clear but you know children less than 2 years of age were
not enrolled in this particular indication, but when you look at the
indication, you know, it is approved for anybody over 6 months of age,
and I was not able to track down the history because the medical officer
has left FDA. So, I was not able to find anything but maybe the sponsor
can answer that.

DR. RELLER: Dr. Leggett, and Dr. Dunne, if you and your colleagues have
any comments on the pharmacodynamics, what data are available, with
azithromycin we would appreciate hearing that and Dr. Leggett?

DR. LEGGETT: Question for either you or the sponsors, what are the
kinetic data on the single-dose azithro for non-gonococcal urethritis or
STDs? Do we have that data?

DR. ALEXANDER: That information was not submitted as part of this NDA,
and the dosing of that is, also, different as well.

DR. RELLER: Dr. Gorman?

DR. GORMAN: I would like to follow up on Dr. Wald\'s question. Have any
of the data that has been generated for this presentation, is it a
response to a written request under the FDAMA regulations and is this
being used as an application for pediatric exclusivity?

DR. ALEXANDER; This is Dr. Alexander. I am actually the pediatric
representative for our division, but no, this isn\'t involved because
azithromycin is a pre-1997 antibiotic. So, it doesn\'t qualify for
exclusivity.

DR. RELLER: Dr. Dunne, do you have any comments in response to the
queries raised?

DR. DUNNE: We do have data as was discussed for PK in children at 60
milligrams per kilo total given over 3 days or over 5 days. That is the
PK that we have in children.

There was a study that was submitted to the agency after the original
application in otitis media that looked at children down to the age of 6
months. We don\'t have that data available on slides today, but that was
submitted, and it was used to amend the label to get the age group down
to 6 months of age.

DR. RELLER: Thank you.

We will next go to the open public hearing. First the ground rules for
this segment. I would like the presenters to disclose their position and
any financial involvements that would be pertinent to the data
presented.

Secondly, those presenters at the open public hearing can receive
questions from the Committee but cannot be queried by the FDA nor the
sponsor directly.

The total time allotted, not necessarily to be taken, but allotted
maximum is 1 hour. The first presentation is scheduled for 20 minutes by
Dr.Ron Dagan who will be followed by Dr. Jacobs and by Dr.Wolfe.

We have had a request for flipping those presentations, and we will do
that. I had ranked them by time, not by my listing. I apologize for
that. Dr. Jacobs will be 15 minutes and will be first followed by Dr.
Dagan and Dr. Wolfe, if he be present after Dr. Dagan\'s presentation.

Dr. Jacobs?

DR. JACOBS: Thank you, Mr. Chairman, Committee members, ladies and
gentlemen. I am Michael Jacobs. I am a clinical microbiologist in the
Department of Pathology, Case Western Reserve University in Cleveland
and I am, also, Director of Clinical Microbiology at University
Hospitals of Cleveland.

I would like to start as far as financial disclosure is concerned that I
have received financial support from a large number of pharmaceutical
companies, and I provided this listing to the Committee which is
available for inspection.

I, also, wish to state that I am representing myself and no one else in
my capacity as a scientist and a physician working on principles related
to the treatment of otitis media and I have submitted full disclosure of
my work related to otitis media in this as well.

What I am going to be looking at today are some of the principles
involved in how you study this disease. Many of these have been covered
and one of the points that we have been made aware of is that resistance
in Pneumococcus and many other organisms has increased remarkably over
the last 10 years and you can see here that treatment choices were a lot
simpler pre-1990 than they are now, and we now have up to one-third or
more of our strains of penicillin non-susceptible and up to
three-quarters of the penicillin non-susceptible ones are macrolide
resistant as well.

As far as macrolide resistance is concerned you have heard about 40
million doses of azithromycin being given since that drug was approved a
few years ago and you can see what this has done to macrolide resistance
rates. They were less than 10 percent or around about 10 percent in
1996, and they are now rounding at 25 percent and this has paralleled
the usage of macrolides.

Also, just to give you a flavor of what has happened to susceptibility,
I managed to get hold of some of the strains from otitis media that Dr.
Halley had studied and Dr. Marchant had studied and you can see here
that out of 50 isolates of pneumococci up to 1985 that amoxicillin,
cefuroxime, cefproxil were very susceptible as were the macrolides with
almost 100 percent susceptibility whereas the MICs have now gone up more
than 100-fold for many of these drugs and you can see that now we only
have between 50 and 90 percent of our strains resistant to this example
of drugs.

If you look at Hemophilus we have seen the same issue. Again, I managed
to get hold of 50 isolates. You can see there is no shortage of isolates
from the current era and you can see again that we have lost a lot of
activity, far more strands of beta-lactamase producing. So, we have lost
a lot of activity of amoxicillin. Cefuoxine has gone down as well,
ceftriaxone/azithromycin and azithromycin have never had much activity
against Hemophilus and I will get into that later on as well.

Now, as far as acute otitis media studies in children are concerned I am
a clinical microbiologist, not a clinician, but being a clinical
microbiologist the role of antibacterials is to eradicate the cause of
organisms from the site of infection and as clinicians, Dr. Dagan and
many other clinicians who have been involved in this area tell me that
that is their goal as well, and if we fail to do this irrespective of
clinical response we really are not doing our patients a service.

Now, what are limitations and the problems with outpatient clinical
studies and respiratory tract infections? There is a high rate of
spontaneous resolution in these diseases that makes it difficult to show
clinical differences between agents. These are very different diseases
to diseases such as bacteremia and meningitis as examples.

The second point is if there is such a high rate of spontaneous
resolution you really need to do bacteriologic outcome studies and these
are not often performed due to necessity for invasive procedures such as
ear, sinus and lung taps to obtain specimens.

More studies are therefore designed to show equivalent clinical outcome
between established and new agents or in other words they are not
statistically powered to show differences between agents and therefore
if there are inadequacies of agents studied they are often not apparent.

Now, again, you have seen this, and again, I have simplified this going
only up to 2000 patients in the study. The Pollyanna phenomenon
published by Dr. Marchant and his colleagues and you can see here that
when you are doing bacteriologic diagnosis and outcome that unless you
have two very good drugs you need very few patients.

When you are doing bacteriologic diagnosis with clinical outcome you
need larger numbers of patients and you need the largest number of
patients when you are doing purely clinical studies and you can see here
that even if you are testing placebo versus a very good drug you need
over 500 patients in a clinical study to make this point.

Also, to make this point this database is done predominantly on children
under the age of 2 years of age.

Now, let us look at azithromycin and acute otitis media. There are four
studies using a common comparator that I could find. The study designs
differed. Two of them were clinical diagnosis and outcome. One was
bacteriologic diagnosis, clinical outcome. One was bacteriologic
diagnosis and outcome.

Patients ages in these studies differed considerably, and there has been
discussion on this this morning. The first three studies involved
patients from 6 months to 15 years old. Means were 4 to 6 years, while
the fourth study involved patients only up to 4 years of age and the
mean was 16 months, 1.3 years.

Sample sizes required for these studies to be powered to show
differences between agents were determined based on calculations
published by Marchant and this is what I came up with.

This is a summary of these four studies. You can see the mean age and
the age range is given here. The mean age was not given in the study but
was presumed to be similar to these two studies given here, and you can
see the differences that I pointed out.

The number were variable. You can see there were fairly large numbers in
these two studies. There are very small numbers in the study done here
and 143 in this study.

Study designs were these two were purely clinical studies. This was
bacteriologic diagnosis, clinical outcome. This was bacteriologic
diagnosis and outcome.

P value for clinical outcome was statistically significant only for the
study with the lower age group patients. Number of patients needed to
show 60 versus 90 percent bacteriologic efficacy is 2000 patients in
these two studies. So, you can see that these studies were way under
powered to show any difference.

So, it is not surprising that these clinical outcomes were not
different. In the bacteriologic diagnosis clinical outcome 800 patients
were needed, but you can see the P value was starting to approach
significance even with 92 patients, and on this study which was the one
done requiring the least number of patients bacteriologic diagnosis and
outcome, there was a statistically significant difference in clinical
outcome at end of treatment and also in bacteriologic outcome during
therapy, and you can see here the 143 patients met the criteria and that
at least 100 patients would be needed to show a bacteriologic
difference, sorry, a clinical difference based on bacteriologic
diagnosis and outcome, and you can see here that if you had placebo you
would need even fewer patients and in fact you can see the study sizes
of these two studies were hardly able to differentiate any drug from
placebo.

Now, the next issue that I am going to address is how can we overcome
some of these limitations because it is very difficult to do studies
that are powered to show these differences and one of the best
approaches that I have been made aware of is to use pharmacokinetic or
pharmacodynamic parameters to predict efficacy, and these are parameters
that are very familiar to us, pharmacokinetics, serum concentration
profile, penetration to the site of infection.

Pharmacodynamics is a relatively new field. It takes the potency of the
drug in which we tend to spend a lot of time and looks at the actual way
the bugs and drug interact in vivo, whether this is concentration or
time dependent and whether the drug has post-antibiotic effects and
basically agents can be divided up into two groups, those that are time
dependent where the time above MSC of the drug in serum is predictable
outcome and those that are concentration dependent where either area
under the curve to MIC ratio based on area under the curve in serum or
area under the curve to MIC ratio will peak to MIC ratio are predictive
of outcome and some examples of this and most of this work is taken from
the work of people working in this field like Dr.Craig who was Dr.
Reller\'s predecessor on this Committee and you can see here that in
animal model this is a mouse model with Strep. pneumo infection you can
see that mortality was reduced to zero once the percent or the dosing
interval exceeded 40 percent of the dosing interval in serum for
penicillins and 50 percent for cephalosporins.

There is human data which correlates with this very well. These are most
of the double tap otitis media studies looking at bacteriologic outcome
and you can see very clearly that to get greater than 80 percent
bacteriologic eradication as seen with time dependent agents when the
concentration of the drug is present for greater than 40 percent of the
dosing interval and you can see that this works over a large number of
studies, a large number of investigators and also applies to penicillin
non-susceptible pneumococci, and if you correlate this with Hemophilus
with a spontaneous resolution rate of about 50 percent you can see many
drugs have been shown to be no better than placebo and with pneumococcus
one study has come up with values that are very close to placebo.

Now, I am, also, showing you this data which you have seen before. This
is the chinchilla model of otitis media with Hemophilus, to make a few
points about this.

Firstly, when you look at this study here this shows azithromycin being
given for 5 days and probably about double the dose equivalent that
would be given to humans, but for the low dose which is the
30-milligrams per kilogram per day and the high dose it is clearly way
higher than any dosing regimen that has been tested in humans, but you
can see that when you follow the natural history of this out that this
is no therapy, 100 percent of cultures positive on day 0, 100 percent on
day 5 and in the chinchilla you get spontaneous resolution between day 5
and day 10, again very similar to that in humans, about 63 percent.

When you look at the lower dose, but again this is relatively high
compared to what we are using in children, you can see that again you
can get no change at day 5 but you are getting a significant decrease
between day 5 and day 10 which is higher than that of placebo, and as
you increase the dose even further you are getting 50 percent
eradication at day 5 and almost 80 percent eradication by day 10.

So, there are some differences in this model between what happens in
humans as far as natural resolution is concerned and what happens in
this model.

When you look at this kinetically again you see the same thing and one
of the questions I have about this model is when you take the drug and
mix it with the organism in the lab the test tube you get killing very
readily, and you saw some examples of that by the sponsor that by day 3,
certainly within 24 hours in most cases you get a 3 to 5 log kill with
azithromycin in Hemophilus, yet we are seeing absolutely no effect for 3
days, and I have a lot of questions as to why that is happening and what
the mechanism is, and I don\'t know the answer to that.

Now, let us look at some other animal models. This is data that has
recently been published in Antimicrobial Agents and Chemotherapy by
Muttman et al. This is looking at azithromycin lung and plasma levels.

One of the points made is that drug delivery is very different. This is
done intracellularly by macrophages and polymorphonuclear lymphocytes
and the tissue level are more important than serum levels, and you can
see here that if tissue levels are indeed important then tissue levels
would be adequate to treat Hemophilus whereas serum levels would not be,
but if you actually look at the experimental data that you get you
don\'t find that is the case.

Looking clarithromycin you get exactly the same parameters. You can see
here tissue levels would be even less or slightly more difficult to be
able to be effective against Hemophilus and certainly serum levels would
not be effective.

When you look at the experiments that these investigators did what they
found in fact was that macrolide susceptible pneumococci with both
azithromycin and clarithromycin indeed could be treated very effectively
based on dosing comparable to that given in humans and they used a whole
dosing range here and they got a very nice straight line relationship.

They tested other agents which followed this line which I have removed
for clarity, but when they started looking at macrolide resistant
pneumococci and Hemophilus they found they had to go to much higher
doses than those comparable to given in humans, and the dosing limit for
azithromycin and clarithromycin for human dosage is approximately 25
milligrams per kilogram per day. In this model you can see that
therefore this model was very effective in treating
macrolide-susceptible pneumococci but failed to treatment
macrolide-resistant pneumococci with efflux mechanism not shown on the
slide because they were off scale up here with ribosomal methylase which
has very much higher MICs and, also was not effective against Hemophilus
influenzae showing that again as had been demonstrated with many other
organisms and drugs that it is the serum concentration of drug that is
driving this not tissue concentration.

So, my conclusion from the study was that dosing comparable to dosing in
humans azithromycin and clarithromycin were able to reduce inocula by
greater than 3 logs in the lungs for macrolide susceptible pneumococci
but were not able to do this for Hemophilus influenzae or for macrolide
non-susceptible pneumococci with either resistance mechanism.

Let us look at the kinetics of azithromycin. This is a conventional
dose, 10 milligrams day 1, 5 milligrams day 2 to 5. Area under the curve
is 3 milligram hours per liter formula to get a break point for area
under the curve divided by 25 gives you a break point of .1. This is
again fine for macrolide susceptible pneumococci, fine for Moraxella
catarrhalis but with an MIC 90 of macrolide resistant pneumococci of 8
is not very good for efflux strains or even worse for ribosomal
methylase strains and also with an MIC 90 of 1 to 2 for Hemophilus is
way above the break point for Hemophilus.

Let us look at what is out there as far as break points is concerned.
Pharmacodynamic break points based on pharmacodynamic principles are
given over here and these are the ones that have been shown to correlate
in animal models and in human data to what actually happens in vivo and
you can see for the Pneumococcus the break points that we currently have
approved by the National Committee for Clinical Lab Standards are pretty
close to the pharmacodynamic break points. However, you can see there
are some examples of NCCLS break points for Hemophilus which are higher
than that of the pharmacodynamic break points and sometimes in some
instances by up to 60-fold and you can see the examples I have given
here of clarithromycin, azithromycin, loracarbef and cefaclor and
cefprozil. Those stand out as being way higher than the pneumococcal
break points or the pharmacodynamic break points, and one of the points
about break points is for organisms causing the same infection there is
no medical or scientific reason for a break point being higher for one
organism than another.

Now, let us look at what happens when you look at susceptibility of
organisms at different break points and I am going to go over this
quickly in the interests of time, but you can see that when you look at
pharmacodynamic break points you get a very different picture with those
examples of the break points that I showed you before when you look at
NCCLS break points, and you can see in some instances there is almost
100 percent difference.

Is Hemophilus susceptible to azithromycin? According to the
pharmacodynamic principles it is not but microbiologically it is
regarded as susceptible.

What I have done to summarize this data just to bring out the
highlights, these are the drugs where greater than or equal to 90
percent of recent US trends are susceptible at both break points, and
you can see here that amoxicillin, amoxicillin/clavulanate and
clindamycin actually came in at 89 percent, but I included it anyway are
the only three drugs that I could find that fulfilled this 90 percent
criterion.

When you look at Hemophilus drugs that do this by both NCCLS and
pharmacodynamic break points are amoxicillin/clavulanate, cefdinir,
cefixime and cefpodoxime. Those drugs that do this only by NCCLS
parameters are cefuorxime, cefprozil which comes in slightly under 90
percent, loracarbef and azithromycin.

Now, let us look a little bit about the specifics of this. As you have
seen pneumococci are divided up into three groups, and I think NSC 90
study that was presented earlier by the sponsor showing an MIC 90 of 2
micrograms per ml for Strep. pneumo is not representative of what goes
on in the US. That study included US and Canadian data and there the MIC
90 was 2. More studies in the US have MICs in the 8 to 64 range.

With Hemophilus MICs are in the .5 to 4 range, unimodal distribution.
You do find occasional strains with Hemophilus with much higher MICs,
but what we have learned about Hemophilus in the last few years is that
the reason they are much higher baseline than they are for Strep. pneumo
is that they naturally have an efflux pump, and you can inhibit this
pump and bring MICs down to about .06 micrograms per ml.

Unfortunately the agents we have at the moment that do this are all
highly toxic. So, what you find with the Hemophilus is that the MIC 90
is 2 micrograms per ml. That is pretty universally accepted.

With Strep. pneumo it is now 32 micrograms per ml. How does this compare
to break points? Pharmacodynamic break point comes out on current dosage
to .1 microgram per ml. When you look at pharmacodynamic data in some of
these more recent animal models this comes out to a break point of
roughly .5 micrograms per ml, and if you look at the dosing where they
used doses equivalent to four times current human dosage they can bring
this break point up to 4 micrograms per ml which will now include
Hemophilus.

So, you certainly can get Hemophilus to be susceptible to macrolides in
vivo, but you have to increase the doses enormously.

So, in conclusion antibacterial choices for empiric use in acute otitis
media most clinical studies are too small to show clinical differences
between agents. Pharmacodynamic parameters correlate with bacteriologic
and clinical outcome in animal models and in humans and can be used to
select agents with maximum potential for bacterial eradication.

Currently available agents vary significantly in achieving these
pharmacodynamic parameters necessary for eradication and few oral agents
approved for pediatric use are active against 90 percent or more of
current US strains of the three key otitis media pathogens at approved
dosage regimens, and finally, bacteriologic outcome studies in children
and animal studies have repeatedly validated these conclusions.

Thank you for your attention.

DR. RELLER: Questions for Dr. Jacobs from the Committee members?

Dr. Patterson?

DR. PATTERSON: Thank you for your nice presentation. Dr.Dagan\'s study
that you cited, is that the one where H. flu was the most common isolate
which seems to be a little different than the epidemiology we have heard
today and wasn\'t the statistically significant difference in the H. flu
infection?

DR. JACOBS: That is correct. The major difference in outcome there was
based on H. flu. Dr. Dagan can probably answer this question better than
I can, but I think there were a couple of points there. One is the age
group that that study was done in was very different from the other
bacteriologic diagnosis studies you looked at and many people believe
that under the age of 2 Hemophilus is probably more common, and you had
a second question, the statistical significance. Because of the MIC
distributions we had very few resistant pneumococci there. So, with
pneumococci the difference did not reach statistical significance but
with Hemophilus with a unimodal population we had enough and that did
reach statistical significance.

DR. RELLER: Thank you, Dr.Jacobs.

Dr.Dagan?

DR. DAGAN: I thank the Committee for allowing me to say several things
about methodology. I just want to tell you I am not from the United
States. I didn\'t not know that I had to bring with me a declaration of
with whom I was contracted but I did send it to the Committee, and you
have it on record, and I reconstructed this from my memory.

So, if I forgot something you have that in your files. I have been
receiving grants and/or consulting with Abbott, Aventis, and
Aventis-Pasteur, GSK, Wyeth, Lederle Vaccines and Lilly Antibiotics,
Pfizer, BMS, Lilly Chemopharmaceuticals, Astrozenica(?) and Merck, Sharp
and Dohme. I may have forgotten something, but at least I think it shows
you that I have quite a wide spectrum of working with various companies.

I thought that first I should answer the question regarding H. flu
because I think Michael Jacobs did not answer that correctly. I am
sorry, Mike. The study that you have, it was published in PIBJ in 2000.
It is a multicenter study including many centers in the United States.
When you analyze the data from the States separately H. flu was more
common than Pneumococcus.

So, either it is changing with time or it is time and age. In France by
the way it is the same thing. We have more Hemophilus. It is not unique
only for one study.

I thought that in presentations of FDA and other places a lot of data we
probably saw so far 220 or 240 sites and there are lots of outcomes and
a lot of data and it is very easy to get confused, and I have been
confused for many, many years, and I think I am less confused now after
working very hard in the last 5 years on otitis, and I would like to
actually change this talk into a second one and try to really show this
point which is I think very important to understand when we read results
of studies or when we design the studies. These studies might be
healthier to your needs.

If you know from preliminary studies the characteristics of your drug
you can actually start and design your studies to show whatever you want
to show and I think you had a little bit already in the talks and
discussion before. I want to highlight that more to make it a little bit
more clear maybe.

Now, first there is much outcome to choose, and I am not going to again
tell you too much about the Pollyanna. We all know now about the
Pollyanna effect issue, but I just want to show that this, if you take
this outcome and again I will show you data from our experience where
you really see a big, big difference between placebo and the best drug
and this is something that can be easily demonstrated and ask a lot of
questions, and I want to show you this is as you already know much more
accurate because the next big sample size and here you almost can show
almost everything, and each one I will show you actually how to play
with it in order to get what you really need.

This is a study that we published years ago looking at the
cefuorixime-axetil versus cefaclor pharmacokinetics susceptible to
penicillin. There was no problem. The two drugs are very, very efficient
and both are effective but cefaclor is really much closer to placebo now
than to cefuroxime-axetil and with Hemophilus, also, cefaclor is very
much close to placebo compared to the other drug. So, here you can show
with relatively small numbers of children as you can see, you can show
your point in a very highly statistical significance.

This is another study that was not sponsored by the industry, but it was
important to look at trimetapolis(?) sulfa because it is still the
cheapest drug and we wanted to see what happens if you have susceptible
or resistant and here unlike beta-lactams you have most of the time
either highly susceptible or highly resistant and so when we get to
children with Pneumococcus or with Hemophilus that were susceptible we
have 100 percent success rate and in this case when we give, when they
were resistant we had placebo effect in terms of bacteriological
eradication very clearly showing that for true resistant both Hemophilus
and Pneumococcus this drug is the same.

When we look at Hemophilus influenzae now and we look at amoxicillin,
there are three studies looking at it and here are the results with
double tympanocentesis and with beta-lactamase negative Hemophilus you
can see that in these three studies although they don\'t get exactly
similar results they are clearly superior than placebo while for all
three studies the numbers are small but very clearly you get placebo
effect, again showing that if you have a drug that is susceptible to
beta-lactamase then beta-lactamase producing organisms may fit a
placebo. Again, very clear results. It is very difficult to argue with
those.

You remember the point 12 cutoff that Michael Jacobs presented from the
theoretical model. This is a study that we did sponsored by Pfizer a few
years ago and published a few years ago, and looking at the
bacteriological eradication and actually the only organism that could
have an MIC less than .12 was Pneumococcus that was susceptible to
macrolide and again we have 100 percent success rate here while those
who were not were quite highly resistant and all of them as I said in
this case. In a second study that we did we had close results to that.

For Hemophilus the lowest MIC we could get is .5 and as you remember the
MIC 50 is one. Ninety is two. So, basically what we got is a success
rate in all MICs very close to placebo. So, the only one that it was
really shown to be good for is Pneumococcus that is susceptible to
macrolides.

So, I think that those examples that demonstrate how you can go with
relatively small numbers and get something which is significant and
bacteriological proof and to the best of my knowledge otitis media is an
infectious disease and the approach should be as for other infectious
diseases. Go to the bacteria and demonstrate the eradication by
antibiotics.

Now, which end point to choose? You already heard today a lot of
discussion and let me just go back to this classical study by Kaleida
that we have already mentioned. Now, which end point to choose? You
already heard today a lot of discussion and let me just go back to this
classical study by Kaleida that was already mentioned before and here
these are children over 2 because you didn\'t use placebo under 2, but
what is shown very clearly that at end of treatment she still had very
good results with amoxicillin compared to placebo and this is looking at
clinical outcome.

However, 2 weeks after the treatment there was no difference at all
between placebo and amoxi and at 6 weeks actually placebo was
significantly better in term of effusion. This is something which may be
strange. It has some biological plausibility and I don\'t have time to
speculate on that. Maybe if there are questions later on, but the point
is very clear that if you choose this placebo is superior to
amoxicillin.

Now, the whole issue of test of cure, I was surprised to hear that in
this very, very important country they call this 1-month test of cure
because they have never proved that this is a test of cure. Actually we
have enough proof that it is not a test of cure.

If we look, this is a study that was mentioned already by Colin
Marchant. If we look, and this is not the only study but this is the
most recent one with the highest numbers. One hundred and eight cases
that had double tympanocentesis studies. They had first tap with a bug.
Second tap bud was eradicated. Children after treatment recur
clinically. We go for third tap and now we can compare to the original
organism. What we found was that of the 108, 20 percent were no growth.
So, they had some viral infection or something or some technical issues.
In 56 percent it was a new infection. New infection means either
Hemophilus was replacing Pneumococcus or vice versa or another bug, but
that Pneumococcus was a different Pneumococcus was proved by serotype or
pulse field or Hemophilus proved by pulse field or beta lactamase.

So, basically what we called test of cure is test of relapse or
recurrence or bacteriological relapse because in only one-quarter of
what we see of clinical relapse it is actually something that comes back
and again, as discussed by Colin Marchant before it could be actually
that the bug was eradicated but not from the nasopharynx and so far
nasopharyngeal eradication or dynamics is not part of what the FDA wants
to get for licensure although that might be very important. It might be
in the future tested for that, too.

Then we had the Pneumococcus that recurred as Pneumococcus. This is 38
cases, 58 percent, almost two-thirds. It was not the same Pneumococcus
and Hemophilus when recurred was Hemophilus in 60 percent almost. It was
not the same Hemophilus. So, even when the same bug was there it was not
actually the same bug.

So, the test of cure is for me not a real test of cure and maybe that
should not be used. Who are the patient\'s contacts? This is very
important, not who are the patients. Who are the patient\'s contacts? If
you really look the patients get the bugs from the contacts. If they
have bad contacts, they have bad bugs, and this is a classical study
that is hopefully going to be very soon published by Robert Cohen from
Paris. He took only this experience of 5 days with this 10-day regimen.
You know there is a big issue whether to treat 5 days or 10 days and
took kids that are at home not going to day care centers and kids that
go to day care centers. Otherwise these kids were comparable, and what
you see first this is at end of treatment there were much more failures
in those kids compared to those who are at home, but if you look at the
5 versus 10 days here you see a significant difference. Here the
difference is not significant.

So, if you have a drug that doesn\'t do very well but you have still to
show 5 days go for this, never go for this one-tailed. So, this is a
test of cure which I call a test of relapse, okay? Again, much more
relapses in day care centers. We all know that, but we never use that to
read the articles, which were the kids from. Not only this, here it
shows clearly that these kids who go to day care center 5 days is not
appropriate, while here, no difference. So, for kids who stay at home,
fine. I never saw that in an article saying that for kids who stay at
home you can give 5 days in our study, but if they go to day care center
be careful.

Kids who went to day care centers carry much more resistant pneumococci.
This was found in so many studies and this is again from that study by
Cohen. Not even that, kids who stay at home they may have brothers who
go to day care center. Does this make a difference? Definitely.
Pneumococcus twice as much carry Pneumococcus if their brother or sister
go to day care center so with Hemophilus and Moraxella and even more
than twice as much with any bug and this is highly statistically
significant.

So, again, you don\'t get otitis if you don\'t have the bug in the
nasopharynx. So, the idea is take the kids who don\'t go to day care
center and who have no brothers and sisters and almost everything will
work.

Age effect, we have heard about, but I want to just bring you something
from the literature, very good studies. Some of them were used for
licensure. Amoxicillin by Kaleida less than 2 years of age, 12 percent
failures with amoxicillin versus only 4 percent above 2 years of age.

Hoberman, amox/clav published I think it was even used for the licensure
of this drug in the previous dose and again this is not to compare from
one study to the other because there were different outcomes, but within
the same study 49 percent unsatisfactory. Look how much you go down with
older kids.

Penicillin in Sweden after 2 years almost nothing and cefprozil the same
after 1 year almost no problem. So, again, if I have a drug that
doesn\'t show too much of an effect I will take the older kids and make
it smaller.

Now, effect of severity, we had that. This is the Kaleida study
non-severe disease, placebo, Amoxicillin .5 percent with unsatisfactory
results at the end of treatment versus 6 percent, still a difference but
not very impressive. You need a huge sample size for that while here you
have a very impressive difference.

Again, if I have a drug that doesn\'t work very well I will go to those
type of kids and actually if I go to the clinics and get kids over 2, up
to 12 years of age I don\'t know how many of the pediatricians here
treated how many kids, of course. It is very difficult to find them, and
if you find them they usually have a little bit of ear pain, a little
bit of red ear and you go to the clinic and you need to recruit a lot of
kids because you get money per kid. So, you take all this was very mild,
and this is in my belief the answer to that question that was asked
before about why do we have so many older kids while almost all of our
patients are younger kids.

Effects for this factor on acute otitis media, and I want to take all
this together. I start to understand now how I can make things according
to what I have. I just want to again last time come to this curve again
to remind you of one thing. The worse the drug is the better the
clinical efficacy is compared to the bacteriological efficacy. So, if I
get a very bad drug then it looks much better on clinical, but if the
drug is 100 percent I can almost never get really better than 90 percent
because of those viral infections.

So, for me the maximum predicted for clinical success in bacteriological
cases is about 90 percent. Above that you may be lucky to get a little
bit more.

So, now, if I take three drugs or three arms in a study and this will be
my last three slides, placebo, antibiotic A that is very, very weak and
antibiotic B that is very, very strong I can predict something like
that. You know that placebo is about, and I take kids under 2 to start
with because these are the kids where you really can do double
tympanocentesis. It is not really surprising that when you go for double
tympanocentesis you don\'t go to older kids. You go to younger kids
because they have the pus and they need those things and the parents or
children will never submit themselves to double tympanocentesis when
they have a little bit of pain in the ear with a little bit of
fraydrum(?). So, when I take the younger kids I will have here 30
percent placebo, 50 percent efficacy in antibiotic A and we saw already
this is somewhere in the middle not very good drug and 90 percent which
is one of the top drugs.

We have calculated from Colin\'s studies that were done together with
Colin Marchant and from our own studies that were published before that
if you see a bacteriological failure on day 4 to 5 about 40 percent only
of those will be clinical failures. The others will still slowly go on
and make better at the end of treatment. So, by using this calculation
you can see that just for those if you go for clinical results you get
76 percent for placebo, 84 for the antibiotic A and 90 or better for
antibiotic B.

Remember this 16 percent or 15 percent is exactly what you find in all
the real good studies looking at placebo versus drug and this is what
you find in almost all the studies with weak drugs in terms of success
rate. They have around 76 percent success rate overall in cases where
you don\'t expect the drug to work very well. This is placebo effect.
This is the best effect. So, the effects are not very big. As mentioned
before you have 24 million cases in the United Otitis. Ten percent is 2
million cases. So, it is a big effect in general, but not in a study.
So, to show the effect here you need as we showed before thousands of
cases.

Now, let us assume that we took only the culture positive but 50 percent
culture negative as we heard before, this is not appropriate in a study
usually but 30 percent this is what you usually find.

So, if you take the clinical cases you have to also assume that 30
percent will be culture negative. Culture negative in my experience are
always doing better much faster than anybody else, no matter if you give
antibiotics or not. So, they actually are not bacterial where you miss
the bug most of the time. They are not bacterial, and so if you include
those 30 you already get to over 80 percent here, over 85 percent here
and here again you cannot improve anyhow. This is the maximum.

Now, remember this is all under 24 months. Now, if you take kids over 24
months and here i don\'t put 60 percent as you had before. I just put 30
percent above 2 and of those only one-third above 3. So, it is still
younger than most of the studies that have been used by many drugs. I
get here over 85 percent. You remember this age effect. Here I get
already equivalence antibiotic A and B, but if I really want to show
equivalence also as Colin said with tap water then I take those that are
totally clinical,just looking at effusion and symptoms, and we all know
that effusion and symptoms is most of the time otitis media, but
sometimes it is otitis media with effusion just with a viral infection.
How can you make really, there is an overlap. The overlap in this case
with excellent investigators they only make an overlap in about 20
percent, not more than that. In other places I would say not, but in the
United States there are excellent investigators. So, only 10 to 20
percent and here you have equivalence of one in three.

Okay, so, you can already play with this. So, if I summarize this, and
in addition to that you heard that I can even make it more influenced by
all those cases, avoiding or including those cases that are difficult to
treat according to which drug I have.

So, now let us say that I am now a director of a new pharmaceutical
company and I have either that drug or this drug. Unfortunately most of
the weaker drugs are, also, convenient. Most of the stronger drugs in
PKPD are not. I always cite my grandmother who says that a drug must
taste like a drug. Otherwise it is not a drug. I don\'t know or they are
injected which is another thing that my grandmother would like,
injections, but the point is if I have a drug here and we often have a
drug with true bacteriological activity, efficacy as predicted by the
PKPD in animal models and others but convenient and well tolerated
versus another drug and on the other hand a drug that has
bacteriological efficacy which is good by PKPD, etc., but is less
convenient and less well tolerated, and I will give you a table how to
construct studies to show to sell this one or I am not saying sell in
terms of money, sell the idea to whoever needs to approve it or sell
that drug.

I call it hand tailored AOM drug studies and this is the weak and well
tolerated and the strong and less well tolerated, and what are the
characteristics? Study population of course. I will try to have much
more of the above 24. I try to take the younger ones that have real
problem in spontaneous eradication. DCC, try to avoid DCC children here.
Try to take as many as I can here. By using older kids you, also, avoid
DCC because 6, 7, 8, 9 year olds don\'t go to day care centers. Other
siblings at home? Try to take single kids, you know, so go to clinics
where you have high society type of people. Don\'t go to the inner
cities. They are going to fail. Recurrent non-responsive, avoid those.
Put them in the exclusion criteria but actually here try to enrich your
population because those are the kids that are difficult to respond. So,
enrich them in this, avoid them here. Baseline clinical diagnosis, never
go to bacteriological here. Here clinical, we have proven bacterial
etiology and tympanocentesis. Otherwise if you go here for clinical then
you miss a lot of these things I said before.

Outcomes, tolerability puts much emphasis here because this is a drug
that is well tolerated, of course. Try not to talk too much about this
because it is not well tolerated. Convenience, the same. Bacteriological
efficacy, don\'t include in your end points. Don\'t include that. Make
it fit your main outcome here, okay, and make clinical outcome, test of
cure. It is wonderful. They all go, Colin, your graph shows going down
in parallel. I don\'t think you are right. They converge. They don\'t go
in parallel. They converge at the end. There is almost no difference
after 1 month eventually between those who responded well or not and so
by going to the end of treatment I can show that everything is like
everything, but here I am going to see the maximum difference and for
conclusion I will be based on equivalence of clinical outcome and
superiority of tolerability, convenience and here will be based on
bacteriological and clinical efficacy in difficult-to-treat cases.

Unfortunately, I am not American. I don\'t deal much with the FDA but my
impression as an outsider being foreign and as you know we don\'t
understand a lot of things in the Middle East until you find the
situation similar to us and then we think alike.

I think that this is the FDA approach most of the time. So, if I have
many drugs that may not be responding to this very difficult criteria,
furthermore if I do this, people that are going eventually to take those
meta analysis stuff and put them on a slide are going to show my end
points inferior to their end points and they are going to say that there
are some limitations to it, but I used what I have. When there is some
limitation in using what you have you choose, also, what you want to
choose. So, the point is here if you use this you are going to have
lower end points in your drug and they are going to compare less
favorably with this. So, I think that now I give you enough tools to
plan your studies according to what you have in hand and my conclusion
is with most of the acute otitis media with clinical outcome as
currently conducted are virtually guaranteed to show no significant
differences between agents, dosing or duration of treatment.

Thank you.

DR. RELLER: Thank you, Dr.Dagan.

Questions from the Committee for Dr. Dagan?

DR. DAGAN: Maybe my English was not clear enough.

DR. RELLER: Dr. O\'Fallon?

DR. O\'FALLON: As a statistician I just thought that was magnificent. We
are always looking for where the sources of variability are. This is
beautiful. Thank you very much.

DR. RELLER: Thank you, Dr. Degan.

Is Dr.Sidney Wolfe present?

If not, we will assume that Public Citizen\'s will not be making a
comment at this meeting.

Before closing for lunch there are no direct questions that are
permissible. Comments from either FDA or from Pfizer are possible.

Does anyone wish to make an additional comment now?

Dr. Alexander?

DR. ALEXANDER: If I could I just wanted to address a couple of questions
that were asked earlier. One of them is related to the Costa Rican site
and Hemophilus influenzae B and what we found looking at the
bacteriology from the microbiologist was that there were patients who
were identified within the trial but only a very small proportion that
did have Hemophilus influenzae type B, so that in the three arms there
were 5 of 14 patients who were treated with the 3 day who had Hemophilus
influenzae type B at baseline. Only 1 of 10 who was treated with the
single dose had Hemophilus influenzae type B and 2 out of 9 who were
treated with ceftriaxone.

DR. RELLER: Thank you. It is twelve-fifteen. We are exactly according to
our agenda. We will reconvene at one-fifteen for discussion of the
questions and vote by the Advisory Committee members.

Thank you.

(Thereupon, at 12:15 p.m., a recess was taken until 1:15 p.m., the same
day.)

AFTERNOON SESSION 1:15 PM

DR. RELLER: Before beginning our discussion and vote on the issue at
hand Tom Perez has an addendum to the meeting statement.

MR. PEREZ: Good afternoon. I stated this morning that Dr. Steve Ebert,
Dr. Ellen Wald and Dr. Mary Glode would be excluded from participating
in the general matters discussion of clinical trials of acute otitis
media. I would like to correct the record and state that in accordance
with 18 USC 208(b)(3) general matters waivers have been granted to all
participants requiring a waiver. Therefore, Drs. Ebert, Wald and Glode
will be able to participate fully in this discussion.

Thank you.

DR. RELLER: Voting today will be the eight sitting members of the
Advisory Committee, in addition the consultants, both Drs. Glode and
Gorman will be voting members for today\'s meeting.

Dr. Soreth?

DR. SORETH: Dr. Reller, I wanted to give the charge to the Committee for
our product-specific questions for azithromycin in the treatment of
otitis media.

The first question, do the data support the safety and efficacy of a
single dose, 30 milligrams per kilogram and/or of the 3-day regimen of
azithromycin for the treatment of acute otitis media?

We would ask the Committee that in their discussion they comment on the
influence and the significance of the following and how they contributed
to the Committee\'s recommendations.

The interpretation of the data from clinical only studies, the
interpretation of the data with regard to studies that have microbiology
with the tympanocentesis at baseline on single tap, the natural history
of the infection and also information from the published literature and
how that influences any specific recommendation. Should the Committee
recommend approval we ask further if there would be any caveats in the
label based on the results of the studies with tympanocentesis at
baseline. If the Committee does not recommend approval what additional
study or studies and finally, if approval of the single-dose regimen is
recommended we ask the Committee for their advice with regard to what we
would advise prescribers and patients concerning increased vomiting
associated with the use of the single-dose regimen.

DR. RELLER: Thank you. Tom Perez will be recording our votes yes or no.
Based on past experience in the discussions I think it would be helpful
if we heard from every Committee member the points of discussion that
you wish to make regardless of in the end how your vote is recorded so
that the importance of the various components that Dr. Soreth has asked
us to comment on we now open it up for discussion.

Dr. Chesney?

DR. CHESNEY: I have a real concern about our lack of pharmacokinetic
data. In terms of giving this drug only once or for 3 days I don\'t know
No. 1 if it is taken up into hepatocytes. No. 2, I don\'t know how very
young infants will handle this and No. 3, one of my concerns is that
children with viral syndromes not infrequently have elevated liver
function tests, and I am not sure if these high doses are taken up into
hepatocytes how that could influence the course of the viral syndrome
particularly since it may be retained for a prolonged half life.

So, I am very anxious about not having pharmacokinetic data particularly
in younger children and I don\'t know if anybody can reassure me on that
score.

DR. RELLER: Other comments from the Committee?

DR. LEGGETT: Jim Leggett. Several thoughts occur to me on a purely
scientific basis. PKPD has not been shown to work either for the single
day or the 3 day. There is some data with the single dose in other uses
leading to increased harboring of resistant organisms. That worries me a
little, and in terms of AUC to MIC while that may be the parameter of
most importance for azithro, that is, also, a little bit experimentally
biased by the way and the timing that those parameters are done in mice
and everyone else, and I worry a little bit about a single dose study
finally running out of its post-antibiotic effects before we get out to
the longer time period at least in terms of having efficacious levels,
especially in view of the 5-day versus 10-day French data of Dr.Cohen
that was presented.

So, in other words if 10 days is better in these sickest patients than 5
days then what does the single dose really do for us in terms of
actually treating the patients?

I don\'t know anything about regulations in terms of whether we should
approve the 1 day or the 3 day because a lot of the steps that are in
the guidance document appear to have been addressed.

However, I am very much worried about the lack of pharmacokinetics in
both the 1 day and the little less than 3 day.

I think that in terms of interpretation of data from clinical only I
think that end is where we are beginning to see, at least possibly see
today leads to sort of a bio-creep that people are worried about so that
we keep comparing ourselves to less and less and less and finally we get
down to no better than placebo.

I am, also, a little bit worried about the clinical only, of the
difficulty at least I as a non-pediatrician have in making the
difference between cured, improved and failed on looking at an ear or in
an infant. I think tympanocentesis at baseline to me is a step better.
The natural history of the infection looking at the degree of
recurrences means that waiting until the test of cure does not seem like
a very good idea, and information from the published literature I think
of good quality is very useful in terms of placing these things in
perspective if we only have active control comparators. It gives us a
little bit of an external grounding at least to some degree.

In additional studies I would recommend further kinetic studies.
Vomiting with a single dose, I think it has to be stated. I am a little
bit worried again with kinetics that those values, the AUCs that were
shown in adults for the single dose 2 grams and 3 grams while the yellow
and green triangles were within the error margin the AUC in those things
said, \"Only 0 to 24.\" With a half life of 68 hours we are still
accumulating. I don\'t know what is going to happen, again to go back to
my point, they vomited, it looks fine up to 24 hours, but what happens
between day 5 and day 10 when that AUC may not still be within those
errors?

DR. RELLER: Thank you very much, Dr. Leggett.

On the points that Dr. Leggett addressed his perspective others who wish
to comment on any or all of those and how they influence your thinking
on the vote that we will take?

Dr. Ebert?

DR. EBERT: Just one expansion. Dr. Leggett mentioned the issues about
AUC and much of that information was developed in animals and that total
daily dose whether it was given in single or divided doses showed equal
efficacy and again, I share his concerns for two reasons. One is that
that data was based on microbiologic response, not clinical response, in
other words number of organisms eradicated in the animal models. I have
not seen a similar corollary to that in a human infection model if you
will and then secondly, again, the concerns about how far can one really
extend the dosing interval and still see adequate bactericidal effect.

DR. RELLER: Dr. Chesney?

DR. CHESNEY: I, also, have a real concern about the vomiting in the
first day because particularly for infants that comes at a time that
they often have high fevers and are already vomiting and not taking
anything orally and perhaps dehydrated, and to give them a very high
dose of a drug that is conjugated in the liver and to add vomiting on
top of that may necessitate hospitalization. So, that is another area
that I have some anxiety about.

DR. RELLER: Dr. Wald?

DR. WALD: I think we have a tremendous dilemma here this afternoon
because we heard some excellent presentations this morning about all of
the parameters that influence outcome in acute otitis media and I think
that they really highlight some substantial weaknesses in the studies
that are presented today, especially the clinical only studies and
especially because the age group that was focused on was older children
rather than younger children, and I think that the microbiologic data
are weak.

I will restate again a 50 percent retrieval on patients in whom one is
very anxious to make a correct diagnosis is very low. Most
tympanocentesis studies have recoveries of between 70 and 80 percent for
positive microbiology.

So, if a positive microbiology is seen in 50 percent of those patients
who I presume are highly selected because you want them to be positive,
then I think we really have to worry that the number of children who
actually had acute otitis media in the remaining clinical only studies
was really substantially lower than 50 percent and so I think these are
sort of the facts.

On the other hand these are not standards that we have held other
products to, and so, I think that the real focus is do we have a new
standard that we use this afternoon or do we create a new standard which
I hope will be the subject of our discussions later this afternoon and
what do we do with this product at this time? So, I think it is a tough
dilemma.

DR. RELLER: Dr. O\'Fallon?

DR. O\'FALLON: I have concerns, also about the analysis. I mean we
didn\'t talk about the fact that what was called a modified intent to
treat is not intent to treat by any definition I have ever seen before.
The people who didn\'t show up for the day 28 or whatever the definitive
test of cure whenever that was, the ones who didn\'t show up were simply
left out. They were not involved in the analysis.

Now, that creates, missing data always creates a real problem. If they
were, indeed, failures for whatever reason, those success rates, those
cure rates that we were seeing are even lower than the numbers that we
were given.

In some of the studies those were very substantially missing including
ones that were used for labeling; the studies for the 5 day that were
used for labeling had very substantial missing data.

I am concerned that maybe what we know ain\'t so. This really is a
worrisome thing. So, I think that the actual success rates are lower
than we have been told in these presentations.

DR. RELLER: Dr.Christie?

DR. CHRISTIE-SAMUELS: I have several concerns and some of them were
already outlined. However, one includes the representational children
are the age 2 years where there is a higher likelihood of failure and I
am not so sure that the role of Hemophilus influenzae type B has been
clearly outlined.

We heard some data from Costa Rica. I realize it is true that here in
the United States the patients are likely to be immunized. We are
actually using a very, very young age group and since they are using a
drug where you may have resistance to HiB I am sort of worry about that.
I am worried that the recovery rate for bacterial pathogens was less
than 50 percent and I am worried, I am concerned that the PKPD data was
not available, especially for young children and the data that was
presented I am not very clear on what was presented but the data that
was presented for those who vomited as far as I can understand that data
was for adults not necessarily children. So that to me has not been
clarified.

The Pollyanna syndrome I wonder how much of that is being shown in the
data that was presented here. One of our presenters showed us that
efficacy needs to be more than 90 percent if we are going to say that it
is significant, and I think the ethical dilemma for us on the Committee
is I think the sponsor was given a guidance document which I think they
followed, but based on the presentations, the three presentations that
we heard from Dr. Marchant and the two public presenters the question in
my mind is should we include, since we are now changing the standard
should we, as a Committee look at the total picture based on what the
guidance, what guidance they were given alone or should we, also,
include what we heard today, and I think that needs to be clear to us
because if indeed we are to include what the three speakers said, well,
then I think I might, well, we will see how the afternoon passes.

DR. RELLER: Dr. Christie has pointed out some of the dilemmas that the
Committee faces. One thing I would like to clarify is that it seems to
me important that we all understand that whatever vote the Committee
takes is not an issue I don\'t believe of whether the sponsor followed
the existing guidelines or not because we must assess the safety and
efficacy based on the study requirements that the FDA heretofore has
provided as guidance for industry.

At the same time following those guidelines the Committee is asked in
their view based on the data presented from the sponsor and from the FDA
whether the information available is sufficient to make them comfortable
if you will about the safety and efficacy of either a product or an
indication or a dosing regimen of an existing product and we will get
there eventually.

Dr. Chesney?

DR. CHESNEY: Another issue for me and I would like to reiterate what
Ellen and Celia and Dr. Reller have said in terms of how do we make this
decision and I think Dr. Reller has clarified some of that, but one of
the other concerns for me is that this is not clearly a better drug than
what we have. It has a prolonged half life which means that the
concentrations are going to decrease and decrease and decrease with time
which we have heard over and over again is the way that you develop drug
resistance and we already have high levels of resistance to the
macrolides and are we only going to be contributing to the problem by
approving a drug which is not clearly better than what we already have
out there with a number of unknowns of which I think I pointed out that
the absence of pharmacokinetic data is another piece to the puzzle.

DR. RELLER: We have heard much discussion from the right side of the, my
right side of the table and I am delighted that Dr. Patterson has her
hand up from the left side, my left side.

DR. PATTERSON: Okay, I just wanted to make a comment regarding the
resistance issue. Based on what we do know about the pharmacokinetics of
azithromycin and granted we don\'t know about the single dose in
children, but there is data to suggest that the efficacy would be based
on the area under the curve over MIC ratio with this drug as compared to
even the other macrolides and certainly the beta-lactam antibiotics, so
that with a single dose you know it looked like certainly compliance was
better but also it might have, you know, less effect on selection of
antibiotic resistance, specifically macrolide resistance than the 5-day
regimen if you were just giving it as a single dose, and I wanted to
make a comment, too, about the Pollyanna phenomenon which I think is a
real one but I think that it is not unique to acute otitis media.

Having been involved in some of the vancomycin resistant enterococci
studies when before we had options for therapy we found that all but the
or many of the patients except those with very severe infections had
some spontaneous resolution, so while I think it is a phenomenon I
don\'t think it is unique to otitis media, and the other issue about the
resistance is that I found it interesting that with the strains that
have the efflux mechanism which is the most common type of resistance in
the United States that six of eight of those patients responded anyway
even though the MIC was eight.

DR. RELLER: Dr. O\'Fallon and then Dr. Wald.

DR. O\'FALLON: One of the things that is making it difficult for the
Committee is the fact that we are back to the business of having point
estimates. Six out of eight is 75 percent. The trouble is that the
confidence interval, any confidence interval you want to choose is going
to be so broad with only eight people that it is going to be consistent
with response rates running from about 35 percent to practically 100
percent.

So, I worry. I am going to come back and say again, I think it is very
important that we see confidence intervals and I want to commend the
company for presenting that nice thing that I asked about because I
didn\'t understand it the first time I saw it, but that is the way I
think that we should be seeing response rates for any of the ways you
define response.

We should be seeing how they line up with everything else and it will
give us a feeling for how big the study was and how big the population
was.

The problem for me with this whole thing is I don\'t know how to put
this politely; so it is just going to be bald. The guidance as written
now rewards sloppy research. If you use a clinical end point without
doing any kind of a tap that is the \-- and then you throw away the
people that just didn\'t show up at the 28 day you can really manipulate
your success rates way up there, and then if you don\'t take into
account the major prognostic factors of the subsets of people that have
different responses innately in the disease, if you don\'t take into
account those things, you can make your drug or your agent look good,
and I am afraid right now I think the guidance is wearing a black hat in
this whole issue today. It was before I came in here and I am even more
convinced of it now.

DR. RELLER: Dr. Wald?

DR. WALD: I think that Dr. Patterson really raises another important
generic issue for our consideration. In the year 2001, when we heard
data that 25 to 35 to 40 percent of S. pneumoniae are resistant,
shouldn\'t it be our expectation that that number of S. pneumoniae
isolates in the clinical study will be resistant? Are NC microbiologic
data addressing that particularly? I know we had a lengthy discussion
about high-dose augmentin around the issue of resistance, but resistance
is now an everyday phenomenon. It is not a special phenomenon. It is
what we are treating when we treat acute otitis media so that we really
have to have an adequate complement of those cases, I think in order to
make a judgment, and I have to say that Joan has really highlighted the
issue of toxicity and hepatic metabolism.

Why do all these studies start at 6 months? Surely the drug is going to
be used in children under 6 months of age. Is that our requirement? Why
do folks start at 6 months? Does anybody know?

DR. ALEXANDER: This is Dr.Alexander. I am actually doing a presentation
a little later that sort of addresses that a little bit, and from what I
was able to research in looking at our previous guidance and the points
to consider document and such, they were looking at children that were
greater than 6 months of age because of concerns about actually being
able to accurately diagnose for the purposes of clinical trials the
acute otitis media in those children that were less than 6 months of
age, that they had concerns due to, I think some related to the
organisms that were identified from children that were less than 6
months of age and some actually related to the physical examination,
being able to accurately diagnose infection in that population.

DR. WARD: Just the last issue that I would mention is the one about
duration of therapy, and I think that there is a controversy about 5
days versus 10 days and again, do we have any \-- and I think the data
support the notion that short course therapy, 5-day therapy is
disadvantageous in children under 2, and we would expect that because
they are more difficult to treat. So, is there any reasonable
expectation that the single dose of azithromycin will have a level
beyond the fifth day of treatment? Is that known? If a
30-milligram-per-kilo dose is given on day 1 is there anything on day 6?

DR. RELLER: Dr. Gorman?

DR. GORMAN; I would like to echo Dr. Chesney\'s comments about toxicity.
Known tentatively to be intracellularly concentrated it presents some
concerns about the young infant in terms of this dosing, and the
resulting need for PK and PD data, also, in children less than 6 months
or let me say over the entire range in which this will likely be used in
the ambulatory setting which would be from birth to the end of the
pediatric age range will be likely.

I look at the Pollyanna effect as the fact that you are using this
chemical that you call an antibiotic inside a host that has a huge
number of other resources that it brings to bear or gets in the way of
taking care of this infection, and one of the things that was not clear
to me when I read the article, while the Pollyanna effect will make a
bad drug look fairly good, it, also, prevents a good drug that is not
being used from looking bad.

So, if you take the best known drug, and I will use an old example of an
oral antibiotic that was unpalatable that people would take and then
throw up and then the patients would not take it again, you would still
get the same results.

Things would look good on this data presentation because of the
Pollyanna effect which would not even let the best drug when not used
effectively, when not used compliantly still look pretty darn good.

I cannot underestimate for my parents, however, how important compliance
and tolerability are in the dosing of these agents, and the concept of
trucking around from work to day care to home different antibiotic
agents becomes an incredible financial burden for these people, and if
there was any data that just got them back into day care faster it would
be a huge clamor for this medicine much like there is for the injectable
medicine in our community, injectable alternative.

Host factors you cannot control for but in any new guidance might be
considered might make the studies impossible to do, but you need to
start looking at those things as either subclasses statistically as you
do your analysis or excluding them from the enrolles so you know who is
in the population.

Since these are short studies in terms of each individual\'s
participation you should be able to figure out who is in day care and
who is not, who had siblings and who did not.

Lastly on the guidance I wear another hat. I sit as an IRB member on two
different IRBs and we would not approve the tympanocentesis study for
otitis media under any circumstances. We feel it is not the standard of
care. We feel it puts children at risk for a disease which has in 2001
basically no sequelae.

DR. RELLER: This is a great opportunity to hear comments from the
Committee after we hear from Drs. Alexander and Soreth about the
importance of the single tap studies as regards the data presented in
evaluation of the product on the table.

Dr. Alexander?

DR. ALEXANDER: This was actually just a question as a point of
clarification for Dr.Gorman\'s statement. Were you saying that any study
with tympanocentesis would not be approved or were you referring
specifically to the double-tap studies?

DR. GORMAN: It would be very difficult in the university or community
IRB that I sit on to have a, in fact, we have turned down single-tap
studies because they appear to offer no scientific benefit to that
child, and they pose a risk. So, it adds risk with no benefit, and I
have had the opportunity to talk to the chair of an IRB in another large
institution who, also, claims that he routinely rejects all
tympanocentesis studies.

Now, clearly some IRBs are accepting them because they are still being
done.

DR. RELLER: Dr. Chesney, and then we will come to Dr.Maxwell.

DR. CHESNEY: I just wanted to comment on your comments. I could argue
very strongly that a tympanocentesis study offered distinct advantages
to the child because you know what the organism is. You know what the
susceptibilities are and you can narrow your spectrum based on that.

So, just a comment, not immediately relative to the issues at hand.

DR. GORMAN; Our IRB would disagree. It offers advantages to science. It
offers not advantage to that child because you are not going to change
the drug inside a clinical trial unless you then set up the trial to do
that which we have not seen yet.

DR. RELLER: Dr. Maxwell and Dr. Wald.

DR. MAXWELL: I just had an additional question. To my question as to how
many children were redosed who vomited in the first half hour the number
was eight, but I really wonder how many children vomited 1 hour, 1 hour
and 1/2 and 2 hours after and then were redosed, and I don\'t know if
anyone here has that answer.

DR. RELLER: Dr. Dunne may have or will have, and we will come back to
him when I see a hand.

Dr. Wald?

DR. WALD: Maybe not to belabor the tympanocentesis discussion, I think
there can definitely be benefits to the patient. There is immediate pain
relief even though there is some experience of pain at the time of the
procedure. I watched one just yesterday afternoon, and then we did have
a sample, and we could if we need to make a precise judgment about
non-response to that therapy we will have information in our hands which
will be invaluable.

So, I think that one can justify it in those terms and some children
are, of course, experiencing quite a lot of pain and for those children
it probably is a bigger benefit.

DR. RELLER: Dr. Marchant?

DR. MARCHANT: To make a comment in response to Dr. Gorman that adds on
top of what Dr. Wald just said about tympanocentesis, the problem is if
we don\'t do tympanocentesis we won\'t know what is going on at all in
drug approval and that means that it will sort of bring to life the
Pollyanna phenomenon that poor drugs with poor efficacy get licensed and
we don\'t know that they don\'t work. We don\'t figure out that they
don\'t work and out there in clinical practice there are going to be
patients that remain symptomatic because we have approved and then as
practitioners prescribed drugs that are less efficacious and so to
abandon tympanocentesis is to basically put ourselves in the dark in
terms of the performance of antimicrobial agents for this disease.

DR. RELLER: Dr. Gorman?

DR. GORMAN: I am sorry I brought my IRB into this. First of all, I
don\'t own this IRB. I just sit on it, and while I don\'t disagree with
the scientific arguments here, you are now in the position of having
your own data used against you that has been developed by
typanocentesis.

Your predictive value when there is bacteriological cure is excellent in
terms of clinical cure. Your predictive value when there is not
bacteriological cure is a coin flip or perhaps a little bit better than
a coin flip.

So, one would have to argue at least in the data presented in one of the
articles that if you didn\'t have a bacterial cure, a clinical cure was
still a 50/50 outcome or roughly a 50/50 outcome, and I understand the
other clinical parameters that come in here.

The second thing that your tympanocentesis has shown me to sort of mute
what Dr. Wald and you have just said is that often when you retap these
people they have different organisms. So, how exactly are you going to
then claim you need to retap them each time they have a reoccurrence
because I am going to then be in the position I have data that shows me
from previous taps that clinical failure doesn\'t necessarily mean the
same organism is present.

DR. MARCHANT: Clinical failure is during therapy when you switch from
one organism to the other. Yes, they do occur, but they are way the
minority of failures. It is a very small number you are talking about.

DR. RELLER: Thank you, Dr. Marchant.

Dr. Glode?

DR. GLODE: I have really two separate issues to mention. One would be
that abstract I gave you. Would this be an appropriate time about
unanticipated adverse effects or not?

DR. RELLER: Sure. We want to get all of the discussion out on the table
before the vote. Please?

DR. GLODE: Okay. I just wanted to mention this briefly because I don\'t
think it is relevant to the vote today, but it is relevant to the issue
of large studies and large study subjects and perhaps unanticipated
adverse events, and that is that this abstract that was published in the
Infectious Disease Society of America, and I just happened to be at the
poster because I happened to be at the meeting whenever that was a week
ago, and I happened to know I was coming to this meeting, and it was
about azithromycin. So, I was paying more attention than I might
otherwise, but it is really interesting for both, I think the FDA
Advisory Committee, the FDA and the sponsors, and it is just an article
looking at azithro or an abstract exploring in an animal model
azithromycin as an immune modulator and in the animal model when you
give azithromycin and you follow with a conjugated pneumococcal vaccine
you have a very statistically significant effect on the immune response
to that vaccine.

That, of course, is very important to me if it had any application to
human beings, and we don\'t know that it does, but someone should look
at that and make sure that there is not an immunomodulatory effect in
children because I actually personally am more interested in preventive
invasive pneumococcal disease than anything else to do with otitis
media.

So, I really, you know, would just want that to be explored and
obviously this is only in an animal model. So, it may not have any
relevance to humans, but is nonetheless interesting scientifically, and
so, I just wanted to bring that to people\'s attention so that it is
something people look at perhaps in the future studies.

Then my comment about the information that we were presented with is I
keep sort of focusing on the less than 2 year old even though that was
not the majority of patients enrolled in these studies but may be the
majority of patients with otitis from what we have heard about, and if I
look now at day 28 failures with single-dose azithromycin it looks like
it is in the range of 24 percent, with 3-day 33 percent, with
ceftriaxone 30 percent, with augmentin 49 percent. So, again, I mean I
really don\'t like any of those clinical failure rates in the less than
2 year olds. That is sort of with all comers, and then if you look then
specifically for Hemophilus influenzae in the less than 2 year old where
it was in the sponsor\'s study, a 47 percent clinical failure rate at
day 28, and I was trying to put that together with the Dagan published
study where they concluded that azithromycin was inferior, but in fact
they are very similar because that is 42 percent for Hemophilus
influenzae clinical failure rate in their study which had a mean age of
16 months. So, it probably fits. I mean probably the data is in fact not
discrepant; it is similar. They just reached slightly different
conclusions, but it helps me that the data is, in fact, sort of
concordant.

So, I have to say that compared to ceftriaxone or augmentin it looks
like it is in the same ballpark even though it is a high, if you will
clinical failure rate overall, but I guess that is just what we have in
less than 2 year olds with otitis media.

DR. RELLER: Dr. Dunne, do you have some additional information for our
consideration?

DR. DUNNE: Yes, I wanted to come back up and tell you about the children
who vomited within the first 2 hours and how they did with redose.

May I have the first slide?

So, these are patients who received a single dose of azithromycin who
vomited on day 1 after this first dose. This population is all the
patients that received that dose, 487 children and those who vomited are
listed here in yellow. We broke it down by the study from which those
children came.

You can see with 30 minutes there were eight. They all occurred on study
1015 and all eight of those were redosed. There were 4 and 10 children
four below the age of 2 and 10 above the age of 2 who vomited within 2
hours.

This includes this group, of course. That is why the fours match up
here. So, six additional children over the age of 2 who vomited in that
30-to-120-minute interval.

We do have children who vomited, and we don\'t have the exact time of
that vomiting. We know that they were not redosed except for this one
child.

Next slide?

Now, how did they do? Okay, we said that there were eight children who
vomited within the first 30 minutes. We had outcome data on seven of
those eight children under the age of 2. All three of those children
were clinically cured at end of therapy and again at the test of cure
visit. Of those greater than 2, three out of four were cured. At test of
cure one out of four were cured.

The next slide is what happened between 30 minutes and 2 hours. This
would have been children that vomited in that interval but did not get
redosed. There were no children less than 2 in that category, four out
of six both at end of therapy and test of cure were cured.

There was one other point that was made about the what do we do with the
missings, and typically you might, well, one way you might handle the
missings is by calling all of them failures and seeing what happened to
your comparison.

If you could put up that slide, please?

This is the only study that had a significant number of missing and by
significant it is in 8 to 10 percent something range. It was R-0581. The
other ones had two or three people missing. So, it doesn\'t really
impact much, and this would be an analysis where we set all the missings
to failure on each arm, and you see the success rate at day 14 is 80
percent and 82 percent on azithromycin and amox/clav. The lower limit of
the confidence bound is minus 11.

At day 28 success rates are 66 and 67. Lower limit is minus 12 on the
difference, similar rates for cure. Lower limit is minus 8. These are
within a point of the lower limit from what we saw before when we had
just excluded the missing. So, we didn\'t see anything really different.
We did sensitivity analysis by setting the missings to failure in all
the studies, but as you can imagine it doesn\'t really change anything
very much.

DR. O\'FALLON: But what bothered me when I was reading this and doing
this was the fact that the Pollyanna effect under those circumstances,
you know, for the mix, particular mix of patients, tap water produced 71
percent at test of cure.

So, here we have numbers that are well, I mean percentages that are well
under 71 percent.

DR. DUNNE: Yes, I mean I think we don\'t as you could imagine, the
studies that we do are comparative studies to approved agents. So, the
issue about comparisons to placebo, that would be a different kind of
forum where that would be probably addressed. I think the best that we
can do to help people get comfortable that at least azithromycin is as
effective as amoxicillin/clavulanate when you start to get the numbers
up was on that kind of meta analysis thing.

If we can just show the slide, pick either one, the day 14 main
presentation tornado chart there? I will just come back to that here.

That would be Slide 115 in the main presentation. Again, we won\'t be
making comparisons to placebo. We would make comparisons to what we
think is an active drug which would be at least amoxicillin plus a
beta-lactamase inhibitor and over the course of looking at 4000 patients
we see point estimates of difference that are in the range of 1 percent.

So, if people are comfortable that at least amoxicillin is something
better than placebo after looking at 4000 patients with these clinical
end points; these are clinical end points; this is not the bacteriologic
end point, it is at an earlier time point. Once you start adding up all
the patients and all the trials which I would say that you probably
don\'t get a chance to see this data very often because it is not often
that you see a drug coming here that has already been out on the market
for 5 or 6 years and has a lot of experience; so, this is an opportunity
to see a lot of patients in a comparison like this and it looks to us
like the azithromycin children did as well as the
amoxicillin/clavulanate within very narrow confidence bounds.

DR. O\'FALLON: When you showed that this morning I looked at it and I
saw the azithromycin versus amox/clav as being almost significantly in
favor of the comparator. That second one up from the bottom, it almost
excludes, yes, the confidence interval almost excludes zero. So, it
looks to me like that is even saying that it is worse.

DR. DUNNE: The confidence interval would say that it is within the
bounds. So, it is hard to say that it is worse, but if it is different
it is less than 1/2 percent.

DR. RELLER: Dr. Cross?

DR. CROSS; Dr. Chesney brought up the issue of giving a single large
dose which is accumulated or conjugated in liver. Do you have any data
on liver function in the single high dose?

DR. DUNNE: Yes, in study 95-001 where we looked at a single dose of
azithromycin, the 3-day dose and ceftriaxone we did collect laboratory
exams during that study.

Let me see if I can pull that slide up?

Slide S21, please?

Again, there were 66 children in this study at baseline. We have
laboratory exams on most of those children, most but a few. Looking at
neutrophil counts ANCs less than 1000 there didn\'t seem to be any
difference between any of these regiments. Total bilirubin, the same
pretty much across all. AST and creatinines again, no abnormalities seen
in that particular group, and this would be consistent with the sum of
experience we have had now with all the patients that have been treated
with a 5-day dose.

The regimen 1, 3 or 5 will accumulate to the same degree. The AUCs are
very similar in each of those regimens. So, the same total amount of
drug will pass through the liver and as people are probably aware a
small amount of azithro is metabolized in the liver. It is not a drug
that is really active to the P450 system. So, in fact, it doesn\'t
really get metabolized much there.

The experience with 5 day, looking at total dose should be similar to
the single dose, and we do have a small patient population here to give
you a sense of labs.

DR. CROSS: This is entry or \--

DR. DUNNE: This would have been at the day 7 to 8 visit. If anyone had
an abnormality later though; they came back with another problem, that
would have been picked up, but this would be in the earlier, yes, that
is my understanding.

DR. RELLER: Dr. Chesney?

DR. CHESNEY: How old are the children from whom you got that data?

DR. DUNNE: The mean age of the children in that study was about 2-1/2
years with a range fro 1 to about 4.

DR. RELLER: Dr. Ebert?

DR. EBERT: My question is again directed towards the vomiting that
occurred in some of these children who received a large single dose.
Certainly in adults who are given excessive doses of macrolides one has
the potential for at least a reversible degree of ototoxicity that can
occur and I am wondering you look at all in any of these children at any
impact of the drug on vestibular function or hearing? Could that have
contributed to the vomiting or was it thought to be a gastrointestinal
phenomenon?

DR. DUNNE: Okay, so the question speaks to the association of macrolides
and ototoxicity, and are we in that range, for example, in these kind of
RTI doses.

About 3 to 4 percent of adults that receive doses in the AIDS program;
so, this was much higher doses, for example, 600 milligrams a day for
life essentially, about 4 or 5 percent of those people would develop
some kind of a reversible hearing impairment, but the earliest that we
really saw any kind of hearing impairment occur in that population, the
earliest of that 5 percent was about 10 grams and the median amount was
about 40 grams. So, it is well beyond what we see here, and that is
consistent with what we know from the 5-day program where we really
haven\'t seen any ototoxicity occur.

We didn\'t do hearing tests during this program. That is an interesting
thing maybe for efficacy end points, actually in otitis media studies,
but we didn\'t do that in any of these programs here.

DR. RELLER: Dr. Patterson?

DR. PATTERSON: I was going to ask you about the vomiting. Was that just
a single episode? Were there any instances of persistent vomiting and,
also, the patients who were redosed, did hey vomit?

DR. DUNNE: The way we collect the side effect data is by dates. So, if
you have an episode of any adverse event we just list the date down
there, but on questioning to the coordinators this is generally
something that happens one time. There was, and I should, also say that
when we look at the mild, moderate, severe assessment of all these side
effects 80 percent of the vomiting was mild. There was 20 percent
moderate. There were no severe vomitings which we interpret as being
persistent and recurring although the investigator is able to assess
that for himself, and the other question was did they revomit after
redose?

DR. PATTERSON: The patients who were redosed.

DR. DUNNE: Yes, there was one of those eight children who did actually
vomit again on the redosing, and then they got amoxicillin, I think
after that..

DR. RELLER: Thank you, Dr. Dunne.

DR. ALEXANDER: Related to the vomiting, sorry, Dr. Alexander. Related to
the vomiting I actually think that there were two patients that were
within the non-comparative study who vomited who were redosed and then
one of them, both of them vomited again and one of them or both of them
received amoxicillin, I believe. One of them was excluded from the MITT
analysis as being considered to have vomited all the medicine that she
received, so was treated as though she never received any medication
within the efficacy analysis of the study.

The other one, I believe, was included as a failure because of receiving
amoxicillin instead.

DR. RELLER: Dr. O\'Fallon, you had a comment?

DR. O\'FALLON: You see that is the problem with leaving people out. That
child, yes, didn\'t get treated, but couldn\'t get treated and therefore
should be considered a failure instead of left out of the MITT analysis,
the one that was left out.

DR. DUNNE: I would have to go back and check on that other patient. I
cannot really comment on that right here.

DR. RELLER: Dr. Goldberger?

DR. GOLDBERGER: I thought perhaps before the vote actually occurs it
might be useful to make a few comments about this issue that came up
about what guidance ought to be utilized in terms of thinking about the
voting.

You know, I think obviously as a starting point the first thing to do is
to make a determination in terms of the recommendation you are going to
provide, is this product safe and effective based upon the current
guidance that exists. Concerns have been raised about the amount of
pharmacokinetic data and other issues, and clearly the expectation is
you will take these matters into account in making your vote.

Then the issue has come up as well about the fact that it would appear
as though the current approach to development of products in this area
may have certain limitations, and I think it should be obvious to
everyone, you know, that we certainly recognize this as well, both in
terms of our asking you to comment on some of the things that were
important to you as part of question 1 as well as in the fact that there
will be some specific discussion about this later in the afternoon.

On the other hand there has been some discussion in the last few minutes
about what studies can and cannot reasonably be performed, and I think
that one needs to take into account that if one takes a new standard as
the de facto standard involving studies in which there is legitimate
disagreement as to whether they can be performed that obviously poses
certain problems.

In addition, there has been some important PKPD data presented here
today that may well be very influential in subsequent guidances, but may
require some additional review before one can reasonably conclude that
it should become the standard.

So, I think that you are free in the end, obviously to make the
recommendation as you see fit. We do, you know, like to understand your
thinking, and you should be aware there can be a situation in which our
regulatory requirements may require us to think a little more in terms
of exactly how to utilize your recommendations given that there may be
some difference between what we would like to be able to do in terms of
developing drugs and what the current standards are today.

I hope that helps you a little bit in thinking in terms of the voting.

DR. RELLER: Thank you, Dr. Goldberger.

I propose the following. We will go starting at my right with Dr. Wald
and ask for since some of the part 2 and the subsets of the questions
require this delineation for Committee\'s advice to agency that we
simplify it to single dose 3 day and give us a yes or a no for each and
if it is yes for a single day, if you want to add any caveats as Part A
delineate please say so, and if the answer is no, any additional studies
for single day and then go to 3 day with the same comments and then we
will take question No. 2 depending on what the majority view is from the
initial vote.

Two yeses or no\'s and plus or minus comments related thereto.

Dr. Wald?

DR. WALD: I guess what I would conclude is that both the single day and
the 3-day regimen compared favorably to the comparator drugs in a study
design which would not allow us to easily distinguish a better from a
worse drug but that this has, in fact been the standard by which we have
judged drugs, and so in that context I would say that the data support
the safety and efficacy as we have until now interpreted it, and so that
would be a yes, yes, without caveats.

DR. RELLER: Thank you.

Dr. Leggett?

DR. LEGGETT: Yes, for single, yes, for 3 day, no caveats.

DR. O\'FALLON: No, for both. I don\'t think that the evidence we see has
established the effectiveness or safety actually of either.

DR. RELLER: Dr. Christie?

DR. CHRISTIE-SAMUELS: I have to say a no for both.

DR. RELLER: Any additional studies, Dr. O\'Fallon or Dr. Christie with
your no votes?

DR. O\'FALLON: Yes, I think that the bacterial studies although the two
in the literature are some start, but I think there should be those and
then for definitely sure the PK studies in the younger children, maybe
even PD but certainly PK in the younger children before we can approve
it, because that is apparently the majority of these patients. I think
we should see evidence in those patients.

DR. RELLER: Dr. Christie, a part B comment for either or both
1-and-3-day regimens?

DR. CHRISTIE-SAMUELS: PKPD data, larger Ns looking at ototoxicity and
hepatotoxicity, children younger than 2 years of age, studies in day
care centers and Dr. Dagan\'s comments, the second to last slide for
hand-tailored AOM drug studies. I think he summarized it pretty well.

DR. RELLER: Dr. Chesney?

DR. CHESNEY: I would say no for the single dose because we have no
pharmacokinetic data and this is such an appealing dose form. It is 100
percent compliance in the office. It will be used instantly for all
ages, and I have problems with that.

I would say yes to the 3 day regimen because it is already being used 5
days, and I don\'t think 3 days is that much different but only for
children over 2 years, again, with absent kinetic data.

DR. RELLER: Dr. Ebert?

DR. EBERT: Yes, for single dose, yes for 3 day regimen. I do believe we
need to do a better job of measuring or comparing response in agents
earlier in the trial period and not waiting for 28 days to assess
outcome.

DR.CROSS: While the data are not optimal I think it would be helpful as
has been brought out by other Committee members to have some better data
on children less than 2 years and have better PKPD data, I think within
the context of the guidelines and its equivalence or at least no
difference with comparators I would vote yes for the 1 day and yes on
the 3-day regimens and no caveats.

DR. RELLER: Thank you.

Dr.Gorman?

DR. GORMAN; I would vote yes n the 1 day and yes on the 3-day dosage of
this form. Caveats is such a broad terminology. What caveats are we
allowed to put on the label in terms of the question of tympanocentesis?
I am looking for guidance on the caveats that are allowed under your
regulatory statute.

DR. SORETH: I think that what you can take into account are issues of
age, if you feel that there are data to speak to differences above and
below the age of 2. Caveats have at times been put into labels not only
for otitis but for other infections as well that some organisms,
patients with some organisms recover better or have different rates of
success than others.

DR. GORMAN: I would then put in a caveat that this drug not be approved
in children under 6 months of age until the sponsor company can provide
PKPD and toxicity data in that group.

DR. RELLER: Dr. Glode?

DR. GLODE: I would think that the data do support. I am going to divide
up safety and efficacy for just a moment. They do support efficacy of
the single dose and of the 3-day regimen compared to the licensed
products.

I will, also, support it with regard to safety mainly on the issue of 40
million doses distributed to people of different ages and presumably
having been used safely, but I am disappointed that there were not
actually more laboratory values for us to look at with regard to safety
issues and certainly the absence of PK data was, also, concerning.

DR. RELLER: I would vote no to both 1 day and 3 day based on the paucity
of pharmacodynamic data on the 1-day dose and with the 1 day and 3 day
where the bacteriologic confirmation is available with one of the
studies and the other it is the pharmacodynamic, and I think that the
total database though the efficacy by the past criteria is comparable I
think the database could be more solid when we go to these new dosage
regimens, and it is just not all fitting together for me for either the
1 day or the 3 days. So, my vote is no for each now. I think additional
studies are needed before approval of those regimens.

So, what we come out with is six to four for single-day therapy and
seven to three for 3-day therapy which enables us to go to question 2
for the single dose regimen. We will come around the table in reverse
order, starting with Dr. Glode. What advice on it if any should be given
regarding the issue of vomiting associated with the 1-day regimen? This
is information for prescribers and patients that presumably would move
its way into a package insert, advice for the agency to consider in
their final decisions on the issues at hand.

DR. GLODE: Okay, advice for the agency to consider, perhaps a statement
that says that with the single dose of azithromycin an increased rate of
vomiting has been observed and then I suppose some comment should be
made to prescribers about under what conditions and how many times the
drug should be recommended to be redosed, and I really with N equals 8,
I don\'t know that I could come up with that. I could make up something.
If the patient vomits within 1 hour you may redose times one, but that
is as far as I can go.

DR. RELLER: Thank you.

Dr. Gorman?

DR. GORMAN: My recommendation would be more in terms of packaging, much
like syrup of ipecac in the past. I would make sure there were two
effective doses for the largest child that you would expect to require
liquid. So, in ipecac if the first dose was not successful you
administer a second dose. In this case it would be exactly the opposite.
If you vomited the first dose I would like the packaging dispensed by
either the pharmacist or the physician to have enough for the second
dose available so that the rescue dose would be available to the parent
without another trip to the pharmacy at no added expense.

DR. RELLER: Dr. Cross?

DR. CROSS: I think, also, that there ought to be some comment about the
need for redosing if there is vomiting within a specified period of time
and on the other hand we don\'t have enough data on that to actually
make that recommendation. So, I think we have to urge the sponsor to
acquire that so it is included on the labeling.

DR. RELLER: Dr. Ebert?

DR. EBERT: I agree that there should be some window at which vomiting
before that time would require redosing and vomiting after that time may
not require redosing. As the previous panelists noted I am not sure that
we know the exact time frame for that window, and I concur that if at
all possible at no increased cost if we were able to give an extra dose
that would certainly save from a consumer standpoint an additional trip.

DR. RELLER: Dr. Chesney?

DR. CHESNEY: I don\'t think we can make any recommendations. If this is
absorbed well in the first 20 minutes and then the child vomits and we
give another dose now we are talking about 60 milligrams per kilo as a
single dose, and if I was nervous about 30, I am really nervous about
60. So, I don\'t think we can make any recommendations.

DR. CHRISTIE-SAMUELS: May I seek some clarification please? I have a
question. The recommendation is from the Committee, if the Committee
recommends that it be approved or is it \--

DR. RELLER: I will give you some help, Dr. Christie. I voted no, and
consequently I have no additional advice because Dr. Chesney summarized
and that was one of the considerations in voting no because I simply
didn\'t know enough about what to do in the 10 percent who vomited, and
I think there are sufficient issues regarding safety that without the
pharmacodynamic data and the group in greatest need if bacteria would be
demonstrated on a tap, and it is not there for me, and it is one of the
considerations.

Now, you can comment or not comment.

DR. CHRISTIE-SAMUELS: Thanks for the clarification. I guess I have to
abstain since I didn\'t make the recommendation in the first place.

DR. RELLER: Dr. O\'Fallon?

DR. O\'FALLON: I, also, did not make the recommendation, but I would
like to point out that I don\'t think there is any evidence or at least
certainly not adequate evidence to try to make a decision on this. There
is not enough here to make a decision, at least from my perspective.

DR. LEGGETT: I would like to point out the fact that many parts of the
world don\'t even use antibiotics for acute otitis media much in the
same age group as these folks. So, the only thing I would say is just
note that increased vomiting is seen with the one dose and not say
anything about redosing.

DR. RELLER: Dr. Wald?

DR. WALD: I think that we have to let common sense guide us here and
that we would certainly give advice or we would let people know that
increased vomiting is observed and I would say that it is reasonable
that if the child vomits in the first 30 to 60 minutes to repeat the
dose.

DR. RELLER: Dr. Soreth, can we provide any additional information to
clarify what we want to convey with questions 1 and 2?

DR. SORETH: Yes, Dr. Reller. There were several comments from Committee
members and guests with regard to additional studies for PK and PD.
Could I just get a little clarification about what those would entail?

DR. RELLER: Dr. Chesney?

DR. CHESNEY: I feel that we need more information at least in the child
under 1. I am just pulling that randomly, but I think as I mentioned
before this is such an appealing dose formulation that it will be used
in 1-month-old infants, and it may be used in 2-week-old infants, and we
know that their excretion mechanisms both liver and kidney are not fully
mature yet. So, I would guess if one had to limit the age groups for me
it would be the lower age group that I would most like to see
pharmacokinetic data on.

DR. RELLER: Dr. Burns?

DR. BURNS: I would say, too, that if you are going to put in a caveat
about redosing after vomiting that you would have to do PK in patients
who had been redosed so you knew whether or not you were getting into a
potentially toxic situation.

DR. RELLER: Dr. Chesney?

DR. CHESNEY: I don\'t know the circumstances under which kinetic data
can always be collected, but if it could be done in febrile infants who
are being treated who may have viral syndrome where the kinetics might
be different than in a perfectly well child who might not be stressed, I
think that would be very helpful.

DR. RELLER: Dr. Soreth?

DR. SORETH: Dr. Reller, you, also, made a comment after talking about
the pharmacokinetics that you thought additional studies were needed.
Did you mean outside the realm of PKPD or what were your thoughts?

DR. RELLER: We have bracketed one single dose and 5-day regimen and
there are some extrapolations to the 3 day based on if the 1 day has the
studies that involved bacteriologic outcome and then we have the data
from the efficacy in use with the 5 days. I don\'t see the studies being
done on each of the regimens is what I am trying to get at, so that the
full database for each of the regimens is not the same magnitude number
of patients, etc.

The studies are different with the different dosing regimens, the
content of the studies available for assessment, the design of the
studies.

Dr. Ebert?

DR. EBERT: This will probably be an incomplete answer, but I noticed
some comments about PK but not a lot on the PD side of things. I think
ideally from a dynamics standpoint we would be talking about
bacteriologic eradication as an end point which we really have not seen
to date with this regimen to compare single dose and multi-dose regimens
with regard to their bacteriologic efficacy.

The secondary issues, of course, would be those of toxicity, whether
there may be an association between serum concentrations and adverse
effects.

DR. RELLER: That concludes Phase I of the meeting. We will take a
5-to-10-minute break very briefly for a stretch. So, those who are not
staying for part 2 can exit and we will launch at 10 minutes of 3 into
the discussion of the guidance document.

(Brief recess.)

DR. RELLER: We will start this afternoon\'s part 2 session with the
presentation by Dr. John Alexander and then we will address the
question.

DR. ALEXANDER: Hello, my name is John Alexander, and now that we have
finished the questions specific to azithromycin we would like to have
sort of a continuation of the discussion that we have had already today
regarding the clinical trials of acute otitis media, and what I am going
to try to present is a little bit of information about our guidance
document.

I will start off with a little bit of history and I promise not to go
all the way back to 1962 and detail everything in painful detail since
then, but just to start out, the Kefauver-Harris Amendments to the Food,
Drug and Cosmetics Act were just significant in that after 1962 was
really when drug companies were expected to show evidence of efficacy as
well as what they had been previously doing which was the safety of
drugs, so that it is really in the sixties and seventies where we began
to consider, well, how do we show what drugs are effective and actually
most of the sixties and seventies were spent addressing what were called
DESI reviews looking at already approved drugs and their efficacy.

So, it wasn\'t until 1977 that we had our first guidance document on the
clinical evaluation of anti-infective drugs, and I wanted to pull out
these two particular quotes from that.

Within that document there was only about half of a page that dealt with
the question of acute otitis media and I thought these two quotes were
reflective of the overall tenor of that particular document, one saying
that it is necessary to confirm the presence of exudate in the middle
ear by pneumotoscopy(?) and needle aspiration to obtain fluid for
culture, meaning that patients, they were looking at pneumotoscopy as a
method for particularly accurate diagnosis of patients with acute otitis
media and the needle aspirate in order to identify those patients who
actually had bacteria on culture, and the other quote, in the absence of
culture of middle ear fluid no specific claim can be made regarding the
effectiveness of any anti-infective drug, and so what we saw after this
guidance document in the seventies and most of the eighties for
anti-infective drugs that were looking for a claim in acute otitis media
was that we had certainly a smaller number of patients that were studied
but in those patients that were identified in those trials, they had
bacteriologic information on all those patients at baseline.

So, we move forward in time to 1992, and the points to consider
document, and this quote should look familiar from the sponsor\'s
presentation this morning that two studies were identified in the points
to consider document, one a statistically adequate and well-controlled
multicenter trial that establishes equivalence of superiority to an
approved drug and a second open study using tympanocentesis at baseline
to establish microbiologic etiology, and this is the first point where
we were actually listing 25 patients with Strep. pneumoniae, 25 patients
with Hemophilus influenzae and 15 patients with Moraxella catarrhalis.

Now, I would, also, point out that in November 1992, in the CID there
was a collaboration between FDA and IDSA, also, looking at studies
looking at anti-infective drugs and that included, also, a
recommendation about studies for acute otitis media that made similar
points to this.

So, now, we move forward in time to 1998, and to the draft guidance for
industry document that we have.

Now, in that two studies are again recommended, and this should look
familiar, very similar to what was in the points to consider document.

Here we just say another trial as opposed to specifying that it can be
an open study and otherwise the trials are the same, so, the first,
being a clinical only study as we have defined it in your briefing
packets from the FDA and the other a single tap study.

Now, for the first trial, the clinical only study the caveats that are
made are ordinarily should not enroll children less than 6 months of age
and Dr. Wald had brought up this question earlier today, and from what I
could tell from looking at those documents there were concerns about the
accuracy of the diagnosis of acute otitis media in those children less
than 6 months of age and that was part of the reason that those patients
were excluded.

There was another caveat in our guidance document related to rigid case
definitions and the goal there being to try to create case definitions
that would identify within the clinical only studies those patients who
are most likely to have a bacterial infection.

Now, in this study it says that baseline tympanocentesis need not be
performed, but we do say that tympanocentesis of patients that are
judged to be therapeutic failures is strongly encouraged to document
potential specific bacterial pathogens that are not adequately treated
within the trial.

Unfortunately, what we end up with especially from the clinical only
studies is that we rarely, if ever see information on tympanocentesis
done in patients who are therapeutic failures.

Now, for the second trial, the micro study, again, post-therapy
tympanocentesis is encouraged in patients that are judged to be
therapeutic failures. To identify that we want to have at least two
investigators in geographically diverse regions for the pivotal studies
for microbiology, and there is a quote that relates to acceptable
clinical and microbiologic effectiveness of all three organisms in which
case if we don\'t have what we think are acceptable effectiveness
against all three microorganisms then for those organisms where
effectiveness is in question, we specifically don\'t list that as, that
we can specifically exclude that from the indication where we typically
list it as otitis media due to and list specific pathogens, and we
could, also, put in a statement that says that it is restricted use and
not as first-line therapy.

One of the other caveats in the draft AOM guidance is related to
resistance in Strep. pneumo, and we make a statement saying that 25
patients may be insufficient when you are looking at a question of a
drug that might be effective due to a resistance mechanism, especially
if the resistance mechanism, for instance, penicillin resistance would
affect your particular drug like a beta-lactam antibiotic.

Now, I am not planning in going through in detail all the inclusion and
exclusion criteria and the guidance document as it currently stands is
within the briefing packet that you were sent from the FDA.

I did want to make some points related to the study visits and the way
that the draft AOM guidance currently reads there is an entry visit. On
therapy at 3 to 5 days there is a strongly recommended visit in order to
assess the clinical status of patients at that point. The end of
treatment in the guidance is currently optional and the test of cure
stands now at sometime between 2 to 4 weeks after entry is when the test
of cure visit should be held.

So, it is not out to 30 to 42 days and sort of later follow-up that had
been seen earlier. There is a late post-treatment follow-up that is
offered as a sort of an optional visit and that is related to the
presence of middle ear effusions that you can follow patients out to
around day 30 to see whether middle ear effusions persist or not.

For the most part we don\'t think that beyond that point whether a
middle ear effusion is present or not is really related to the
effectiveness of an anti-infective drug given 30 days earlier.

Now, in addition to these guidance documents we have had four different
advisory committee meetings out of the past 11 that have in some way
addressed acute otitis media, and I am going to make points related to
each one.

In spring 1997, we had an initial presentation of our guidance document
and this was within the context of actually presenting several different
guidance documents on several different indications so that the
discussion about acute otitis media was about an hour or so worth of 2
days of meetings, 2 or 3 days, but some of the issues that came up
during the discussion after the initial presentation of this guidance,
one was related to baseline clinical findings and again making the point
about concerns about how do we get a case definition that will
adequately define those patients who are likely to have a bacterial
infection and truly need an antibiotic for treatment especially for the
clinical only studies.

There were some comments at that meeting about the timing of the test of
cure visit and at that point these were just a few comments that were
related, some questioning what is the value of taking a look at the
end-of-therapy visit when the 2-to-4-week visit is probably acceptable,
some comments that were pushing towards looking at the earlier time
point, the day 3 to 5 visit as an important point to look at clinical
efficacy of the drugs and that is why the, that is in part why the
guidance reads the way that it does, having a test of cure visit at 2 to
4 weeks and making a strong recommendation for an on-therapy visit at
day 3 to 5.

One of the other issues that came up was addressing the number of Strep.
pneumoniae isolates that were needed in light of the increasing
resistance, and that is where the comment that I had made before about
25 patients may be insufficient with Strep. pneumo, but that is not
really something that we likely to get into a great deal today.

Then the fourth issue that was discussed was related to follow-up of
middle ear effusions out to 30 days, and again I made those comments
earlier with relation to the post-therapy late follow-up visit.

Now, in fall 1997, we had a meeting on ceftriaxone for acute otitis
media and for the most part the discussion focused on the product itself
as you would expect.

There were at that time also comments that were made related to the
resistant Strep. pneumoniae and concerns about how to adequately address
those patients within the designs of these trials, and there were, also,
other comments that were related to study design. For the most part they
addressed the issue of the use of pre-therapy antibiotics, studies which
excluded patients who had antibiotics more than 30 days or less than 30
days prior to starting the study versus just less than 7 days.

In 1998, we revisited the guidance and the FDA presentation was of
changes that were based on the spring 1997 advisory committee where
those issues were discussed and leading to what I had presented as what
our current draft guidance for AOM is.

At that same meeting there was a lot of discussion that surrounded the
letter from the CDC to the FDA and this is a quote from the
recommendations of the CDC that since clinical only studies would need
to be prohibitively large to detect a difference if one truly existed
between two drugs that they were recommending smaller bacteriologically
driven studies that would be more effective in showing the effectiveness
of a drug.

So, at that point there was a lot of discussion about the different
trial designs and alternatives and some of the members of the Committee
that were there during that point are here today and hopefully can speak
to some of those points.

There was, also, a lot of response from the industry during that
advisory committee meeting about the concern of how to do even single
tap studies, about the difficulties of enrolling patients in those
trials and again, what ended up being left after this meeting was over
was the current copy of the draft guidance that you have in your
briefing packet.

In January of this year we had a meeting that was on Augmentin ES-600
and I am hoping even more of the Committee was here at that time and
will remember that. Again, the discussion focused on the particular
product. We, also at that time asked questions related to the timing for
the test of cure visit and got some input as to actually looking more
towards the end of therapy visit as opposed to the later 2 to 4 week
test of cure and there were, also, comments made at that time related to
the assessment of bacteriology and clinical failures and how that could
potentially be important which leads us to today and again, today\'s
discussion focused on the product itself and it seemed natural from the
issues that were being discussed that there are issues related to
clinical trial designs that we would like to have some input from the
Committee on.

Now, I wanted to make at this point it clear that anything that we do in
terms of trying to address the guidance in the future and from comments
earlier today as well as from comments at the augmentin ES meeting it
seems apparent that we are likely to need to change the guidance
document, but any kind of changes would be something that we would
probably announce in terms of the Federal Register and open it for
comments from the public, looking at different fora to get experts in
the field together and probably again take it to another advisory
committee where our purpose is to actually discuss the guidance document
itself rather than to discuss a specific product.

But given that we do have some issues that we would like you to discuss
further and flesh out for us as sort of a lessons learned from today\'s
discussion and these questions are intended to be in a way provocative
in order to try to engender some discussion, the first one, should
clinical only trials continue or should all enrolled patients have a
tympanocentesis at baseline. The second question is should the
non-comparative microbiology studies continue; so, should we be actually
looking for only comparative data.

A third is should guidance incorporate stratification by age less than 2
years and if so, what proportion of patients should be under the age of
2 years, and what we would like you to consider in your discussion is to
comment on the merits of studies with clinical information only, studies
with tympanocentesis, the ideal timing of clinical assessments, the
end-of-therapy versus a later follow-up and alternative study design,
so, comparative trials with microbiology, double-tap studies,
placebo-controlled studies with early escape if you can define an
appropriate population and we are hoping that what these, what we have
outlined here will be issues that the Committee will discuss more
thoroughly, and before I stop talking I would just like to acknowledge
the hard work of all the review team as well as the contributions of the
entire Anti-Infectives Division to putting together the information for
this meeting today.

Thank you.

DR. RELLER: John, thanks very much. We look forward to the discussion. I
think it will be rigorous and people will make pointed recommendations
for your consideration.

Who wants to open it up? We will take question No. 1. Should clinical
trials, clinical only trials continue?

Dr. Dagan?

DR. DAGAN: I think that you like to have efficacy data, but you need,
also, to have safety data, and if you do very, very thorough studies
with microbiology, let us say even with tympanocentesis and you get a
relatively small number of kids with very good efficacy data, you still
are not going to have enough safety data.

So, I think that for that purpose you need studies with a lot of kids,
whatever is your criteria for getting satisfactory safety data. So, I
think that this discussion should be separated for efficacy and for
safety and since for efficacy you may find yourself eventually hopefully
for me at least, I hope that you will be doing less kids but more
thoughtfully studied then one would like to divide this into if one
needs more kids for safety what are we going to do, just give the drug
and see the safety or are we going to design a study that looks for
clinical outcome and within that to build on the safety, and in my
opinion therefore the first bullet is yes, we should do clinical only
trials but as a secondary importance for efficacy but probably important
for safety and then, of course, it is answered the same way, should we,
the lack of comparative microbiology studies, I guess this is all
related because I think this is the wrong, I am sorry, I think this is
the wrong sentence because if I understand what you want it is when drug
only with no comparison to another drug but the other comparative
microbiological studies if you do the ears or if you do azithro or
whatever and then with azithro we did see cases; it was not done in
double tympanocentesis but you have different cutoffs of MICs and
actually these are double-blind studies because when you look at the
second tympanocentesis or when we look at whatever you don\'t know the
outcome. You are just going to more to tap. You do the evaluation and
how are you going to see what happens and then break it by MICs and you
see if you have very sensitive susceptibility, make it susceptible and
resistant and you look at the clinical outcome. This is extremely nicely
constructed double-blind comparative study but instead of comparing
azithro to augmentin you contrast susceptibles to intermediate or
resistant and then you can come with what type of cutoff to approve to
children.

So, I think this is extremely important and they are comparative, but
they don\'t compare one drug to another, that although they give you
actually the most important information, this is up to what level of
resistance you should still approve that drug and if you ask it as well
of your requirements then the sample size should be calculated and then
people are going to come with enough data, not just 1 of 6, 3 of 20 and
1 of 4 or whatever. They should calculate the sample size to answer that
question which is extremely important, I believe.

DR. RELLER: Dr.Marchant?

DR. MARCHANT: Notably absent from the questions posed is the question of
what differences are you looking for and what sample size is needed to
calculate. If the guidance doesn\'t address that issue then we will
continue to look at a lot of small studies, look at a lot of data which
never would have shown any difference. An example would be the questions
raised whether you should look at 25 pneumococci or more because there
is resistance.

Underneath that question is really still the question of sample size.
What you question, what is an important difference in terms of
pneumococcal resistance, how many resistant serotypes do you need to
look at versus how many sensitive; what kind of outcome and all that
underneath all that question is the size of the expected difference, the
important difference and the sample size questions from that and if this
guidance continues to ignore that, then these meetings will continue to
on the basis of very small studies that wouldn\'t have passed the tap
water standard to approve drugs or regimens that are not effective. So,
that is absent from the mix here.

So, even addressing question 1 you need to figure that into question 1.

DR. RELLER: What do you think it should be?

DR. MARCHANT: Well, I think, so, this is clinical; so, actually those
are the same questions here. Well, I think that if you do a
tympanocentesis at baseline you have a better chance given any given
sample size of showing a difference than you do if you do not do
tympanocentesis at baseline, but the fundamental problem is you need to
if you are going to do a single tympanocentesis study and look at
clinical differences you need an outcome that you are going to be able
to show a difference with or you are not doing a scientific study. You
are going to stay under the tap water standard.

What is that difference? When you look at the clinical data from
placebo-controlled trials the maximum difference you can find between a
placebo and a drug is about 15 percent for some end of therapy outcomes,
and that is with enriched populations that are highly symptomatic and
not just taking all comers.

So, you have to then link not only the sample size questions to the
outcome but also to the population you choose to study the outcome in
and all those things can be calculated based on samples in the
literature, but the question has to be refined more.

DR. RELLER: Dr. Dagan, Dr. Jacobs, yourself and others on the Committee
have, there have been some very thoughtful and specific comments made on
clinical trial design.

If you were the FDA what would you want done to consider first the
efficacy and then as Dr. Dagan pointed out the safety? What numbers
would you want? How would you do it?

Let us say you could just unilaterally make the decision. How would you
want the data presented?

DR. MARCHANT: I am going to broaden your question, but I am going to get
to all of it. The first issue I would do is as follows: Because the
analysis that I presented that Dr.Jacobs presented and Dr. Dagan and so
forth, I would do a double tympanocentesis study and I would look for a
sample size which will detect the difference between a drug that is 90
percent efficacious bacteriologically and one that is 70 percent
efficacious and that requires under 300 total recruited patients to do
it.

Now, do I like double tympanocentesis studies? No, I don\'t entirely. I
mean it is a painful procedure and as I mentioned in my recommendations
we need to look at how to deal with the painful procedure part of it. My
colleagues whom I respect in the academic field who, also, don\'t like
tympanocentesis believe that we could show differences with clinical
outcomes if we really drilled down and focused on better clinical
outcomes, and that would include specifically saying, \"How was the
child on day 1 and day 2 and day 3 and so forth?\" and then summing a
cumulative response over time, that kind of approach to get at it.
Studies should go on to develop a better clinical outcome because maybe
there is something we can do by looking at clinical outcomes. I don\'t
exclude that, but that is, also what we should do. In the meantime we
should be doing double tympanocentesis studies if we want to show, find
out whether drugs work or not, but I am not saying that that should be
forever and ever the approach. There could be new science and better
outcomes looked at.

For safety how big should that be? That is, also, the question you are
asking. Well, you should take an event like well, okay if I don\'t like
2 days of vomiting, that that is a side effect that is very troublesome
clinically and I want to detect whether my drug makes kids vomit for 2
days and I care that, you know we have to make a judgment here, and I
care that if a drug had 10 kids out of 100 let us say that had that
outcome.

Then you can calculate the sample size that it is going to take to show
a 10 percent increase over the baseline noise that you see in clinical
studies with antibiotics, and there are ways to calculate that sample
size. Statisticians know how to do that.

So you define, and that is rather asking the total sample size for
safety as Dr. Dagan mentioned and on the vaccine side, for example, they
are getting interesting events that would occur 1 in 1000 or 1 in 10,000
and then you start driving up your numbers but it depends on how severe
they are, but you should be able to create some professional guidance
about how big a safety problem you what to look for. Again, it is a
statistical question on the safety side just like it is on the efficacy
side.

Have I addressed your question?

DR. RELLER: You have got us started because then we can come around the
Committee as to whether or not this is in the ballpark, should be more
or less, but, John, you had a comment?

DR. ALEXANDER: In order to try to focus the discussion a little bit more
on the issue of efficacy one point that I would make is that typically
when we are dealing with safety where we are talking about drug exposure
what we are looking at is not only studies of acute otitis media, but we
have, also, got studies of patients receiving the drug for pharyngitis,
studies of patients receiving the drug for multiple other indications
that could include young children and so for the purposes of the
discussion I think that what we would like to try and sort of focus more
on is the issue about really demonstrating effectiveness in acute otitis
media.

DR. RELLER: One approach might be that if someone comes with an outcome
for which there already is an appreciable experience with other
indications that could be included in the presentation but if we didn\'t
have that you may need larger numbers at the outset with a new drug, a
first indication but again those numbers could be forthcoming from
within the agency and the consultants thereto on the statistical
aspects.

So, let us concentrate on the efficacy.

Dr. Cross?

DR. CROSS: I think what we would like to do to handle the efficacy issue
is to actually enroll informative patients as opposed to less
informative patients. I think that in the last 10 years since many of
the guidelines have been written for this and other processes we have
learned a lot through clinical research who are the high-risk patients
who are the more severe patients. This is certainly true in our last
discussion on sepsis. It is certainly true in issues of febrile
neutropenia and I think in each of those areas we see in these studies
patients who might not be as important in the case of febrile
neutropenia folks who have very short durations of neutropenia as
opposed to long durations. In the case of sepsis we had the issue last
time of patients who were more informative at the more severe end.

I think that Dr. Dagan had a very nice presentation of what we have
learned over the last 10 years in terms of which patients are more
likely to have difficulty with therapy than others. I think if there is
something which we might be able to add in terms of having some mix of
severe patients who might be more informative based on a previous
experience I think that would be very helpful in evaluating patients.

DR. RELLER: One of the things I would like to comment on in the emphasis
on the tympanocentesis and I know that there are different views, that
they shouldn\'t be done and they are very important, and Dr. Marchant
has pointed out that smaller numbers, better studied would yield more
information and one of the things that struck me over the time span that
we have had these discussions on otitis media is the field has shifted,
that the decrease in Hemophilus influenzae with immunization and the
conjugate vaccine for pneumococci, Dr. Glode pointed out some
forthcoming information that may continue on the interaction of
antimicrobials and immunization practices and to me the beauty of
tympanocentesis and the microbiology and of course it applies to
resistance issues as well is then you have a study design in place that
can capture the ground that is constantly shifting underneath you
whereas these differences clearly get buried with the emphasis on
clinical outcomes, particularly clinical outcomes at a time when the
reinfection rates are very impressive to me when you look at things too
late after the acute events.

Dr. Wald, and because I can\'t remember whose hand came up first we will
just take one round around the table and then I will try to watch for
whose hand goes up.

Dr.Wald?

DR. WALD: I think that Hemophilus influenzae type B vaccine has had any
impact on acute otitis media, I mean acute otitis media even in the
heyday of encapsulated systemic disease was classed almost exclusively
by non-typable organisms. So, I think that really hasn\'t had an impact,
and the impact of the pneumococcal conjugate vaccine remains to be seen.
I mean there may be a shifting of types but it may not be a very
dramatic impact.

DR. RELLER: Granted. I only mentioned that as changes in the
microbiology of respiratory tract infections, not necessarily with
otitis media itself and as things change if you know what you are
dealing with you can handle any change that comes about.

DR. WALD: Right, and so I agree with you entirely. I think that it is
very important for us to perform tympanocentesis and I think that groups
of children that we should be studying are children with severe disease.

I mean there are tons of arguments these days about non-treatment for
acute otitis, but I think what we would all agree on is that severe
disease needs to be treated and so I think those are certainly children
in whom one can justify diagnostic tympanocentesis without any, I think
without too much trouble. I think the double-tap design is another issue
and I think it is going to be difficult to get people to do that and I
don\'t think I would submit my child to a second tympanocentesis if they
were doing clinically well. I mean that I cannot justify, but I think a
diagnostic tympanocentesis for children who have severe disease which
means we should load that clinical cart with young children, with
children who may have had recurrent infections, with children who do
attend day care and we should put in a very stiff requirement for there
to be a bulging tympanic membrane which again is going to make our yield
higher.

If we were going to consider doing clinical only trials my own bias
would be that they only be done in centers who have already proven by
virtue of their tympanocentesis studies that they have a yield of more
than 70 percent positive bacteriology. I think to do studies in places
where they have not proven that they can make a diagnosis, an accurate
diagnosis of acute bacterial otitis media is really to waste
everybody\'s time and energy and is not fair to patients.

DR. RELLER: Jim?

DR. LEGGETT: To follow up on that which is sort of the reason I brought
up the question during the earlier period, if you can\'t make a
diagnosis of otitis, how do you make a diagnosis of cure of otitis at
the end of therapy? That bothered me a lot and as with all these
studies.

I agree with many of the things being a PKPD person myself obviously but
I would sort of want to go through the handout and just make a few
points that I think relate to these questions so far.

The first thing is we don\'t require double sampling of other infections
that I am aware of except maybe endocarditis. We don\'t do an LP twice.
We don\'t do paracentesis twice. We don\'t do urinary tract infections,
and so we have got to think about that and I think I would approach drug
companies with the idea of what is statistically adequate which is the
third slide, and so we give them the choice. You can either enroll 3000
people in a clinical only study or you can enroll 100 with a double tap
or intermediate number with a single tap. If we do do the single tap I
think that what we should do is require tympanocentesis of everybody who
is called a failure either at 3 to 5 days or at 10 days which I think
should be our major, at the present time, the end-of-therapy trial
should really supersede the 1 month which should just sort of be to see
if there is still a chronic effusion.

I, also, agree with going away from the 25 H. flu, 25 Pneumococcus, 10
Moraxella and just sort of look at those numbers in terms of what is a
statistically adequate sample and that way it allows you to capture any
emergent pathogens as well as really emerging resistant pathogens and
allows people to look at so now we have 25 percent efflux things and we
can go back and look at the MICs and find out what PKPD breakpoint might
be.

Then I think in terms of the final thing for the time being it was that
there was a thing about not being able to use antibiotics within the
last 7 days of the last month. I think that would be another way to
actually enrich the resistant population because isn\'t that who we have
the trouble with, the more severe illness and the more resistant
pathogens?

So that should actually probably I don\'t think require an exclusion
unless the antibiotic was sort of like the day before or something, and
I will shut up.

DR. RELLER: Thanks.

Any other spontaneous comments on this issue and after we go around the
table I want to come back and ask Dr. Dagan his views on double tap,
single tap, required taps with failures unless patient or parent
refuses.

Dr. O\'Fallon?

DR. O\'FALLON: Remember that I am a statistician. I am not taking care
of these sick kids. I, however, have been the mother and grandmother of
such sick kids. So, I know a little bit about what we are talking about
here.

One of the things in looking over the data that has really impressed me
is the high cure rate in the natural history of the disease. The
patients without bugs recover, 80 percent I think was what it was.
Patients who even failed the antibiotic therapy recovered, what was it,
62 percent? It was some very high percent. So, in a certain sense the
stakes in this game aren\'t as high as in some others because over half
of the kids are going to recover with or without any kind of therapy.
So, you can fight with me about that, but that is what I am seeing in
the data.

The second thing that is bothering me a lot, I have been listening to
you guys, and you are very worried about the promotion of drug resistant
bugs, and if we are treating a bunch of kids that don\'t need it what
are we doing to them for their future? Are we being good to them in the
long run? Are we being good to the community in the long run? I think
there is a big issue here more than just these children.

It is for each of these children because the drug resistance is an issue
for each of these children potentially anyway, but it is, also, for the
community, and I think we have got to worry about that.

Because placebo has such a large success rate I think that, and because
this disease is shifting so fast, look at even the 3 years I have been
on the Committee the drug resistance rate has shot up, tripled,
quadrupled in just the 3 years I have been on the Committee. So, we have
got a fast-changing disease here. Should we, I think maybe that makes an
argument for placebo-controlled studies and it was a good idea there
about having a back out. If you tap them, if they are a failure, you
know, they look bad after 3 days, tap them again, find out what it is,
but I think that is an important thing to do. Then you can go on and
give them something decent, I mean something that you know has a track
record for whatever they. So, I think it is not a bad idea, and I lay it
out for you.

I think it is important to do the randomized double-blind and
concurrent, the concurrent to deal with the rapidly shifting mix of
studies, I mean mix of diseases that we are seeing here.

One thing I would like to see is maybe the FDA could ask these guys now.
They treated a whole lot of patients that turned out to have no bugs in
their original thing. We didn\'t see anything about them. We never saw
the information about what happened to those guys. I think they had the
data in the database. I think it would be important for us to see how
did it work with those guys because they just disappeared when they
didn\'t have any of the bugs of interest. So, I would like to see that.

We know that the age groups are important. All who deal with them know
that the children under the age of 2 maybe under the age of 1 are
different versus 1 to 2 versus greater than 2, react differently
possibly.

When we do that sort of thing we say stratify so that you have adequate
sample sizes for subset analyses and so I think that type of thing has
to be built into the studies for the future, and well, I have said the
drug resistance.

So, those are my main points off the top of my head.

DR. CHRISTIE-SAMUELS: I agree with my colleagues. I agree with
everything that has been said so far. Another point though, it is true
that the FDA develops guidance with regards to antimicrobials for the
United States, but as a practitioner who has been here for several years
and now practicing in a part of the Third World in Jamaica for the last
2 years I would like to say that the minute something is approved here,
it is also immediately marketed and used in other parts of the world,
Jamaica for instance.

The problem though is that you can get drug resistance developing in
those patients and because airline travel is so wonderful essentially
the resistant organisms which develop in another country again become
America\'s problem. So, I think I just wanted to say that we need to be
very, very rigorous in what we do here because what you do here impacts
the whole world, and then it comes right back to you a few more years
later.

DR. CHESNEY: Many incredible issues, and I really, really appreciate
that the FDA has asked us to be so open in this session today. I think
we haven\'t had \-- we have had discussions before, but I think this is
terrific and particularly with the experts we have here.

Just a couple of brief comments. With respect to the double
tympanocentesis studies, I think we have to have those because Jim\'s
comment that you only tap failures unfortunately we know from the
natural history that some of the failures have negative cultures and
some of the successes have positive cultures. So, if we really want to
know whether we are eradicating the organism then we have to do double
studies, and then your comment, Jim about maybe we don\'t have to retap,
but I think we learned that we didn\'t have to retap because of the
studies where they did retap and told us that things were going to be
sterile in 24 or 48 hours. So, then we didn\'t feel like we had to do it
so much anymore.

I think the shift of organisms that Judy raised and that Ron raised in
the discussion is really key and we are all very interested to see what
is going to happen here. We just submitted a sickle cell center grant
and one of the issues was to look at what is going to happen to those
patients who are going to be on prophylactic penicillin. They are going
to be on azithromycin for their chest syndrome. They are going to get
the 23 valent. They are going to get the 7 valent. Who knows what is
going to happen in that population, and they may be representing the
extreme, but I think we have to know whether we are going to get rid of
pneumococci get rid of the resistance problem or whether it is going to
emerge in new strains, and this is one of the key ways that we are going
to find that out, and I think that that really leads into Dr.
Marchant\'s comment that we really have to decide what is the question
that we want to ask because the study that we do is going to be based on
the question that we want answered. Do we want to know toxicity in which
case it has been pointed out that we need probably lots of patients or
do we want to be maintaining change, be advocates for children
maintaining a susceptible population and I think that we have to try not
to forget that.

So, thank you for, also, bringing that up.

DR. RELLER: Dr.Cross?

DR. CROSS: We spent some time this morning expressing our concern that
there was a lack of PKPD data, but I am looking at the guidance for
industry and it isn\'t mentioned there. I am just wondering whether
there is the expectation that this is naturally done in the course of
things or whether this has to be stated explicitly what the expectations
might be especially for different age group populations.

DR. RELLER: Dr. Ebert and then we will come to Dr. Gorman.

DR. EBERT: Obviously as we go around the room it becomes increasingly
difficult to add anything that hasn\'t already been said, but let me
just say that at least my ranking of what we have been talking about as
far as studies with regard to efficacy would be that at the top of my
list would be double tap studies because of the issues that have already
been addressed.

Next would be single tap studies at the initiation of therapy to
determine what patients are in fact infected and to assess clinical
response in those patients but that the clinical response be assessed at
the end of therapy as opposed to at day 28.

The third would be where the patients are enrolled based on clinical
findings but that taps are done in patients who fail. That would I think
probably mimic the clinical scenario most closely, would limit the
number of taps and then finally I think probably the lowest on the
benefits would be the purely clinical studies and again for the reasons
that were mentioned and the higher N that would be required.

The other issue that really gets into I think a little bit of PKPD and
also the non-comparative trials would be that as Dr. Dagan mentioned
certainly by giving a certain dose and looking at organisms with
different MICs we have the ability to do some PKPD analysis, but I think
we should, also, consider the possibility at least in early studies of
some dose-ranging studies to look not only at a fixed dose but various
dose sizes especially because of the variation in the pharmacokinetics
in these children as they progress in age.

DR. RELLER: Dr. Gorman?

DR. GORMAN: I think the clinical studies continue to have a role mainly
for safety data generation, strictly again because the large numbers you
will need to see rare or unusual safety aberrations.

Over the last 3 years I have become a connoisseur of labels which I
understand is the FDA\'s end product. The most interesting label that
the FDA has ever written is the label for Ritalin. This is my personal
most interesting label which talks about the use of this drug in a total
clinical care package, and I would recommend to the FDA to consider in
its labeling of agents for otitis media some of the reasons why these
agents fail, host factors, age less than 2, day care attendance,
siblings so that the expectations for the clinicians as well as for the
pharmaceutical manufacturers are there are reasons that these fail and
reasons that they do not fail, reasons that they should be more
successful which may start to get around some of these other issues that
we bat around as we are talking about the microbiology which is so
important to this particular group.

I think the entry criteria for any clinical study that deals with
microbiological cure rates has to be enriched.

One of my previous mentors did a clinical study where after tapping
these patients had a 95 percent bacterial, 95 percent of the ones that
he had a 90, 95 percent of the tapped ears had a bacteria identified.
Those criteria if that has been implicated in other clinical studies
might be adoptable by the FDA as reasons to tap people to do a primary
tympanocentesis upon entry into the study.

Children less than age 2 have to be studied, and I think they have to be
stratified to be at least 50 percent and perhaps 100 percent because
this is the place where the drug is most likely to fail due to the host
factors which we have no control over and also the ones in which we have
the least PK and PD data and will need to be generated prior to these
drugs being used in these populations if they have not already been
used. I am sorry, if the drug hasn\'t been used in these populations
previously then the PK and PD data has to be generated for this
particular indication.

Placebo controls. I, personally, think placebo controls will never go
away, and I hope they never do, Helsinki and whoever else stands between
me and my placebo controlled studies.

Even placebo-controlled study of otitis media I think there needs to be
very stringent requirement that adequate analgesia and antipyresis be
available for children in the placebo arm so that their long-term
microbiology can be cured but their short-term pain and suffering can be
relieved.

Now, on to disease resistance. I don\'t share my fellow pediatricians\'
belief that we should use, I do share that we should use the antibiotics
judiciously, but I refuse to sacrifice children on the altar of drug
resistance. Less than 75 percent of the antibiotic use in this country
is in humans, I am sorry less than 25 percent of the antibiotic use in
this country is in humans. The vast majority is in agricultural feed and
veterinary medicine. So, now when you go to the antibiotic use in
humans, children don\'t make up the majority of that either. So, if all
pediatricians immediately adopted no antibiotics for anything we would
probably have a very minimal impact upon the evolutionary pressures on
bacteria.

Having said that I support the efforts to limit the use but I won\'t
sacrifice children before chronic bronchitis is not treated routinely,
before clinical pneumonia is not treated and before urinary tract
infections are not treated, other illnesses that have incredible
spontaneous cure rates and no proven clinical efficacy of antibiotics in
changing clinical course.

Thank you.

DR. RELLER: Dr. Glode?

DR. GLODE: I think the reason this has been so confounded over the years
is that it is virtually impossible to design the perfect study for
otitis media. I would post to you even the two-tap issue which sounds
great microbiologically is fraught with problems because what about drug
A which has no bacteriologic efficacy and the culture is going to be
positive when you do it? Of course, when do you do it, 48 hours, 72
hours, 96 hours? Is the fastest working drug the better drug, and if one
drug has no efficacy and the next drug has a 2 log kill and the third
drug has a 3 log kill unless you are doing quantitative cultures from
the middle ear you will not be able to assess that.

So, I just think it is so difficult to actually design the right study
for otitis. It may be impossible to do that. I was wondering about the
two-tap study or the single-tap study where you then take the organisms
that are resistant from the first tap to the agent being studied but by
what definition of resistance, a macro standard the PKPD standard that
was shown today, but you know I say to the family of that child, \"You
child had a number of resistant organisms. So your child falls into the
category of children that we would like to repeat the tympanocentesis to
make sure that this organism which is more resistant is really gone,\"
and maybe you could do that, but I think there will still be a huge
argument about when the second tap should be done, and I think that
there will potentially be a need for quantitative bacterial cultures
which I have no idea if that is possible to do with the small volume of
fluid that one gets back.

DR. RELLER: Dr. Burns?

DR.BURNS: I have been impressed today that there seemed to be two groups
about which we either are or should be the most worried. The first of
these I think has been well addressed, the child under 2 where we see a
lot of disease. We see a lot more invasive complications and we see an
innate lessened immunity to those organisms that might be invasive such
as Streptococcus pneumoniae, and that does concern me that we don\'t
want to neglect that group by any stretch of the imagination.

The other group that seems to me to be important is the group in fact
that does have Streptococcus pneumoniae. Certainly any patient who has a
positive culture is more worrisome to me than one who doesn\'t, and it
strikes me that it might be reasonable to design trials where we look at
specific organisms like say, Streptococcus pneumoniae causes invasive
disease; it has an increased risk of resistance, and it is more
clinically recognizable according to some of the data that Ed O\'Rourke
presented.

So, perhaps it would make sense to do that initial tap and then actually
conduct the study on those patients who have Streptococcus pneumoniae
where we not only expect it to be a higher risk but also expect if we
have got a good drug that it would in fact demonstrate better efficacy.

So that would be my thought process to take a very heterogeneous group
of microorganisms and then focus on one that we identify as being a
specific and real pathogen.

DR. MAXWELL: Not being a pediatrician most of the discussion that I
heard makes a lot of sense, but I have a question to the pediatricians.
Since it is clear that a good percentage of the children that develop
otitis media resolve spontaneously what I want to know is what
percentage of those children that resolve spontaneously develop some
adverse sequelae, hearing deficits or do they develop anything at all
and if they don\'t develop anything at all then what is the real need to
treat everybody if you have not determined that the bug has some
potential for doing something somewhere down the line and so I don\'t
know the answer to those questions and would really love to hear because
it seems to me that you sort of have a natural history both into your
cohorts and now, the way I would look at this I would like to know what
the bug is. I would want to go after the bug, treat the bug and then see
if I eradicated the bug, but you were saying that even if you identify
the bug a kid might resolve spontaneously without an antibiotic and
clearly we know that antibiotics are not without risk. So, it would be
very difficult for me to answer this question, and I would be ideally
bent to having a tympanocentesis at the beginning and at the end but I
don\'t think that that is practical at all, and I would just like to
hear the Committee address what happens to those that resolve
spontaneously.

What is it that they have?

DR. RELLER: Thank you, Dr.Maxwell. We have multiple, numerous
pediatricians on the Committee, and who wants to respond to her query?

Dr. Wald, why don\'t you start?

DR. WALD: Data have been presented today suggesting that one can
identify to some extent the children who are more likely to have one
organism than another but it is far from perfect. So, if you are looking
at a child who has a bulging tympanic membrane you don\'t know which one
is going to resolve spontaneously and although let us give the benefit
of the doubt and say 50 percent do, 50 percent don\'t, and I think when
we prescribe antimicrobial therapy it has a couple of purposes. You
know, one is to make children better sooner and I think that isn\'t
something to which we have paid a lot of very careful attention and I
think that for those children who resolve spontaneously it is probably
true that antibiotics benefit the children who are treated by virtue of
the fact that they get a quicker cure than those children who eventually
resolve spontaneously and then we hope to prevent complications
recognizing that complications are not common but that they rarely exist
and that with resistant organisms there is some suggestion that they may
be increasing.

DR. RELLER: Your name, please?

DR. ROCHESTER: My name is George Rochester. I ama statistician with the
Division of Anti-Infective Drug Products here at FDA, and actually I was
associated with this product being presented today.

My comments are not directed to the product specifically in any way but
in general I think that our take on the FDA guidance probably needs to
be seen as guidance in terms of a minimal standard not in terms of a
maximum standard and that in fact I think needs to address the two
probably more important issues which are data quality as well as data
quantity.

The way I envision that most sponsors seem to approach drug development
is in a very simultaneous fashion so that both studies are running at
the same time. They get a dash to the 100-meter-yard line without any
recognition of real underlying safety concerns there may be that need to
be paid attention to.

So the time when the studies are designed and they are sized they are
sized with very little information especially when we are talking about
the new molecular entity, very little information about what kind of
safety end points we are truly interested in and are really truly
important. So, probably what I am thinking is that it would be more
helpful if we had at least the early bacteriologic studies the studies
that are specifically designed to pick up efficacy information early and
some preliminary analysis of those studies and then plan the larger
probably clinical only studies with more specific interest in safety end
points at a later phase so that we plan the studies adequately and we
are pairing them to actually detect the things we want to detect.

The other point that I am interested in however that I haven\'t heard
any discussion is that we have some underlying recovery rate for
patients that we tap or even in other infectious diseases like community
acquired pneumonia. For example, we may do blood cultures for those
patients.

There is a certain rate basically even if we think that all the clinical
signs or other corroborating evidence suggests a patient may really be
infected with a pathogen, we do not always recover that pathogen, just
doing one blood culture or just doing one tap and if you do a tap and it
came back negative that does not reassure me that in fact that patient
may not have a pathogen and that that patient is in fact in any other
safer zone than a patient from whom I really recovered a pathogen. I
haven\'t heard any discussion at all about that.

DR. RELLER: We will ask Dr. Marchant and Dr. Patterson if they have
anything to say at this point and then we will go next to Dr. Dagan to
comment on single, double with failures, etc.

Dr. Marchant?

DR. MARCHANT: I thought I would respond to a couple of things. You asked
me what would I do, and I said, \"Double tympanocentesis.\" Ellen, for
example, said, \"Single tympanocentesis,\" and gave her reasons.

Single tympanocentesis could be an acceptable way to go with good
clinical outcomes but the next step in thinking about it that needs to
be addressed is how big a difference are you really going to look for?
What difference do you care about; what does the literature on the
behavior of the disease tell you that difference is likely to be and
then are you prepared to face the sample size required to follow that
design?

Again, being somewhat of the devil\'s advocate or throwing out a little
challenge, Dr. Glode said pointed out the difficulties of doing various
otitis media studies and very difficult to design the ideal study and so
forth, and I would throw down the gauntlet if you will and ask the
question are you prepared, for example to just license drugs based on
PKPD because it is hard to do a clinical study and have an outcome that
is scientific or a data set that is really telling you anything and
maybe we should forget doing clinical studies. Are you prepared to do
that? I sort of throw that down as the question. Those are the kinds of
questions that should be faced if you are going to scientifically
approach the question of efficacy and address many of the questions that
people have brought up and then the other thing is,Dr. Rochester, I
believe, you asked the question of what does it mean when you get a
negative culture.

DR. ROCHESTER: Right.

DR. MARCHANT: If you eradicate the organism what does it mean?

DR.ROCHESTER: Well,no, if you did a tap and the tap was negative, you
didn\'t grow a pathogen but that does not necessarily reassure me that
there are none at baseline. That doesn\'t reassure me that the patient
did not have a pathogen just because you did not recover.

DR. MARCHANT: You mean at baseline. There is no question that that
exists and when you count on electrophoresis looking for the capsule of
Pneumococcus as has been done on strong middle effluence Pneumococcus
was there. It is not viable and growing now, but it was there in some
cases and there is no question that some of those were and there may be
a few cases in which there could still be bacteria there that you
didn\'t grow, but we know that the number, an important point is we know
that if the bacteria is there and then you don\'t treat it you don\'t
effectively eradicate over 4 to 6 days that your clinical outcome on
average is worse. So, on that side of the equation it is an important
thing that you are finding although you haven\'t proved that one.

DR. RELLER: What I want to do is we will have Dr.Dagan and hear his
comments and then we will come back to Dr. Patterson and Dr. Gorman.

DR. DAGAN; Look at those who were culture negative versus culture
positive. We actually look at different bugs. Look at interleukins and
leukocytes and at clinical response and as a group they had much less
suppurative inflammatory response, have much less leukocytes and the
respond to nothing very rapidly, at least no difference between the
drugs for that group. So, this is for me as a group. Individuals you are
right, here we are talking about group. Now, in order to explore that I
would just like the Chairman to give me a few minutes. It took me 24
hours to get here, another 24 hours to go back just to hope that you can
hear what I have to say.

So, if you can give me a few minutes it would be very, very \--

DR. RELLER: Dr. Dagan, we ask you to come to the microphone, please and
tell us what you want to tell us.

DR. DAGAN: This is with respect to what was said around the table. I
want to start just with some general stuff and I think I was very
impressed by some general stuff. I think I was very impressed by the
fact that you were the only one to mention that we don\'t know how to
diagnose otitis. So, how can we know how to diagnose cure?

Years ago, at that time SKD did a study with good investigators from all
over the world, the United States and Europe, and they wanted to do a
study. They put us there, and they brought people from Pittsburgh who
showed us a video.

Now, this is the best investigator, recognize that this is the best
investigator, showed us videos with otoscopy, whatever. We all failed
the test. Every single one, we failed the test, okay? So, we don\'t know
how to diagnose otitis in general.

We miss plus or minus and definitely if you put a needle in, and you get
a bug out, plus all the symptoms that is at least the most likely to be
acute otitis media.

Now, it goes again for the cure. If you don\'t know how it is when it is
there, you don\'t know how it is cured. So, the only way is to say that
the bug has disappeared.You can add to that leukocyte count, poor
inflammatories and things like that that we are looking. So, this is one
answer for sure that if you want to be sure that your sample of kids
have otitis media, bacterial, take those who had all the things, but
after you put the need you, also, get some pus, and it is, also,
positive for culture. This is a real case of otitis media in over 90
percent of the cases.

Now, No. 2, the question of, well, I have to read my handwriting which
is not that easy.

DR. RELLER: You wanted double tap versus single tap.

DR. DAGAN: I am sorry, but this is all really related because the
question is why do we need double tap. This was, also, the question, why
do we need double tap. We don\'t do it in other studies. We have to do
it only in studies where we don\'t know how to do it in a different way.
Okay, if you see a big abscess in the skin I know when it is cured,
okay, but if you go a little bit wider, I have to do repeated sugar
tests for diabetes. I have to do repeated blood pressure tests for
hypertension. I have to do repeated cholesterol tests because I don\'t
know how to do it without the test, and I think that if we don\'t know
how to diagnose otitis and how to diagnose improvement the best test is
to look at bacteriological eradication. So, that is for me the most
important rationale for doing that.

Now, tympanocentesis failures, and here again I apologize not being able
to say it gently. The industry needs to bring 600 kids or 500 kids in no
time in order to be able to be on time and go against the competitor,
and to go with stringent criteria, and you do the best patients you can;
you get X amount of dollars per patient if you do it appropriately and
then part of doing it appropriately is when you say, \"Someone has to
tap the child.\" So, I mean there are so many doctors. Not all of them
are good enough, and that is why you see all those 12 year olds or 10
year olds or whatever. They know those kids and then when they see
failure they have to do taps, and they don\'t want to do taps. So, there
are less failures because if they say, \"Failure\" and there is a
protocol violation they don\'t get the money.

I am sorry to say it that strictly, but some of the investigators work
for the money, not for the science, and the point is here and this is
proved; that is why when you decide to have tap at failures you are
going to have older kids. You are not going to have failures, and they
don\'t have to be bothered with the taps, and that is why it is not a
good idea. It is very selective cases of taps, and actually if you look
at centers always selected if you go to Alejandro Alderman in Pittsburgh
he does a lot of taps at failures. You go to other centers, nobody does
it. These are not failures. Okay? So, that is a very important issue.

The auditory second tap is you do it or you don\'t get into the study.
That is a different thing. As for talking single or double
tympanocentesis I think that we can deduce, we can say that kids that
need most the antibiotics, the ones that are under 24 months, etc., if
for them antibiotic A is good and you can show that it is at least as
good as antibiotic B, it will be good for the reverse of media test, for
sure because you just dilute then with more kids and more kids that
don\'t need antibiotics.

So, if FDA comes, and this is a motion for the design, if FDA comes and
says, \"Okay, you do limited number of double tympanocentesis and then
go for single tympanocentesis because we want the safety, etc.,\" but
really instead of doing 500 kids, 6 months to 120 years you do 500 kids
under 2. First off, we don\'t want to see adults if it works under 2 it
works adults. Then you are going to have at least results here 10
percent difference under 2 between augmentin and azithromycin as shown
by the company. It was not significant. Ten percent would be significant
if all the kids that they had were under 2.

So, this is just one way to say that you get the same type of expenses.
It costs you the same, but give us patients under 2. We will be happy to
extend that to older ages with otitis that are seen, okay? Rather than
take above 6 months, mostly above 2 and extend it down, this is for me
more dangerous. So, that is the motion in terms of if you do that
single, take it only for the young children.

Then we talk about safety and this is not related but this is related to
efficacy, nasopharyngeal changes are part of the safety and it is not
recognized by the FDA as part of the safety because this is actually
more safety than vomiting. Vomiting is tolerability. It is not safety.

Safety is an issue where by treating a child you make his situation or
his surrounding situation more dangerous in the future, to be
complicated and to have problems, and by changing with drugs these
florae and by proposing to that child for the next infection a more
resistant flora is a question of safety exactly as now in the vaccine
they recognize, WHO started to recognize that changes in carriage by the
pneumococcal conjugate vaccine is a safety issue because it will
determine the next epidemic or the next infection with Pneumococcus.

So, I think that now some companies have started to do it, and I think
that one of the things to be done together with the double
tympanocentesis is to look at efficacy or the dynamics of the
nasopharynx because it follows the same type of PKPD but in a different
site and you have to look at that because some drugs are making some
issues, to mention for them junatopin(?) sulfa with the multi
resistance, junatopin sulfa increases very impressively the penicillin
resistance carriage which means next problem. So, that is another thing.

Now, talking about double tympano and single tympano without talking
about what will be your end point is also inappropriate in my opinion. I
think that the term \"test of cure\" for 28 days should be taken out
because it is not test of cure. I think this is already proved, and if
it is taken out then the FDA has to decide what is a test of cure.

Now, you only can offer with antibiotics what you can offer with
antibiotics. The child is prone to infection. The child is going to get
whatever they have in the nasopharynx next time and it is going to do
more infections. So, I think the test of cure is at the end when you
finish giving antibiotics that is what you can achieve with the
antibiotics. The rest is not, but you can still follow it, but let us
call it test of cure at the end of treatment and let us call recurrence
clinical recurrence or clinical relapse rate which is not a test of
cure. So, that is another suggestion for that specific issue, and then
again, the question was should we go only for Pneumococcus testing. This
was double tympano. This was suggestion, okay, and we had a talk today
how Hemophilus is so important and H. flu, really doesn\'t, I mean how
Pneumococcus, H. flu really doesn\'t do much. Well, that did not stand
with the data we saw from Pfizer.

From Pfizer they had the highest clinical failure rate with Hemophilus,
not with Pneumococcus. So, if Hemophilus is not important then it should
go away anyhow. So, the highest clinical failure rate is with
Pneumococcus because with Pneumococcus it is resistant, okay, and it
goes on and on. Hemophilus is maybe less fulminant than Pneumococcus,
but it is there. If you don\'t respond, you do have clinical problems,
and we struggle with now 8000 tympanocentesis results in our, all of us,
all the bugs in our hands. we struggle to how do we describe the
clinical differences between H. flu and pneumococcal patients and we
don\'t really know how to do it. We don\'t have any clue how to make it
clear that one is different than the other.

So, maybe when we have 20 cases it is easy. When you have 2000 cases you
start to see that what you find is this is exactly coming to the
confidence interval. When you have 2000 you realize that the 20 cases
were purely chance that you have some differences and that is why you
have so much debate.

So, definitely H. flu is not a benign bug and therefore if you do double
tympanocentesis you probably have to do it for all bugs or otherwise it
is not appropriate unless you have specific questions for a specific
drug or Pneumococcus and then you need to do it only on Pneumococcus and
so I think that I covered what I wanted to say in terms of response, and
the point is again I don\'t see how if you want to get the right
answers, I don\'t see how you can go without doing double
tympanocentesis. You have no answers that can be answered by the
tympanocentesis. So, you did additional studies, but if you don\'t do
double tympanocentesis in my opinion some of the real important answers
are not going to be there, and we are going to get again and again
things regarding the inappropriate or semi-appropriate recommendation.

The last point that is related to this is how ethical is it to do all
these things, and ethics is really something very relative and it is
perception and it is tradition. You do, I mean Pfizer had to present
here I think altogether 2000 or 3000 cases. Each kid submitted to a
study had a lot of uncomfortable situations. If you can make 10 percent
of those cases double tympanocentesis you save a lot of uncomfortable
situations to 800. That is something, also, that has to be counted, but
in addition Dr.Gorman is ready to accept pharmacokinetic studies.

Now, the tympanocentesis in my center is done by ENT under microscopy
and it is 1 second, and you are finished. Blood is taken by my intern
and they dig like half an hour before they find the vein. You know how
interns do it. They have to learn how to do it. You can\'t be born with
the knowledge how to do it, okay? So, repeated blood tests is so much
more painful to the children, but this is always accepted because you
know repeated blood tests plus urine and all the stuff that you
submitted kids for pharmacokinetics, this is a real torture. I never
agree to do pharmacokinetic studies because for many children who stand
before my eyes and for hours there and we can\'t explain to the mother
what benefit does the child get from that.

However, the mothers like when we do the double tympanocentesis studies
because first it is our standard of care to do one, but in addition to
get the best treatment by the best group, to get the attention if they
come after 3 days with a failure we already know what is the bug. With
multi-resistance this is more complicated now because with
multi-resistance stuff we can really change the drug after 3 days
knowing what the child had before. We have documented in many children
super infection with new bugs knowing that they did not fail. They just
had a real problem, and we identified with this the children with severe
problem where you don\'t even finish one study and they get to another
infection and this kid now gets followed by a physician.

Talk about safety, we are doing routinely in our center 2000
tympanocenteses a year. Out of this about 15 percent or so are part of
the study. The others are not.

In the last 6 years we had 12,000 tympanocenteses and about 2000 in
studies. We didn\'t see even one complication. However, we see every
year several complications of acute otitis media that are severe. So, I
don\'t agree 100 percent with what you say. They come with severe
mastoiditis. They go to surgery. We get how they call it,
synosiventroposis(?). We get two patients in the last 5 years with
abscesses, intracranial, all from acute otitis media that did not
respond appropriately. So far tympanocentesis is less dangerous for us
than inappropriately treated otitis media.

So, I think that again when you measure all those things if you are used
to you get different proportion and in my opinion the most of the
problem if you submit the whole population to treatment that you don\'t
know what it is it is so much ethical versus doing something in good
controlled hands when you see what the child has and you can correct it
at a given moment.

My ethics committee thought the last time that I submitted them a study
versus azithro that it was unethical to do a study with azithro because
we proved it doesn\'t work very well before, and they agreed finally to
do it because it is standard of care still in Israel in other cities,
not in our city. So, sometimes ethics is very much a relative thing.

DR. RELLER: Thank you, Dr. Dagan.

Other comments or questions not posed?

Dr. Patterson?

DR.PATTERSON: Yes, I would agree with those who think that there should
be more representation of severe disease, particularly as manifested by
pain and fever and that would be more associated with pneumococcal
infection based on what we know about that compared with H. flu and I
think that would be important for looking at rates of DRSP and also
suppurative complications and so forth.

I, also, think more young children should be included, at least 60
percent or so. I don\'t think that those over 2 should be excluded
because based on what we heard today there may be some difference in
etiology.

Perhaps H. flu is more common now in young children. Maybe Pneumococcus
is more common in older children based on some of the things we have
heard today and I think because Pneumococcus can cause suppurative
complications we don\'t want to ignore that.

I think the single tap is quite important for bacterial etiology and
epidemiology and so a substantial part of the application should look at
bacteriology and I think the double tap is difficult to justify in many
centers where it is not a standard of care and those where it is I think
it is very helpful to have that knowledge, but I don\'t think it should
be required for all the data that is submitted.

The clinical only studies I think may have a role in safety and
tolerability. Somebody mentioned today about you know, did vertigo
contribute to the vomiting and so there may be something about the
particular disease state that could have a role in safety and
tolerability. So, I think that could have a role in that.

I think there should be an emphasis on analysis by previous antibiotics
within 1 to 3 months and, also, in day care, particularly in terms of
the outcome in bacterial etiology and in the clinical only study and
single tap study I think it would be important to have a substantial
amount of failures with follow-up tap, at least 70 percent or so, and I
think a placebo study would be difficult to justify in IRB for those
less than 2 years of age.

DR. RELLER: Thank you, Dr. Patterson.

I would like to comment on the numbers by organisms that were presented.
My recollection is that the genesis of some of those numbers was when a
particular sponsor was interested in an indication for a specific
resistance mechanism or a subgroup of organisms that were resistant so
that one could not get an encompassing claim that included resistant
organisms where the efficacy was buried in the larger numbers as opposed
to having to have for example, with tympanocentesis and even double
tympanocentesis documented resistant organisms to extend to include
specifically resistant pneumococci as an example.

That every study should have some of the numbers mentioned may be
difficult as the ground shifts in terms of the distribution of organisms
and again, I think that the getting too hidebound with specific numbers
and distribution of organisms isn\'t largely obviated if one has the
emphasis on the efficacy studies, the smaller numbers of
well-characterized patients with at least initial, if not a high
proportion with double tympanocentesis along the lines that Dr. Marchant
has emphasized.

Other comments, and we want to make sure, Dr. Soreth and Dr. Alexander
that if something has not come out already that you raise it so that we
can cover it before concluding our comments.

Dr. Jacobs had his hand up and in the good tradition of this Committee
people have been very forthright and outspoken which is to the good, and
there is clearly plenty of fodder for changes in the next draft.

Dr. Jacobs?

DR. JACOBS: Thanks, Dr. Reller. I would just like to emphasize the
comment you made about distribution of organisms, and I think you need
to apply the same standards to each individual organism based on the
principles that you have heard this morning from Dr. Marchant and others
that you can based on the known natural history of Strep. pneumo. You
need a smaller number of Strep. pneumo than H. flu to be able to tell
what goes on in a double tap study, and when you have subsets of
organisms as you mentioned with resistance you again need to have each
subset having the same, having a number that is statistically valid, and
I think coming up with arbitrary numbers saying that you need 25 Strep.
pneumo, 25 H. flu for the drug to get an indication is not applying any
of the principles we have heard about. You need to base it on what type
of study it is, what age group and so on and then come up with a
projection that is statistically meaningful.

DR. RELLER: Thank you.

Drs. Wald and Leggett?

DR. WALD: That sort of troubles me because it seems to me how many
resistant organisms did we hear about today, a dozen resistant S.
pneumoniae and a lot of, out of what 100 and they did about 166
bacteriologically proven cases? I don\'t think we can make a judgment on
12 cases, some of which are split between 1 day and others are getting 3
days. I can\'t make any judgment about that. I do think we have to have
minimum numbers of resistant cases because if a study is done in an area
where resistance isn\'t very high but the drug is going to be used
nationwide where the numbers are 35 percent or 40 percent or 50 percent
I don\'t think that we can say that the drug is approved or a good
treatment for that particular indication without having had specific
experiences.

DR. DAGAN: If you go for otitis media as a design as we know that about
two-thirds of the beta-lactam unsusceptible bugs are, also, macrolide
non-susceptible bugs, then by having, by the approach of non-responsive
otitis media you are going to increase it. You are going to have a
little bit more negatives, but those who are going to be positive, are
going to be more enriched with the resistance and this is based not on
my assumption but on what we have as bacteriology from our studies on
non-responsive otitis media, especially that first drug of choice is
usually amoxi and the second one is azithro. So, when you go to
non-responsive you are going to really get those two to augment the
resistance.

DR. WALD: Maybe then we have to say rather than prescribing precise
numbers we have to say that it has to in some way mirror what the
national figures are since when we license or approve a drug that is the
way it is used.

DR. DAGAN: Then be careful because the national numbers that are given
to you are of all ages and of all types of bugs.

DR. WALD: They are specific.

DR. RELLER: Actually I know Dr. Wald and I if we vetted this adequately
would be in agreement. The concept is that clearly there is a number of
organisms that would be required and statisticians would help us if we
want a specific plan for a resistant organism, but one of the things
that has troubled me repeatedly and it came up in the discussion this
morning is that from a clinical standpoint an approved drug will be used
in the population at large and if the studies on which we have adequate
objective information are done in a population that does not mirror the
one that is going to be treated when a drug is approved then we have a
problem, and that came out this morning in that we had a
disproportionate number of patients over age 2 and had inadequate in my
view parameters of resistant organisms where we actually knew what the
organism was to be comfortable that we were dealing with a distribution
of organisms that is what the real world is in otitis media that needs
to be treated currently and the numbers where one knows what was going
on are quite small.

Dr. Wald?

DR. WALD: One more comment about the double taps because I think there
are very few institutions where practically speaking that is going to be
done, and again, I can talk about the discomforts of venipuncture, and
you can do other terrible things to children but if a child has no
symptoms referable to their ear except some residual fluid then again I
think that it is hard to justify that procedure and I will just let it
go there.

DR. RELLER: Thanks. Dr. Leggett or Dr.Christie?

DR. LEGGETT: A question was made about placebo controlled trials and we
haven\'t really talked about that very much, but one thought just
crossed my mind for the kids who are over 2 or the ones that are most
likely going to have these more viral pathogens and perhaps we are less
worried about them, one of the ways that we could capture the placebo
cure rate or kids over 2, say, would be to do the placebo-controlled
trial with an early escape so that if symptoms persisted at day 3 or day
4 we then proceed to that single tap. We then accumulate that as our
clinical only trial group for the safety data so that you end up doing a
lot fewer of these tympanocenteses and following people along, and I
wondered what the pediatricians thought about something like that. That
is just spur of the moment.

DR. MAXWELL: That strategy was actually used by Dutch investigators, but
what you try is you try to go with not treating a bunch of people and
kids and letting them hurt for a while instead of doing tympanocentesis
which, also, hurts, okay. I mean you are just trading it off, but that
strategy has been used by as I said, the group in Holland and I am not
even sure that that would be an easy sell to patients in North America,
saying, \"Okay, you want to enroll in this clinical trial, and the
standard of care is that we treat with antibiotics, but when a child is
still symptomatic for 2 days then we will do something?\" I think it is
a hard sell.

DR. RELLER: Dr.Christie and then Dr. Gorman?

DR. CHRISTIE-SAMUELS: This may be a little bit controversial, but since
we are collecting so much information if they couldn\'t just look at the
type of H. flu with regard to Hemophilus influenzae type B and I don\'t
think it would be much of a problem to just collect vaccine efficacy,
some information with regard to vaccine coverage, HiB vaccine and
pneumococcal vaccine, please?

DR. RELLER: Dr. Gorman and Cross?

DR. GORMAN: To revisit the tympanocentesis, Dr. Dagan presents the local
ethics issue which I find very convincing and if in my community there
was a group of pediatricians that routinely tympanocentesis some
relatively reasonable fraction of their children in their routine
clinical care of otitis media I don\'t think our local IRB would object.

Dr. Dagan was not trying to imply that at all. What I am trying to say
is since it is part of your routine clinical care for your patients we
would have very little difficulty with you incorporating it into a
study, and I hate to sound like a Luddite when I say that our IRB will
not approve things like this because it is not the purpose. It is just
where is the risk/benefit in our clinical practice for the children that
surround us, and last time I was able to listen to another group in
another state in the United States that does routine tympanocentesis and
if you are going to take routine tympanocentesis that would be an
approvable study and when you said that it was local you were absolutely
correct. It is a local decision.

The second question I wanted to ask, and I can ask this because I am a
simple country pediatrician. Why are there no surrogate markers for
infectious diseases that will help you in this case? I have heard so
much about amplification of proteins for both DNA and capsid proteins.
Why can\'t you once you know what the organism is after the first
tympanocentesis, look for that organism using an amplification technique
of a protein that is specific in the blood to follow its cure rate?

DR. RELLER: Dr.Cross has had his hand up.

DR. CROSS: Actually this addresses in part a comment you made earlier
about the perhaps clinical outcomes correlating with the MICs and one
piece of data in their Slide No. 75 was at least very intriguing that 18
of 25 of the Strep. pneumo which were either intermediate or resistant
to penicillin were listed as clinical cures. i mean something like this
would argue that we cannot simply rely on in vitro microbiologic data
even based on the first isolate, on the first tympanocentesis but would
seem to argue that in this situation we would love to know whether or
not the organism was there. So, these very limited data would argue
strongly for need for tympanocentesis because otherwise you cannot
evaluate this small limited data.

DR. RELLER: Thanks.

Dr. Dagan, you had \--

DR. DAGAN; I would answer for the DNA stuff.

DR. RELLER: Please?

DR. DAGAN: Actually we did that study in a different way but it answered
this question, and it was published years ago in JCM, Journal of
Clinical Microbiology. We wanted to see if we can use a PCR for
Pneumococcus in the blood to diagnose pneumococcal infections, and what
we proved is the following. If you want to do a PCR for Bacillus
anthracis, it is a good idea because you shouldn\'t carry that in your
nose or anywhere else but if you take and you do PCR for something that
kids carry in their nose continuously and the majority carry in the nose
a little bit of DNA is enough to get in the blood and you detect it, and
what we showed is we have so many true positives in terms of the PCR but
false positives in terms of infection and it was really proportionate to
the age and how much you carried, and if we detected carriage we could
detect up to 50 percent in the blood. So, PCR is too sensitive for a bug
that is routinely carried in the nasopharynx and for what you said I
would predict that 18 out of 27 or so would be clinical failures only
because we know that of the bacteriological failures you only have 40
percent that are clinical failures. So, I would predict that the
majority will be bacteriological failure but only 40 percent would be
clinical failure and I would come exactly with that number by the way
that you mentioned.

DR. RELLER: Dr. Gorman?

DR. GORMAN: I would, before you sit down Dr. Dagan it strikes me that I
can understand screening blood looking for pneumococcus would be very
inefficient. However, once you know the specific Pneumococcus couldn\'t
you follow titers looking at your amplification as some sort of
surrogate marker for cure watching titers fall during the course of the
antibiotic therapy?

DR. DAGAN: Yes and no. You could follow the titers, but you have a lot
of assumptions there that you didn\'t prove, that you have to prove, and
you didn\'t prove. When is the DNA the broadest proportional to the
amount of the bacteria that are in the ear and not in the nose? Now,
some of the drugs are excellent for ears but not for the nasopharynx,
for example, ceftriaxone. Some of them are excellent for the nose but
not always for the ears or at least azithromycin is excellent to
eradicate susceptible organisms both from the nose and from the ears in
terms of Pneumococcus.

So, the point is that you are following the blood, something that is
spilled off in another place. So, it could be very good for bacteremia.
It could be very good in meningitis; it is easy for meningitis, but you
don\'t know how to measure the amount in respiratory infection of DNA
that gets accidentally into the blood.

DR. RELLER: Dr. Marchant?

DR. MARCHANT: There have been a number of issues raised about ethics and
IRBs and tympanocentesis, etc., and because I know these issues will be
discussed at great length in the future, I think there are some
provocative questions to raise, and that is we should, also, ask other
ethical questions, other than focusing on the individual child in an IRB
situation, but, also, the question of is it ethical to do a study which
is not adequate to address the question of efficacy; is it ethical to
license, market or prescribe drugs without really knowing how
efficacious they are? Those are also ethical questions that we should
face

DR. RELLER: Thank you.

Dr.Wald?

DR. WALD: One last thing, I would say that double tap studies, which I
sort of lost my train of thought before, and that is I think in some
sense the most valuable studies are those that mimic clinical care, and
I absolutely concur that a diagnostic tympanocentesis is essential in
the bulk of patients who we are trying to learn about.

I think once we start tampering with that TM on multiple occasions we
are influencing the outcome, and outcome is one of the things we are
trying to judge, and so, I will just sort of keep that in mind that by
tampering with the system many times that it makes a judgment about
clinical outcome a little bit more difficult, and in the end clinical
outcome is still an important thing. I understand bacteriologic outcome,
but the things that Dr. Glode said before, you know, when is exactly the
best time to tap; is an earlier sterilization substantially different
than a sterilization on the fourth or fifth day, and I don\'t think we
know the answers to those questions.

DR. RELLER: Dr. Marchant?

DR. MARCHANT: In response to the issues you raised, Ellen I would say
that bacteriologic outcome is only important because the studies that
have been done have been shown that it correlates with clinical outcome.
If it were not that it would not be an important outcome, but rather
draw your attention that it is a surrogate that if you study enough
numbers it does predict a clinical response, but that is one of the
reasons it is important. It would be unimportant totally if that were
not the case, but that is what the data show.

DR. RELLER: Dr. Soreth, have you heard enough?

DR. SORETH: I think we have heard enough at this point, Dr. Reller, and
I guess we will take this to another public forum wherein we focus
specifically on the guidance I presume at that point with votes making
it clear how the guidance should go.

At this point I would say that there is not unanimity but consensus on
continuing in some measure having an assessment of clinical response
although we have to talk specifics in terms of the size of the trial and
the kind of difference that we are trying to detect between a test drug
and a control drug.

With regard to microbiological studies, again, I would say that there is
more consensus on a single tap study, tympanocentesis and baseline and
still a fair amount of controversy or lack of agreement with regard to
an actual requirement for double-tap studies.

Is that a fair assessment?

DR. RELLER: What I have heard today on this issue is that the agencies
and alternately the sponsors and most importantly patients and
practitioners would be better served by having studies of higher quality
where we know what one is dealing with microbiologically and clinically
and those two are complementary and that one is kidding one\'s self if
one can make any honest with realistic numbers, any honest assessment of
efficacy in the absence to tympanocentesis, and that the clinical
studies have their complementary role and are important in adequate
numbers especially when there are no data from other patient populations
for assessing safety of a compound and that the pharmacodynamic
information is of interest, but is not a substitute for clinical trials
and microbiology and in patient populations where drugs may not act the
same at different age groups that it is important to actually have the
pharmacokinetic, pharmacodynamic data from those age groups to properly
assess safety, as well as whether things all fit together in terms of
efficacy, and I think that summarizes what we have concluded or the
consensus view that we discussed today.

Lastly, I would say that in this issue of a study done well that
adequate numbers is the best thing to do in the public interest. Quite
honestly the numbers required to do that that are dependent upon design
we need expert help from our statistical colleagues to pin those numbers
down and those numbers will be different depending on the quality of the
study done and in general the better the study the smaller the numbers
required to show the targeted differences which are a judgment call.

Have I missed anything, Dr. Marchant?

DR. MARCHANT: No, i think you have covered it pretty well, and I would
just like to reinforce your last point. The clinical outcome of
persistent symptoms during therapy, if you look in the literature from
single studies, single centers you come up with a much lower sample size
estimate of what is required to demonstrate that outcome than if you
take the meta analysis that Dr. Rosenfeld used pooling multiple studies
from multiple time points and multiple centers. It is just not as
precise and as soon as you spread the whole game around to multiple
different studies or investigators you are going to get less precision,
and you are going to have less ability to show anything.

So, that is another wrinkle in the mix here of the difficulty of doing
these studies, but a difficulty that you could overcome if you really
want to.

DR. RELLER: Thank you, all for your contributions. The meeting is
adjourned.

(Thereupon, at 4:50 p.m., the meeting was adjourned.)